Award Recipients: 2018 Exploration

Today’s internet, built upon the laws of classical physics, continues to revolutionize all our lives. A future quantum internet, based upon the richer laws of quantum physics, will offer additional revolutionary capabilities which are otherwise impossible. Known applications include the teleportation of information, super-classical clock synchronization, perfect secret-sharing, superior remote sensing, quantum radar, secure election and agreement protocols, and unhackable secure private communications. Importantly, these applications do not require large-scale quantum computers to function: even a few quantum bits (qubits) will be enough.

International researchers have been trying to build a quantum network for a few years. These impressive laboratory experiments are currently based upon quantum systems which are for the most part commercially impractical. While developing qubits for quantum computers, a very recent and serendipitous breakthrough by SFU researchers identified a key quantum network ingredient in silicon, with all the needed parameters to be the backbone of a commercially viable quantum internet. This breakthrough combines silicon’s famously ultra-long-lived qubits with easy optical access to the telecommunication bands, deployable using standard silicon chips.

The key objective of this work is to be the first to develop and link two commercially-compatible quantum internet nodes. This proof-of-principle landmark could then move into established technology translation pipelines. This is a more ambitious objective than accomplishing such a breakthrough by any means possible. Our objective is to accomplish this technical feat while simultaneously adhering to industrial manufacturing and design restrictions as well as practical end-user restrictions and standards. Navigating this complex landscape requires dedicated technical and strategic thinking as well as close collaboration with future end-users. The upshot of having this multidisciplinary foundation is that, if successful, this high-risk work has the greatest chance of being usefully deployed.

The long-term reward may be as significant as the full re-definition of global communications, remote sensing, telescopes, and more. By simultaneously addressing both the technical and practical real-world aspects of this challenge we will be well-placed to spin-off these revolutionary inventions within Canada before this exceedingly rare first-mover advantage is capitalized upon elsewhere.

Ammonia is one of the most important chemicals worldwide and is primarily used to produce fertilizer, thereby improving food security for billions of people. It can also be used as an energy storage medium and a source of hydrogen in fuel cells. Currently 2-3% of the world’s annual electrical energy is expended making ammonia using the Haber-Bosch process, emitting more than 300 million metric tons of CO2 annually in the process. Small-scale devices that can produce ammonia will enable on-site production systems that will help minimize distribution costs, especially in developing countries and geographically vast nations such as Canada. Electrochemical ammonia production using nitrogen and water directly would represent a significant leap forward, especially when coupled with electricity generated from a renewable resource. To date, the electrochemical transformation of nitrogen into ammonia in water has suffered from low conversion efficiencies (<1%) at ambient conditions owing to the strong chemical bonds of the nitrogen molecule and competing chemical reactions.

The proposed research aims to electrochemically convert nitrogen and water into ammonia using plasmonic ceramic nanoparticles. Our research group has recently developed a scalable method to prepare plasmonic transition metal nitride nanoparticles that strongly interact with visible and near-IR light, resulting in localized electric field and temperature enhancement that can potentially break strong chemical bonds in a way that is not otherwise possible under ambient conditions. Plasmonic metal nitride nanoparticles will be prepared using a solid-state method and their optical and electronic properties will be investigated experimentally and computationally. The electrochemical nitrogen reduction activity will be screened, and operando studies will be performed using synchrotron X-ray techniques to elucidate the reaction mechanisms and enable catalyst engineering to suppress undesired competing chemical reactions. The plasmon-enhancement pathway (field enhancement vs. localized heating) will be determined using operando Raman spectroscopy measurements. The shift towards more environmentally friendly methods of ammonia production based upon new technology will reduce our carbon emissions and help produce food in a more sustainable manner. 

Imagine a world where pills are irrelevant. Where instead of ingesting a drug, your own cells manufacture and secrete the correct medicine, at just the right time, and at just the right dose. Currently, this type of real-time monitoring and control of human physiology is science fiction, but next-generation biological treatments will combine therapy with diagnostics (i.e. theranostics), and thus offer hope that this science fiction will become a reality. An integral component of theranostics will be biosensors that can sense and respond to small-molecule metabolites or markers of disease, in complex biological milieus. In living beings, ligand-gated ion channels do just that. These proteins form small ion-permeable pores embedded within the cell membrane that only open when they bind a specific ligand. By coupling the opening of their ion-permeable pores to specific recognition of small molecules, ligand-gated ion channels convert chemical signals into electrical impulses, making them Nature’s ultimate biosensors. Unfortunately, the repertoire of naturally occurring ligand-gated ion channels is limited, and thus their potential as medically and industrially relevant biosensors remains untapped. We aim to exploit ligand-gated ion channels as biosensors by re-engineering the ligand specificities of naturally occurring channels.

OBJECTIVE

The Objective of the proposed research is to develop a platform for engineering ligand-gated ion channels as small molecule biosensors for medically-relevant disease markers.

APPROACH

Our Approach will employ two complementary strategies that leverage the combined expertise of our interdisciplinary team. We will implement a directed evolution strategy (daCosta) in parallel with a computational design approach (Chica). This will allow us to both evolve and design ligand-gated ion channels with unique and desirable ligand specificities. Both approaches will take advantage of recent advances in Machine Learning (Fraser) to guide mutant library design.

NOVELTY & SIGNIFICANCE

A platform for engineering tailor-made ligand-gated ion channels that specifically and efficiently respond to small molecule markers of disease or metabolites, will be indispensable in future cell-based theranostics. For example, a genetically encoded glucose-gated ion channel could be used to impart glucose sensitivity to cells that secrete insulin, and thus play an important role in next-generation biologic therapies for Type I Diabetes.

Paleoproteomics — the application of high-resolution mass spectrometry (MS) to the study of ancient proteins — is a new frontier in biochemical research. Inherently interdisciplinary, paleoproteomics draws upon advances in MS to address challenges in fields such as evolutionary biology, anthropology, and cultural heritage.

Our project brings together expertise in biochemistry, geochemistry, and archaeology with Indigenous communities, to advance the state-of-the-art in paleoproteomics, focusing specifically on proteins preserved on archaeological ceramic and stone artifacts/belongings. Proteomic approaches have the potential to provide unprecedented insight into the preparation and serving of Indigenous plant-based foods, beverages and traditional medicines by identifying diagnostic proteins from a variety of plant products prepared together within a single vessel. Specifically, our objectives are to: 1) investigate how the mineralogical composition and porosity of artifacts influences protein survival; 2) co-develop ethical guidelines and standards of practice for proteomics analysis of ceramic and stone artifacts/belongings from archaeological contexts; and 3) apply these optimized methods to elucidate Indigenous plant use in the South American tropics and Pacific Coast of Canada.

Working with our Musqueam and Sts’ailes partners, we will train Indigenous community members in the use of non-destructive instrumentation for material composition analyses, facilitating their capacity to investigate their own history with Western scientific techniques. Capitalizing on our optimized laboratory methods and protein survival models, we will co-organise knowledge transfer events with Indigenous knowledge holders, community members and scientific researchers to co-develop guidelines, policies and standards of practice for paleoproteomic analysis of archaeological artifacts/belongings, tailored specifically for the expressed needs and values of Musqueam and Sts’ailes, as well as for the broader scientific community. We will develop new tools for identifying mixtures of foods prepared and served within ancient vessels, which can be harnessed to advance the study of Indigenous plant-use worldwide, and concurrently enhance Indigenous analytical capacity to underpin their Title and Rights negotiations, by demonstrating long-standing connections to plant resources and the places where they are/were gathered. 

There is no cure for rheumatoid arthritis (RA). Current treatments non-specifically suppress the entire immune system leaving individuals more susceptible to infection and cancer. By combining new chemistry, computer design, 3-D bioprinting and biology, we are instead targeting the initiating event that leads to RA leaving the rest of the immune system unimpeded.

The overall goal of the research is to create custom-tailored peptide drugs that block the molecular event that initiates and propagates the autoimmune response: the binding of a self-peptide by human leukocyte antigen (HLA) receptors. This strategy could provide a cure for all autoimmune diseases. This grant focuses on RA as a starting point: the specific peptides made in this grant would benefit 240,000 Canadians, 65% of all RA patients.

The specific aims are to use computational modelling to screen 10,000s of putative artificial amino acids and peptides and then synthesize the amino acids and integrate them into peptides in our lab. Simultaneously, we will 3-D print synovium (the tissue inflamed in RA) to use as an ex vivo model of RA. We will then evaluate the binding affinity of our peptides using biophysics and evaluate their ability to inhibit the autoimmune response both in a mouse model and in the ex vivo printed model.

This entire program is unprecedented: we have designed new computational methods, new ways to make amino acids, and designed and built a custom peptide synthesizer for our unnatural amino acids. We will use our revolutionary Canadian-designed 3-D bioprinter to print synovium for the first time ever, and will use all the tools to develop an entirely new treatment paradigm for autoimmune diseases: HLA blockers (HLABs).

This research is extremely convergent bringing together basic and clinical researchers, immunologists and chemists, researchers in Canada and Australia, and partners at universities, hospitals, and private industry. The research naturally combines our innovation in fundamental computational modelling, synthetic chemistry, bioengineering, immunology, and applied biology. It is driving our development of new general methods to make amino acids, and new peptide engineering to make polycyclic peptides. It will generate fundamental advances in our understanding of the immune system by creating HLABs and printed synovium as new tools to study HLA-antigen interactions. When successful it will lead to an entirely new way to treat autoimmune disease.

Radiation therapy, one of the three main treatment options of cancer patients, is not only known for its benefits, but also for its negative side effects. Among those, fatigue, nausea, hair loss and skin problems are the most common radiotherapy side effects. Examples of more severe side effects include problems with memory and speech for brain treatments, vision and hearing problems for head and neck treatments, radiation pneumonitis and fibrosis for chest treatments and incontinence and fertility and sexual problems for treatments of the pelvis.

The goal of the proposed project is to decrease, if not eliminate the side effects of radiotherapy by combining two novel treatment techniques: ultra-fast (FLASH) radiotherapy and spatially fractionated microbeam therapy (MRT). FLASH radiotherapy consists of delivering radiation in the span of few seconds, much faster than the current state-of-the-art multi-minute delivery. Unlike the current radiotherapy delivered with a broad beam, MRT is delivered with a large number of submillimeter beams. Small animal studies have demonstrated that both FLASH and MRT result in decreased radiotherapy side effects but maintain the ability to kill cancer cells. Both delivery techniques require complex modifications to already specialized equipment and their investigations are therefore limited. We propose to build and test a FLASH MRT irradiation site in Canada.

We will capitalize on the world-wide unique TRIUMF infrastructure and modify an existing electron beamline for the delivery of x-ray FLASH MRT. First, we will build a computer model of the TRIUMF beamline, based on which we will then optimize and design the necessary components to enable FLASH MRT. Next, subject to animal protocol approval, we will investigate the reduction of lung radiotherapy side effects in a preliminary small animal study. The proposed research will bring engineers, accelerator and medical physicists, oncologists and imaging experts together to achieve a common goal to alleviate radiation side effects and improve the quality of life for all cancer patients.

Upon a successful completion of the proposed research, we will have built and tested a unique research FLASH MRT infrastructure. The infrastructure will be made available to radiobiology teams around the world who, with the help of TRIUMF researchers, will be able to reveal the underlying mechanisms of FLASH MRT and make great strides towards cancer radiotherapy with no side effects.

About 1 in 5 Canadian adults have some type of disability, and the number will increase with our rapidly aging population. Persons with disabilities carry a greater burden of ill health, but much can be prevented. Enhancement of accessibility in public spaces can facilitate disease prevention and health promotion through opportunities for participation in physical and social activities, which can also lead to reduction of health inequity and healthcare cost saving.  

However, the level of accessibility in built environments in most cities is still far from optimal. Part of the reason is due to uncertainties around how both government and private sectors can work together to create accessible public spaces (outside of private homes). Currently, little information exists that allows comprehensive cost-benefit analysis of accessible spaces, thus governments are unable to devise financial incentives to get the private sector on board.

This exploratory study employs an unconventional mix of an action- (and activist-) oriented planning research methodology—called Tactical Urbanism—and economic valuation, engaging the community in an experience of accessible spaces (e.g., touch, sit down, use). A well-known example of tactical urbanism is the pedestrianization of Times Square in New York, where the city government initiated the experiment of turning the roadway into a plaza with foldable chairs. Using the approach, we aim not only to 1) improve the conventional method of economic valuation through making it experiential; but also to 2) help accelerate consensus building and buy-ins in the community for creation of accessible public spaces through a mini-intervention which sets up the accessible space in real settings.

The impact of this research can be significant, as the findings will help improve the methods of assessing potential economic return, enabling co-creation of accessible spaces by the building industry and governments through identification of possible cost sharing strategies. The tactical urbanism approach may also lead to faster implementation of larger scale accessible space creation than ‘business as usual’ planning processes. Increase in accessibility in the built environment is likely an effective population-level intervention for health promotion, disease prevention, and community-level enhancement of opportunity in the built environment for equal participation in society.

The parasitic witchweed, Striga, infects food crops resulting in devastating yield losses for over 100 million African subsistence farmers. As an obligate parasite, Striga requires a plant host in order to obtain nutrients and water. It is essential that Striga seed germinate exclusively in the presence of host. Striga seeds germinate upon detecting a class of molecules, strigolactones (SLs), which are exuded by plant roots. Striga’s dependence on host-derived SLs is a weakness that can be exploited for the development of technologies to combat Striga infestations. This will require a detailed mechanistic understanding of how Striga seeds perceive SLs as a “wake up” signal.

We have previously identified a family of α/β hydrolases and demonstrated their function as SL receptors in Striga (ShHTLs). Although we have elucidated physical structures of ShHTLs, the conformation of ShHTL in the presence and absence of a ligand appeared to be very similar despite significantly different outcomes of these two states. Our understanding of receptor sensitivity and function is limited because these structures are static and represent “snapshots” in time. To improve our understanding, we will combine chemical probes with Nuclear Magnetic Resonance (NMR) techniques, which have been applied successfully to study dynamics of protein structures in relation to human diseases. Despite its success in the medical field, NMR has rarely been used to solve critical agricultural problems. Our objectives are to: (1) elucidate the dynamic states of ShHTL receptors in the presence of different ligands and; (2) monitor transduction of these signals as mediated by receptor activity.

To achieve these objectives, the Lumba lab will collaborate with Lewis Kay’s lab, a preeminent leader in the development and application of cutting-edge NMR techniques to elucidate protein dynamics. Our collaboration will also include Yuichiro Tsuchiya’s group, which has been very successful in engineering specific ShHTL chemical probes in order to monitor receptor activity. Our novel strategy integrates techniques from a diverse range of disciplines: physics (NMR), chemistry (probes) and biology (in vivo function), to solve a severe agricultural challenge. The perception of SLs by this receptor class adversely affects 100 million lives every year. Furthering our knowledge of this biological process has the potential to provide food security for millions and lift their lives out of poverty.

Background: Humans are exposed to a vast array of chemicals, many of which can exert detrimental health effects such as cancer, neurological diseases, or birth defects. The default paradigm for chemical risk assessment is to extrapolate “acceptable” exposure levels from laboratory animal testing, but a growing body of evidence indicates animal studies poorly predict adverse outcomes in humans. Animal testing is also expensive and time-consuming. Hence, there is an urgent need for alternative testing methods that are faster, cheaper, and provide human-relevant information.

Objectives: Our objective is to develop and validate a novel approach to establish acceptable exposure levels in humans by combining state-of-the-art in vitro and biological/computational modeling technologies for chemical safety assessment. Specific aims are to:

1) conduct proof-of-concept studies on two case chemicals with publicly available in vitro data, exposure models, and epidemiological studies demonstrating adverse health effects;

2) apply the approach developed in Specific Aim 1 to emerging chemicals with published in vitro data, but for which health risks have not been assessed.

Approach: For Aim 1, we will review and compile in vitro results from human cells for case chemicals. Minimal cellular levels eliciting adverse responses will be determined by mass-balance and benchmark dose modeling tools. Human doses required to reach these minimal cellular levels in the target organs and associated plasma levels will be estimated using pharmacokinetic models. These estimated doses and plasma levels will then be compared to exposure data from epidemiological studies to validate suitability for risk assessment. For Aim 2, the results obtained above will be applied to emerging chemicals to derive safe exposure levels based solely on in vitro data.

Novelty and significance: This innovative project will generate a much-needed tool to overcome the limitations of the current animal-centered paradigm in chemical safety assessment. With combined expertise in toxicology, biological/computational modeling, and epidemiology, our multidisciplinary team is perfectly positioned to explore and successfully validate this new approach. Not only will this approach provide a long-awaited alternative to animal testing, it will enable rapid evaluation of chemicals, thus providing policy-makers with reliable and timely data to establish regulatory parameters protective of human health.

Mild traumatic brain injury (mTBI), commonly referred to as concussion, is a major public health concern, with 42 million (0.6%) of the world’s population clinically diagnosed with concussions annually. Even more alarmingly, subconcussive head impacts (i.e. without clinically diagnosed concussion) may also cause brain changes, since the accumulation of these impacts are shown to be associated with long-term neurodegeneration. This is a pressing health issue to be addressed, especially for children and youth (with developing brains) in contact sports sustaining repeated head impacts. There are two major gaps in current research: unknown mechanism of cumulative brain trauma and few studies with sex and gender-based analyses. We will address these gaps with two main objectives: 1) gather contact sports data to investigate brain responses from each and all individual head impacts sustained over a sports season; 2) compare differences in brain responses and symptom reporting between male and female players adjusting for factors including sensor-measured/self-reported impact exposure and anthropometric measurements.

Here we propose to continuously monitor head impact accelerations and brain electrophysiology in ice hockey players using wearable head impact sensors and electroencephalogram (EEG) sensors. Male and female ice hockey players will be instrumented to measure all head impacts sustained over a season. After each practice or game, we will use questionnaires to assess self-reported head impact exposure and symptoms. For objective 1, we will analyze the acute and cumulative EEG response to head impacts. For objective 2, we will analyze and compare the brain responses and symptoms resulting from head impact exposure between male and female players.

This is a novel investigation of the cumulative effects of subconcussive head impacts incorporating sex and gender-based analyses with both objective measurements and subjective reports. The rich field data will enable new perspectives on brain injury mechanisms and may open new avenues of collaborative mTBI research spanning biomechanical engineering, neurophysiology, and sports psychology. The wearable sensors designed and employed in this research have the potential to be further developed into real-time continuous monitors of impact exposure and cumulative brain trauma on the field. Findings in sex and gender-based analyses may lead to different mTBI management strategies for male and female players.

Zeolites constitute a rich class of materials with great potential for humanity. Their application within the chemical and petrochemical industries is quite diverse including ion-exchange resins, gas separation and catalysis; escalating needs in agriculture and construction materials (Global market evaluation of $40+ billion per year) are other potential applications for these meso- and micro-porous materials. Despite their wide range of synthetic approaches and applications, the sub-nanometer atomic environment defining the active site(s) is not fully understood. The research objective is to decipher the unique chemically active catalytic sites in these materials responsible for their vast capabilities in efforts to design a structure-function roadmap for precision catalytic synthesis improving performance for a sustainable future. Until now, an incomplete understanding of these complex solids has hampered these efforts. Using an interdisciplinary approach, combining an emerging hyperpolarization nuclear magnetic resonance (NMR) technique called dynamic nuclear polarization (DNP) we propose a strategy to target active-site insertion for heterogeneous catalysis enabling next-generation applications in catalysis. This combination of DNP and chemical tuning offers a needed game-changing approach to design and engineer novel sustainable catalytic materials. Tailoring these materials will provide the needed performance, opening new frontiers in energy, environment, and health that are vital components for Canadians (energy production, clean water, and secure food supplies) while ensuring healthy economic growth in the chemical and petrochemical industry.

Neutron scattering has proven to be one of the most powerful methods for the investigation of structure and dynamics of condensed matter on atomic length and time scales. Neutron techniques have a broad range of applications in physics, chemistry, magnetism and superconductivity, material sciences, cultural heritage, biology, soft matter, health, and environmental and climate science. We propose to carry out an initial design and proof of concept study for the development of a next generation compact accelerator-based neutron source. This new source would be the first of its kind in Canada; a source designed by accelerator and material scientists and optimized for the specific investigation of condensed matter and materials.

The basis of neutron production will be the nuclear reaction between a low energy proton beam and light elements such as beryllium or lithium. This approach will avoid the drawbacks associated with large-scale neutron sources such as the Spallation Neutron Source in the USA or the European Spallation Source (ESS) in Sweden, which are extremely costly to build and operate. Through a collaboration (partnership) with TRIUMF, Canada's particle accelerator centre, we propose to build upon existing Canadian accelerator expertise and technology for our low energy proton beam source. For this reason, the majority of our efforts will focus on the design and implementation of the neutron target and associated instrumentation.

With the retirement of the NRU Reactor at Chalk River Laboratories, Canadian researchers and companies face a huge challenge to maintain and expand the scientific resources needed for research using neutron beams. Our compact accelerator-based neutron source is a new approach to tackle this challenge with the aim of delivering neutrons to investigators to meet their needs in a cost-effective way. This work will be the first phase in a longer-range research program to develop a compact accelerator-based neutron source which will provide scientists and industry with the neutron beams required to probe the structure and dynamics of matter in many areas of science. The successful completion of our long-term goal, the construction of a new, fully operational accelerator-based source, will provide a future for the Canadian neutron scattering community, which includes over 240 scientists, engineers, and students from over 40 Canadian institutions from 8 provinces, including over 60 university departments from 30 universities.

Antibiotic resistance has developed into a global problem and has led to a dire need for innovative strategies that are able to quantify efflux and influx of agents into bacterial cells for the assessment of potential new and reliable antimicrobial candidates. [1] The proposed research lies at the intersection between electrochemistry and medical microbiology. The overall goal of the work described in this proposal is the development of an electro-bio-analytical tool that can A) detect and quantify antibiotic DR to provide a diagnostic tool for the assessment of DR phenotypes, and B) assess potential new and reliable antimicrobial candidates. The following objectives will be addressed: Objective 1: Electrochemical characterization of antibiotic agents. Objective 2: Quantification of bacterial efflux by electrochemistry.

Objective 3: Electrochemical detection and quantification of antibiotics in single bacteria.

With national and international interdisciplinary collaborators, the interaction of pathogens with antibiotic hybrids will be investigated by electrochemical methods as well as specialized instrumentation, such as scanning electrochemical microscopy, an electroanalytical technique employing microelectrodes. These probes will be rastered across samples of bacteria, precisely positioned on a glass substrate. By monitoring the redox chemistry of antibiotics, their release from cells within a population as well as from single cells will be quantified.

The increase of resistance in Gram-negative bacteria in particular is a major cause for concern [2], as many Gram-negatives cause serious infections, such as pneumonia, and few antibiotics effective against Gram-negatives have been developed. Newly developed antibiotic hybrid drugs were recently found to restore the efficacy of its individual components in drug resistant organisms.[3] Studying the efflux from single bacteria and across populations of these compounds will provide a numerical quantitative measure for drug resistance leading towards the development of a resistance biosensor. Furthermore, by monitoring the bacterial response time to antibiotic hybrids this research will help to better understand resistance adaptation and progression, leading towards the development of new agents and strategies to ultimately overcome drug resistance.

References:

[1] Rice LB. Hosp Epidemiol 2010, 31, S7.

[2] Silver LL, Bioorg Med Chem 2016, 24, 6379.

[3] Gorityala BK, Angew Chem Int Ed Engl 20

Uncontrolled blood glucose levels, largely due to excess body weight, diet and physical inactivity, has propelled the number of people with diabetes to a pandemic level. Systemic metabolic alterations can severely affect the course of prostate cancer (PCa), the most prevalent cancer in men and a leading cause of cancer-related lethality. Greater insulin secretion meant to regulate blood sugar is associated with higher risk of prostate cancer mortality. Importantly, androgen-deprivation therapy (ADT), the standard first-line treatment modality for metastatic PCa, is associated with increased risk of incident diabetes or the worsening of diabetes control among men with diabetes. Recently, combination of ADT with Metformin, a blood glucose-lowering drug, has been associated with improved oncologic outcomes. While these clearly highlight the interplay between disease progression and glucose levels, the outcome defies our present understanding of tumor biology.

A fundamental consequence of hyperglycemia is the glycation of proteins commonly known as the Maillard reaction. This non-enzymatic reaction is a slow process that mostly affects proteins with a low turnover such as hemoglobin and collagen and is defined by the condensation of a reducing sugar with a free amino group of a protein which form advanced glycation end products (AGEs). These AGEs are known to crosslinks proteins.

Given that we have recently demonstrated that the use of collagen glycation is an excellent model to generate engineered scaffolds of tunable stiffness to study tumor stiffening and disease progression, we hypothesized that uncontrolled blood glucose levels drive PCa metastatic progression through tumor transcriptional reprograming due to an altered extracellular matrix. Our objectives are to: 1) Determine the impact of hyperglycemia on prostate extracellular matrix stiffness; 2) Characterize the AGEs-related impact on PCa transcriptional reprograming; 3) Define the role of AGEs on PCa metastatic potential.

Our research approach will combine expertise in engineering, physics, biology and bioinformatics with in vitro / in vivo models in order to address this fundamental knowledge gap in regards to the interplay between tumor progression and hyperglycemia. This raises the exciting near future possibility that AGEs quantification from tumor biopsies could be used to identify patients likely to progress to a metastatic, lethal disease and would benefit from an aggressive treatment.

Quantum information processing is concerned with what we can and cannot do with quantum information, which

is the physical information that is held in the state of a quantum system, as predicted by the physical theory of quantum mechanics. Quantum computers (devices that process quantum information) are known to enabling extraordinary feats: for instance, ultra-fast computations and secure communications. 

Today's digital infrastructure relies on cryptography in order to ensure the confidentiality and integrity of digital transactions. These protocols mainly rely on the assumed difficulty of certain computational problems, such as the factoring problem. However, quantum computers are known to completely break this assumption, compromising most of our existing security systems.

Is the security of our digital infrastructure ready for the advent of quantum computers? Our interdisciplinary team will address this pressing question from the perspective of mathematics, computer science and physics. While security is our underlying goal, the mathematical theory of algebra is our general methodology. Algebra is a broad and rich theory that models  the technical tools used for the design and analysis in this research. We will push the frontiers of theory and application according to three themes.

-Quantum Entanglement:  Using the tools of noncommutative harmonic analysis and unitary representations, we will form a deeper understanding of the nonlocal correlations emerging from quantum entanglement, addressing some of the today's most pressing theoretical questions, and informing the following two more applied themes.

-Post-Quantum Cryptography:  We will use an interdisciplinary approach that addresses the  need to develop and demonstrate the security of cryptographic protocols that are resistant to quantum attacks. Our approach is via non-abelian groups, which offer a rich supply of complex and varied problems for cryptography. At the same time, we will advance knowledge in quantum cryptanalysis, for instance by developing techniques from representation theory that are applicable to novel quantum algorithms.

-Quantum Protocols: We aim to develop new quantum protocols for new quantum cryptographic functionalities, together with new algebraic proof techniques. We will forge new links between entanglement, operator algebras and random matrix theory, all with the goals of unleashing new quantum protocols, together with improved security methods.

Objectives:

Cytokines are small proteins that play an important role in the body’s response to inflammatory stimulus, and have been linked to a variety of diseases, including cancer, diabetes, Alzheimer’s, and cardiovascular diseases. The standard methods for quantitation of cytokines include immunoassay-based techniques such as enzyme-linked immunosorbent assays (ELISA), and bead-based immunoassays read out by flow cytometry. Although these standard methods are very accurate, they are time consuming, requiring long incubation times, and expensive, and requires highly trained personnel to operate. There is therefore a need for a rapid and low-cost method to detect and quantify cytokines. This project will explore the utility of diagnostic sensors based on a nanomaterial called monolayer transition metal dichalcogenides (TMDs) to detect these cytokines. In recent years, monolayer TMDs, have been shown to have extraordinary properties such as piezoelectricity and potential current on-off ratios exceeding 10 billion, making them promising for high sensitivity sensing applications.

Research Approach:

Dr. Rosin’s team (Biomedical Physiology and Kinesiology, SFU) will investigate the link between cytokines and disease.  Dr. Kavanagh’s team (Physics, SFU) will characterize the selectivity and sensitivity of cytokine detection methods. Dr. Adachi’s team (Engineering Science, SFU) has grown monolayer tungsten disulfide (WS2), a TMD, having lateral crystal sizes of 10s of micrometers by chemical vapor deposition (CVD). The monolayer thickness of WS2 were confirmed by Raman Spectroscopy. Monolayer WS2 will be incorporated into free-standing acoustic wave sensors. The proposed project will be carried out by an interdisciplinary team consisting of researchers from three different departments and will take into consideration EDI.

Novelty and Expected Significance:

The first experimental demonstration of the piezoelectric properties of monolayer TMDs was recently reported in 2014. To the best of the applicants’ knowledge, the proposed project would be the first to apply acoustic wave sensor technology to detect cytokines and the first to develop acoustic sensors using 2D materials. The long-term goal of the project is to develop low-cost sensors for early detection of diseases by non-invasive testing of patient’s saliva for cytokines. 

Health Problem/Potential For High Impact: Neurodegenerative Diseases Are a Prevailing Medical Challenge. Alzheimer’s disease alone is the 7th leading cause of death in Canada and costs Canadians $10 billion in care annually. These numbers are expected to increase two-fold by 2031.

The majority of drug design strategies can be classified into two areas: symptomatic relief and inhibition of protein aggregation. All current therapies result in symptomatic relief; they slow cognitive deterioration for up to 6 months, demonstrate minimal quantifiable improvements based on the Alzheimer’s Disease Assessment Scale, and do not increase life expectancy.  Protein aggregation inhibitors have potential to slow or halt disease progression, but none have been successful in clinical trials thus far.

High-Risk: Pursuing a Dramatically Different Drug Development Strategy. In order to enable meaningful drug discovery, new mechanisms of therapeutic action must be pursued.  We propose a medicinal avenue which has enjoyed little attention: the triggering of neurotrophic responses in the brain by small molecules. Neurotrophic responses include pro-survial, pro-proliferation, and pro-differentiation responses, which are antithetical to the pathology of neurodegenerative diseases: premature degradation and shrinking of brain tissue. 

Interdisciplinary Approach: A chemistry and biology ECR team (Williams lab, Principal Applicant, and the Epp Lab, Co-Applicant), will explore neurotrophic natural products as medicinal leads to combat neurodegeneration.  Variations on a natural product (phenylbutenoid dimer, PBD) originally isolated from Javanese ginger, will be generated synthetically and tested for efficacy in cell culture. Mouse studies on active compounds will provide data on changes in brain tissue resiliency/regeneration and in memory and learning.  In addition, a series of biochemical and proteomic analyses will elucidate mechanism of action.

Objectives:  The following objectives are proposed to evaluate the hypothesis that neurotrophic small molecules have the potential to slow or even reverse the abnormal degradation of brain tissue in neurodegenerative diseases, providing a uniquely impactful strategy.

1) Synthesize PBD and a series of structural derivatives

2) Determine mechanism of action

3)     Optimize efficacy/potency

4) Test active compounds in mice models of Alzheimer’s disease to evaluate impact on learning and memory and to measure neurogenesis

Non-invasive liquid biopsies offer hope for rapid, risk-free, point-of-care ‘real time’ glimpse into the molecular hallmarks of the disease, including drug resistance and targets. Tumor-derived exosomes (EXs) are unique liquid biopsy platforms in that they possess important biological roles (intercellular tumor communication) and serve as natural carriers of oncogenic mutations and biological information. Standard molecular analyses of bulk EXs by polymerase chain reaction (PCR) and other methods are beset by preparative challenges, high background of irrelevant (normal) and by ‘averaging’ of diagnostic signals. This reduces multiplexing opportunities and obscures molecular beacons of tumour heterogeneity. There is thus a need for a diagnostic tool that can isolate single nucleic acid carrying exosomes and yield high throughput quantitative and comprehensive analysis of nucleic acid contents and multiple cancer markers.

We propose a new nanofluidic platform for isolation and molecular analysis of single-exosome nucleic acid contents with applications to cancer diagnostics and therapeutics. Our approach uses nanofluidics to confine single EX’s in photonically active nanocavity wells, enabling targeting of DNA-derived EX cancer markers at the single EX level via sequence-specific fluorescent probes. In detail, single EX’s will be isolated in nanocavities (~50x200nm) that are surrounded by a molybdenum disulphide (MoS2) film. The nanocavities will be embedded in a flow-cell sealed with membrane lids; these lids will be pneumatically deflected to close the nanocavities and trap individual EX’s. Biochemical processing, to lyse EX’s and release/label EX contents, will be performed by permitting thin gaps between the nanocavity and surroundings so that chemical exchange of nanocavity volume is permitted while retaining EX’s and released DNA. DNA probes, based on hybridization or CRISPR/Cas9, will have a fluorescence signal amplified by exciton coupling to the MoS2. In cavity DNA-binding events will thus be amplified relative to background and readily detected.

Our technological approach requires no surface markers for exosome isolation, offers multiplexed marker sensing using a single color probe and performs high throughput and quantitative analysis at the single-exosome level.

Studying the cellular diversity of the brain has been fraught with several limitations including detection and anatomical cell-of-origin. In the first case, limitations with regards to antibody availability and specificity have made the task of identifying some proteins sometimes difficult. In the second case, the non-homogeneous morphology of brain cells makes it difficult to trace the cells-of-origin of a given protein, even if the antibody staining works. These pitfalls have slowed the progress of understanding protein diversity within the brain, thus impacting our understanding of their function in health and disease. The advent of genome engineering, 3D tissue clearing, and advanced data visualization and computational frameworks have converged to enable cell-defined anatomical studies in an unprecedented manner: an immense opportunity for exploration.

We will establish a rapid, straightforward pipeline to determine the cell-of-origin for synaptic, membranous or secreted proteins using alpha-synuclein (a-syn) as a prototypical protein. We generated a knockin mouse line that endogenously tags a-syn with a Flag tag (enabling visualization via immunodetection) and a nuclear localization signal (NLS) which permits tracing of a-syn (a mostly synaptic protein) back to its cell-of-origin. Using state-of-the-art tissue clearing and data visualization, we will characterize the organism-wide anatomical cell-of-origin of a-syn in 3D and generate an interactive atlas for data visualization based on these datasets. We will validate target regions (established and novel) and identify subsets of cell types that express a-syn to gain insight into disease mechanism(s). Lastly, we will expand our approach to additional synaptic proteins, thus establishing a pipeline to visualize any difficult-to-target protein.

The generation of an NLS-tag reporter mouse is a one-step approach to study cell-of-origin (this classically requires a much more elaborate approach using Cre-driven reporters with lower success rates). Moreover, the integration of 3D stained tissue data into an easy to use interface through our interdisciplinary computational approach will render this technology more broadly applicable to study virtually any synaptic, secreted or otherwise hard-to-study protein. Indeed, building on the high-risk, high-reward nature of this study, our straightforward user pipeline will make this approach amenable to virtually any laboratory.

We engineered several brain-penetrating antiviral peptides that work against Zika virus (ZIKV) and other enveloped viruses, providing a breakthrough for treating neurotropic infections. The lead peptide and analogs show high therapeutic efficacy in a lethal ZIKV mouse model. However, the efficacy and safety of brain-penetrating peptides in the course of treating in utero infections are unknown.

In utero therapy is considered as a high-risk intervention and limited to surgical treatment of anatomical fetal abnormalities. The lack of relevant animal models complicates the further development of in utero therapies. To address this gap, we established a fetal pig model of in utero ZIKV infection which reproduces key aspects of ZIKV infection in humans.

In this project, we will combine the expertise of two groups working across large animal models, virology, and chemical engineering to test the potential of brain-penetrating antiviral peptides to treat fetal viral infections. Also, we will test the safety of these peptides for developing fetuses.

We hypothesize that in utero administration of a brain-penetrating antiviral peptide will reduce ZIKV infection in fetuses and will not cause developmental pathology.

Aim 1. Efficacy of a brain-penetrating antiviral peptide against in utero ZIKV infection

We will test whether in utero administration of the peptide decreases viral loads and inflammation in fetal brains and the fetal environment.

Aim 2. Safety of a brain-penetrating antiviral peptide after in utero exposure

We will conduct morphological, histological, and genomic studies on fetuses after in utero administration of the peptide. We will also determine whether in utero administration of the peptide affects the proliferation of neural progenitor cells, which are a crucial cell population in fetal brain development.

There are currently no in utero therapies for congenital viral infections. As soon as ZIKV or any other fetal pathogen crosses the transplacental barrier, there is no alternative to solely ultrasound observation of dying fetuses. In utero therapy will be particularly relevant during outbreaks of congenital infections in non-immune populations, when vaccines are not available. Curing infections in utero will reduce the long-term sequelae in offspring and treatment required after birth. It will be highly-rewarding for patients, families, and society and will decrease the social and economic burden associated with congenital infections.

With the ever-increasing global population, our world is currently faced with an energy crisis of unprecedented proportions. As a result, energy-related research has become a top priority in contemporary materials science, e.g., discovering new materials for energy capture, conversion, storage, and transport. In the area of energy transport, high-temperature superconductors are considered one of the holy grails of materials science. Superconductors are materials that conduct electricity without resistance, and thus transmit energy without power loss. While many superconductors already exist, none of them can exhibit this special property above cryogenic temperatures, which renders them useless for large-scale implementation.

The research proposed herein entails a high-risk, high-reward interdisciplinary endeavour to explore and probe novel molecular structures for excitonic superconductivity. Specifically, the goal is to synthesize organic (i.e., primarily carbon-based) materials based on new and unconventional molecular structures, and then test their optoelectronic and magnetic properties in search of high-temperature superconductivity. The main materials of interest will be pi-conjugated organic polymers functionalized with polarizable dyes. Such molecular designs are prime candidates for exciton-mediated superconductivity according to William A. Little’s somewhat controversial theory of excitonic superconductivity, which predicts superconductivity well above cryogenic temperatures. More precisely, the theory posits that virtual excitations in the dye sidechains could induce superconductivity within the polymer scaffold at relatively high temperatures. Over the years, Little's theoretical model has neither been experimentally disproven nor verified, which leaves many tantalizing opportunities and questions open to exploration.

In this proposal, one can envision exciting cross-disciplinary collaborations at the interface of materials chemistry and condensed-matter physics. Success in this high-risk endeavour would not only provide insight into the basic mechanism of unconventional superconductivity, but also introduce a major advance in a field that has seen few breakthroughs since the mid-80s. In terms of wider societal impacts, high-Tc excitonic superconductors would be major game-changers that can revolutionize energy transport and storage, and thus help to alleviate the current energy crisis.

Appreciable evidence suggests that gut microbiota interact with the brain and may play a key role in the pathogenesis of mental illnesses. Several trials support a role for probiotics in the normalization of brain processes related to stress responses and in mood and anxiety improvements, while others report no benefit in this regard. The mechanisms by which psychobiotics modulate the microbiota–gut–brain axis and improve mental health remain hypothetical. Here we postulate that the mood- and anxiety-improving probiotic strains are those that exert their effects through a microbial endocrinology-based mechanism. Depression and anxiety have been related to reduced γ-aminobutyric acid (GABA) levels. Lactic acid bacteria (LAB) are an important source of glutamate decarboxylase (GAD; enzyme converting L-glutamate to GABA) and thus can be regarded as promising GABA-producing candidates with psychobiotic effects, especially as they are “generally recognized as safe” and commonly found in fermented foods (e.g., kimchi, dairy products). Harnessing the GABA production ability of probiotics or LAB in the gut could increase GABA levels along the microbiota–gut–brain axis and improve mental health. The overarching goal of our proposal is to demonstrate that GABA production is a mechanism by which probiotics and LAB exert psychobiotic effects and improve mood and anxiety in a mouse model and humans with subclinical mental health symptoms. As depression and anxiety are more prevalent in females than in males and that the microbiota-gut-brain axis is sexually dimorphic, outcomes mice and humans will be analyzed based on sex.

Aim 1: Determine the presence of genes encoding GAD and levels of GABA produced by commercial probiotic strains and by LAB from fermented dairy products (e.g., cheese, yogurt).

Aim 2: Confirm the capacity of GABA-producing bacteria identified in Aim 1 to grow and produce GABA in-vitro in a simulated human colon and modulate colonic microbiota.

Aim 3: Confirm the capacity of a selected GABA-producing bacterium to produce GABA in-vivo and to reduce depressive- and anxiety-like phenotypes in a mouse model using a chronic social stressor.

Aim 4: Investigate the capacity of the selected GABA-producing bacterium to influence brain GABA activity in-vivo and to improve mood and anxiety in individuals with subclinical stress-related mental health symptoms.

Over 250,000 Canadians sustain a concussion annually. About 30% experience persistent post-concussive symptoms (PPCS) that entails severe chronic daily headaches, dizziness, cognitive impairment and poor sleep. Effective treatments with an understanding of the physiology of treatment response for PPCS are urgently needed, as many individuals suffer for years with debilitating symptoms, impacting their quality of life, and causing a significant burden on the health care system.

Preliminary studies suggest aerobic exercise (AE) may improve acute and chronic concussion symptoms despite traditional advice for patients to avoid activity until recovered. Early studies in concussion suggest imbalances of GABA, glutamate and glutathione on MR spectroscopy (MRS), which may drive PPCS. We suggest that AE restores balance and promotes recovery. Further, studies suggest blood biomarkers of brain health, such as brain derived neurotrophic factor (BDNF) and markers of serotonin activity and autonomic response are altered in chronic disease. AE has the potential to increase them, mirroring clinical recovery.

We hypothesize AE will improve symptoms in patients with PPCS and MR spectroscopy and blood biomarkers of brain health will indicate treatment response.

We propose a single blinded, randomized cross-over controlled trial of patients with PPCS who will receive either an aerobic exercise protocol (AEP) or stretching protocol (SP). The primary outcome will be a 4.5-point improvement on the Rivermead Post-concussion Questionnaire reflecting significant clinical recovery, with associated positive changes in GABA, glutamate and glutathione measured using MRS and significant increase in blood markers of brain health post-treatment.

Participants will complete pre-assessment questionnaires, MR spectroscopy and blood tests. Following randomization to AEP or SP, participants will be followed during a 6-week exercise intervention and the SP group will cross over at 6 weeks. Post-treatment assessments including questionnaires, MRS and blood samples will be completed, with questionnaires repeated 1 and 3 months later.

There is a dire need for successful treatments in patients with PPCS. This study will use cutting edge methods not previously applied to concussion to measure brain and blood metabolites that quantify response to exercise treatment for individuals with PPCS. These measures will provide unprecedented information about PPCS and its recovery.

Background: Limitations of the current energy systems research paradigm

The ongoing energy system transition, empowered by technology developments, fueled by shifting investments, and motivated by decarbonization, is one of the 21st century’s most urgent tasks. However, current energy system models fail to deliver the holistic perspective required by decision-makers to navigate complex policy choices. Instead, energy system analyses are plagued by rigid model platforms and discretized researchers who focus on specific sectors, spatial-temporal scales, or energy vectors. By transforming our approach to energy systems modelling, this work will accelerate decarbonization efforts. 

Objective: Designing the next generation of energy system platforms

The transition to a sustainable energy system depends on leveraging three themes: increasing renewable energy, the rise of the grid edge, and energy systems integration. However, our current suite of production cost, capacity expansion, and integrated assessment models cannot represent these transformations. This research project will pursue the development of an extensible and adaptable multi-scale, multi-sector, and multi-vector M3 Modelling Platform that links distinct but integrated modules to span spatial-temporal scales, the breadth of energy system services, and each energy carrier.

Research Approach: Interdisciplinary energy systems modelling

The proposed holistic representation demands a model scale and scope that would not be computationally tractable with accepted engineering approaches. As such, we will employ novel computer science techniques, including multi-objective active learning, advanced visualizations, and parallelized computing. By leveraging the energy system expertise found in civil engineering with the algorithm, visualization, and software architecture expertise found in computer science, we can take the next major leap in energy system modelling. The M3 Modelling Platform will be a useful tool as environmental and public policy practitioners translate high-level municipal, provincial, and federal decarbonization targets into resolved implementation plans.

Significance: Accelerating decarbonization transition

The M3 Modelling Platform will significantly advance the methods used in energy systems analyses, thereby delivering near-term insights for environmental and public policy while remaining adaptable as new technologies emerge and trends evolve.

Glioblastoma (GBM) is an aggressive and lethal form of cancer, with a five-year survival rate of only 14% regardless of stage at detection. Immunotherapies are a promising class of new treatments that stimulate a patient’s immune system to attack cancer. While clinically successful in melanoma and leukemia, there are fewer successful immunotherapies in solid tumors, particularly GBM. Novel methodologies are needed to improve our understanding of how immunotherapies work and develop new biomarkers of success.

Imaging offers opportunities to longitudinally assess the response of an individual’s cancer and evaluate heterogeneous responses to therapy. Magnetic resonance imaging (MRI) offers multi-faceted contrast, and advances such as MR fingerprinting (MRF) provide fast quantitative measurements. The emergence of simultaneous positron emission tomography (PET)-MRI creates opportunities for further multiparametric analysis of the tumor environment. From all of these types of images, it is possible to derive quantitative parameters called radiomic features that can augment studies of novel immunotherapies.

We propose the development of a novel multi-parametric imaging and data analysis platform for discovering radiomic biomarkers that predict therapeutic success in GBM, or that inform on the state of immune infiltration, to better design and adjust novel therapies. These machine-learned radiomic features will be obtained using a preclinical GBM model treated with two immunotherapies: a peptide-based vaccine and a checkpoint inhibitor. Tumors will be imaged longitudinally using simultaneous PET/MRI. We will obtain 1) B cell recruitment maps with a 89Zr B cell specific PET probe, 2) T1 and T2 maps with MRF, 3) tumor vasculature parameters, including blood brain barrier stability, with dynamic contrast-enhanced MRI, and 4) T2* maps of tumor-associated macrophages with TurboSPI MRI following an injection of iron.

This project will bring together multiple disciplines building upon basic science disciplines, including machine learning and other advanced informatics, and then progressing into health sciences for discovering imaging biomarkers for immunotherapies. These biomarkers will improve the optimization and clinical translation of immunotherapies, and assist in design of clinical trials, benefitting a large number of patients with glioblastoma and similar cancers.

Surge-type glaciers are ice bodies that undergo variations between long, quiet periods (decades) of near-stagnation and short, active periods (months to years), with velocities that can increase by a factor of 100 and ice front advance by 5km or more. This rapid advance can cause significant hazards by damming lakes that may trigger downstream floods, and sending ice into regions of human infrastructure. In Canada, oral accounts passed down through First Nation communities describe events that killed significant numbers of Tlingit people in the 1800s, while modern scientific methods have captured numerous recent surges in the Yukon St. Elias Mountains. Glacier surging appears to be driven by changes in water flow and thermal conditions within the glacier, but little detail is currently known about these processes and how they might be changing in a warming climate. Surging glaciers also provide some of the best analogues for the potential instability of the large ice sheets, so understanding the drivers of rapid accelerations in ice motion is of importance for establishing future Antarctic stability.

Previous analyses of surging glaciers are restricted to satellite data or to in situ data collection during the quiet, stagnation period. Hot water borehole drilling can tell us about the ice temperature and basal water pressure, but once the surge begins, extreme levels of crevassing causes loss of surface instruments and the rapid ice motion quickly snaps the wires of any subglacial instruments. As such, existing data concerning conditions during surges are very limited.

Here we propose an innovative and interdisciplinary combination of glaciological, engineering, Traditional Knowledge and mathematical modelling approaches to examine surging glaciers in the Yukon and improve our ability to predict the associated hazards. Historical information provided by Kluane First Nation collaborators will be combined with data collected from custom wireless instruments that we will develop and install in surge-type glaciers, with collaborators from the UK. Wireless instruments provide a novel approach for gaining previously elusive data during surges, and could be transformative for many glaciological applications around the world.  This research will therefore be of strong international interest and, while high risk due to the developmental engineering approach, would produce significant results applicable to environmental and social issues.

This interdisciplinary project will harness expertise in materials science and neurosurgery to advance the standard of care in spinal cord injury (SCI).  Worldwide, between 250,000 and 500,000 people suffer SCI each year. To date, there are no proven cures to ameliorate the effects of SCI and return function to normal. Surgery is commonly performed to decompress the spinal cord and provide structural stability. Unfortunately, strategies for internal repair of the spinal cord and associated peripheral nerves have been elusive. In an attempt to reduce impairment following nerve injury, approaches have been devised to guide regenerating axons across the site of injury, most notably through use of nerve guidance conduits. However, several critical obstacles limit the efficacy of existing nerve guidance approaches, namely the inability to promote axon growth over long distances and ensure that axons reach their appropriate targets.

We will overcome these challenges through the design of a multi-functional, fiber-based biomaterial. Nerve guidance fibers will be produced using a patented process developed by the principal applicant, whereby viscous solutions of biocompatible polymers are elongated into flexible fibers of approximately 10 microns in diameter and up to 50 cm in length. These fibers can be doped with a variety of bio-active materials (e.g., collagen and growth factors), woven and assembled into virtually any configuration and stored under ambient conditions without any discernible degradation in their performance. Three objectives will take us from ideation to pre-clinical testing.

Objective 1. To explore the physical and chemical processes that govern elongation of fibers from viscous polymer solutions and give rise to their emergent properties. (Discovery Science)

Objective 2. To design and implement systems for assembly of the elongated fibers into multi-functional bundles capable of guiding neurons. (Engineering Challenge)

Objective 3. To apply the materials for precision nerve guidance in a pre-clinical spinal cord injury model. (Biomedical Application)

This project will lead to the discovery of novel materials and approaches for neural tissue engineering and will be the first step in the development of novel surgical products for treating SCI – a high-risk/ high-reward proposition that has potential to improve the quality of life of hundreds of thousands of patient suffering from traumatic injury.

In children with end-stage renal disease (ESRD), a typical week includes 3 hospital visits to receive 4-5 hours of hemodialysis or peritoneal dialysis. In addition to the direct physiological effects of ESRD, it is not surprising that these highly sedentary youth present with low fitness, physical function and quality of life (QoL). Strategies to alleviate the physical and psychosocial burden of chronic hospital visits for these youth are urgently needed. Virtual reality (VR) may represent a novel tool to engage patients in an immersive, digitally-generated, life-sized environment. Combining VR and physical activity may allow these children to maintain or improve their fitness and function, interact with peers, while also providing an escape from the real-world hospital environment. Therefore, our objectives are to:

1) Develop a Google maps-based VR cycling game called Cyclescape;

2) Optimize the game interface and gamification features of Cyclescape;

2) Test the feasibility of VR cycling in a dialysis unit;

3) Evaluate the effects of Cyclescape on dialysis efficiency, fitness, physical activity, QoL, and mood.

In Year 1, we will develop and optimize our VR cycling game. We will integrate Google Street and Terrain maps with a stationary bicycle, allowing for automatic adjustments in cycling difficulty based on topography and elevation. Our design will allow communication between units so players can cycle together in VR. In Year 2, 20 patients receiving dialysis will be recruited for a 18-week training study. Participants will cycle for 10-45 min during dialysis in the VR environment of their choice. Feasibility will be defined by recruitment, compliance, completion, and adverse event rates. Fitness, QoL, and mood will be assessed at 0, 6, and 12, 18 weeks; dialysis efficiency will be assessed for 1 week prior to the start of training, and continuously during training.

Children receiving dialysis spend a disproportionate amount of time in hospitals compared to their healthy peers, which interferes with participation in typical activities of childhood. This VR cycling game novel and meaningful in that it will allow these youth to actively engage with the external environment while in hospital. Unlike existing VR, this game will incorporate real-world maps and terrains to maintain the patient’s connection with a familiar setting and allow them to try routes they might normally avoid. This can help alleviate anxiety and support an active lifestyle.

According to the DCI Donor services, more than 120,000 people are waiting for allograft transplantation in the United States alone, while in Canada the numbers rank around 40,000 patients. Due to the higher cost associated, skin grafts are exclusively used in treating emergency chronic wounds, venous ulcers, diabetic ulcers, and burns; however, skin transplants possess moderate to high risk of rejection and complex post-surgery care. Therefore, tissue engineered material development including artificial skins and wound healing materials has become one of the frontiers in material and health-related research. Synthetic polymers such as polycaprolactone and poly (lactide-co-glycolide) are extensively studied in wound healing applications due to their consistency and reproducibility but clinical applications are hindered due to lack of biocompatibility. Renewable polymers such as collagen, chitin, chitosan, alginate, pullulan, keratin, and cellulose have been extensively studied with moderate success due to poor mechanical properties, poor cell adhesion, potential infections & rapid degradation.

We hypothesize that mimicking mussel adhesion and incorporating cell adhesion promoters combined with nano-reinforcement of keratin-chitosan blends will improve the skin cell adhesion, cell proliferation, and mechanical properties while reducing infections. The long-term objective of the proposed research is to use inherent properties of two renewable polymers, keratin, and chitosan and use biomimetic modification and nano-reinforcing to develop advanced wound healing materials such as electro-spun wound dressings and hydrogels. Keratin and chitosan will be extracted from poultry feathers and shellfish by-products, and either biomimetically modified to impart 3,4-dihydroxyphenylalanine (DOPA) functional groups or blend with cell recognition motifs to promote cell adhesion. Keratin-chitosan polymer blend along with nanocrystalline cellulose will be optimized to maintain optimal mechanical properties and other functional properties.

In our research, we propose an innovative concept to develop wound healing materials using renewable polymer blends of feather keratin and chitosan, two major by-products of agricultural and food processing industries. Use of renewable/bio-based polymer blends with unique properties and nanomaterials such as nanocrystalline cellulose will enable the creation of all-biobased advanced functional materials for biomedical applications.

Canada’s population is aging. In 2016 for the first time, seniors outnumbered children in Canada. As such, age-related health problems are of increasing concern, but treatments or interventions that can reduce the effects of aging have been elusive.

Of particular concern is frailty, defined as a decreased ability of the body to cope with stress, as it is associated with poor long-term health and reduces quality of life for many aging Canadians. Recent evidence suggests the presence of blood-based biomarkers that can predict frailty and subsequently aging. Combined with previous work that showed that transfusing old mice with young blood rescues aging by reinvigorating affected cellular pathways, there is mounting evidence that blood contains aging-associated factors which may be the key to understanding, and eventually reversing aging.

Two new areas of research, never before analyzed together, could help identify these blood-based aging factors. The first is epigenetic age, a measurement of biological aging. We know that accelerated epigenetic age, or having an epigenetic age higher than your chronological age, is associated with higher frailty and risk of mortality. The second is age-related changes in extracellular vesicles (EVs). EVs are produced by all cell types and are crucial for cell-to-cell communication. Think of EVs as emails. Just like an email can have text, video or audio files, EVs are versatile in the messages they can carry, and the size and content of EVs is different in older versus younger people.

Our hypothesis is that EVs from young blood carry ‘youthful’ factors which can potentially reverse aging, including reducing the effects of frailty. Thus our objectives are to:

1. Characterize the biochemical properties, density and molecular cargo of EVs obtained from healthy and frail women of the same chronological age.

2. Measure epigenetic age in blood from healthy and frail women to identify biologically younger and older participants.

3. Cross-culture EVs isolated from biologically younger and older subjects with skeletal muscle cells derived from old and young human donors, and determine if it rejuvenates the a) epigenetic clock and b) muscle metabolism.

This work will determine whether we can turn back the epigenetic clock and reverse frailty using isolated EVs from younger subjects. It could lead to new treatments, which would reverse the effects of frailty and aging on health.

Our lives critically depend on civil and concrete infrastructure on an everyday basis. Such infrastructure is designed with a lifespan of 50-75 years, and a large number of critical structures built in the 1960’s to 1980’s in Canada and worldwide are now reaching the end of their service lives. Action is then needed to ensure adequate performance over their last few years or even to extend their lifespan. The goal of this project is to provide engineers with reliable and efficient tools for detecting, diagnosing, and acting on dangerous structural deterioration of concrete.

Unexpected deterioration and failure of civil structure is, at best, disruptive for the daily lives of a large number of people and the economy. In the worst case, it may bring cities to a halt and result in tragedy with lives lost. Currently, experts rely on standard protocols to perform condition assessments of critical concrete infrastructure to determine the damage cause and extent (i.e. diagnosis), the structural consequences, and the likelihood of further deterioration (i.e. prognosis); and to initiate timely and efficient management actions. Assessment is based largely on tools that appraise mechanical properties, physical integrity, and durability of the deteriorated materials and structural components. However, the current methods require in-situ investigations, as well as time-consuming visual and microscopic techniques performed by experts, and are thus unscalable and widely inaccessible. Artificial intelligence techniques such as deep learning (DL) have made headlines in recent years, especially convolutional neural nets (CNN) which have brought image analysis to the masses. Likewise, a field of applied math called topological data analysis (TDA) has enabled a new range of visualization and analysis tools for biomedical images that surpass human experts. The combination of DL and TDA moreover is garnering much attention in medicine. Because of the strong role local texture plays in detecting both lesions in tissue- or cracks in concrete we anticipate there is much to be gained by applying a hybrid TDA/CNN approach to concrete. For this we need a combined team of TDA and concrete experts. The tools we aim to build will be extremely beneficial to infrastructure owners, governments and communities, enabling quicker, less expensive and more accurate decision-making and thus increased safety for society. 

Un gel obtenu par auto-assemblage d’un peptide laitier non synthétique a récemment été généré et étudié au sein de l’équipe de recherche. Ce peptide très hydrophobe, soluble uniquement entre pH 2 et 3, forme des structures de complexités variables (nanofibres, hydrogel) selon sa concentration et le pH réactionnel. De par ses propriétés atypiques, il devient possible d’utiliser ce peptide pour le développement de nanoparticules en vue d’applications biomédicales novatrices. En effet, la recherche dans ce domaine a littéralement explosé ces dernières années puisque divers peptides synthétiques amphiphiles et hydrophobes de structures moléculaires spécifiques ont démontré des capacités d’auto-organisation exceptionnelles et ont, à titre d’exemples, été ciblées comme nouvel agent pour prévenir l’athérosclérose ou les ulcères diabétiques ischémiques. Ainsi, en lien avec les caractéristiques uniques du peptide laitier à l’étude, deux applications biomédicales seront évaluées en modèles in vivo. La première approche visera à étudier ce peptide comme nouvel agent protecteur naturel de la paroi intestinale en lien avec son aptitude à former une couche naturelle protectrice contre divers éléments de stress. En effet, les parois de l’intestin se doivent d’être très étanches afin de ne pas laisser s’échapper certains métabolites bactériens, hautement inflammatoires, vers la circulation sanguine. Ce phénomène de perméabilité intestinale étant mis en cause dans différentes pathologies (maladies auto-immunes, le diabète de type 1 et 2). Connexe à la 1ère approche, la 2ème approche visera à tester le potentiel thérapeutique de notre peptide sur des modèles animaux des troubles de l’humeur. En effet, des études cliniques récentes suggèrent une hausse de la perméabilité de la paroi intestinale chez les patients déprimés ce qui favoriserait une réponse immunitaire accrue à la suite d’un stress et le développement de symptômes dépressifs. Fait intéressant les femmes sont plus vulnérables aux effets du stress sur la perméabilité de la paroi intestinale. Ainsi, nos études incluront tant des souris mâles que femelles, d’autant plus que la dépression est deux fois plus prévalente chez les femmes. À terme, ce projet vise le développement d’un nouveau nanomatériau organique naturel pour la mise en place de nouvelles thérapies spécifiques capables de protéger la paroi intestinale et d’influer positivement sur les pathologies liées au syndrome métabolique et aux troubles de l’humeur.

Goal: Generate, validate, and leverage a new biosensor to interpret the role of a critical molecule in fear memory formation.

Background: Fear-memory-associated disorders (e.g., PTSD) impose pronounced health and financial burdens. Revealing the mechanistic neurobiology underlying fear memory will guide treatment of these disorders and simultaneously address a central question of basic neuroscience. Strikingly, in a mouse model of PTSD we have recently acquired preliminary data that illustrates the gastrin-releasing peptide (GRP) can be targeted for after-the-fact disruption of fear-inducing memories. Understanding the sites and time windows of GRP action may open the door for an entirely new approaches - prevention - of PSTD-like memories.

Hypothesis: We hypothesize that GRP acts as a slow neuromodulator in the subiculum, a key brain region in fear memory, to promote memory formation.

Aim 1: Generate a GRP sensor that enables fluorescence-based readouts of GRP activity

Hypothesis: GRP is amenable to sensor-based interrogation.

Approach: We will utilize a high-throughput capable protein engineering platform, which for the first time provides true functional testing of large sensor libraries. We will engineer a fully optimized GRP sensor at unprecedented speeds.

Aim 2: Ex vivo validation of GRP sensor in slice preparations

Hypothesis: GRP is locally released following activity in excitatory subiculum neurons.

Approach: We will perform both single-cell and full-field stimulation of subiculum neurons to characterize GRP signaling via our novel sensor.

Aim 3: In vivo examination of GRP mechanisms of action

Hypothesis: GRP acts locally within the subiculum to help create fear memory.

Approach: We will image GRP signaling across our experimentally controlled fear memory paradigm to identity the site and dynamics of GRP action.

Expertise: M.S.C. has extensive experience in physiology and fear memory. A.B. has engineered several pioneering protein tools in the last ten years.

Significance: In the short term, our work will provide a previously inaccessible interpretation of a molecule underpinning fear memory, benefitting both basic science and potential clinical applications.  As GRP is critical molecule in other systems and functions, our biosensor will provide a foundationally new tool with broad scientific applicability.

Obesity is a challenge that compromises social and economic well-being. Self-regulation of caloric intake is a key driver of  weight loss, thus digital tools in the form of mobile fitness apps have been developed to assist with tracking caloric intake and expenditure. However, individuals struggle to achieve or maintain weight loss, in part due to difficulty maintaining healthy eating habits. Improved understanding of the multiscale and dynamic patterns of eating behavior through predictive computational modelling will assist in designing more impactful personalized interventions for weight loss. In collaboration with a leading weight loss app (Lose It!), this research will generate empirical, predictive, and prescriptive findings to enhance the design of digital weight loss tools. Our interdisciplinary approach combining computational science with dietary data is needed to better understand the dynamics of eating patterns and their relationship with body weight. Previous research has abstracted away from granular eating patterns due to high-dimensional computation issues, yet we will circumvent these computational hurdles by applying recently developed machine learning techniques. Our specific objectives are to: 

1) Develop a predictive model of food intake patterns according to complements/substitutes and timing of caloric intake.

2) Assess associations between patterns of consumption (timing of caloric intake and combinations of items consumed during the same eating episode) on body weight outcomes.

3) Simulate the effects of mobile-delivered personalized “nudge” interventions that target intake of specific foods on the overall eating pattern and body weight outcomes.

To meet these objectives, we will adapt a predictive model of consumer grocery shopping choices to trace the eating behaviors of millions of users on the Lose It! platform. We will conduct simulation experiments to assess the impact that mobile-delivered personalized nudges have on the dynamics of eating. Our team possesses the necessary expertise in machine learning and eating behaviour to conduct this research. Findings will disrupt conventional thinking surrounding caloric intake and body weight, and will enable new personalized nudge-based interventions aimed at sustaining individuals along a trajectory of healthy eating. This research is urgently needed as current weight loss strategies lack long-term success and our approach will uncover novel targets for intervention.

Emerging nanotechnologies have the potential to transform our understanding of biology and impact multiple domains of health sciences, from diagnostics to drug delivery. In advance of this transformation is a requirement to blend approaches in physics, chemistry and engineering with biology to create innovative nanodevices that provide reproducible and informative data on biological systems. Here, we propose the fabrication of nanoscale conductance-based devices able to detect both conformational exchange and specific interactions for crucial GTPase ‘switches’, gating proteins used by eukaryotic cells to control nearly all cellular signalling events. We will develop arrays of miniature electrical circuits made from graphene nanomaterial, interfaced with multichannel microfluidics and functionalized with purified GTPase proteins. These small proteins provide an ideal biochemical system to develop nanodevices reporting on protein function, as they undergo conformational exchange dependent on a bound nucleotide and magnesium ion that governs downstream signalling interactions. As GTPase proteins are reversibly switched on/off, nanodevices will directly report on GTPase activation state or interactions with partner proteins via electrical signals without requiring photoactive labels or optics components. The novelty of employing these miniaturized devices for studying macromolecular proteins requires a calibration phase. We will first use RAS small GTPases to standardize the devices, taking advantage of the extensive characterization of their interactions and kinetics due to the notorious involvement of RAS gene mutations in numerous human cancers. In the next phase, we will exploit our comprehensive database of small GTPases to functionalize multiple nanodevices in parallel and screen for specificity of GTPase interactions with GTPase binding effector proteins, an open question of huge importance to our understanding of cell signalling and related clinical matters, including drug design and patient acquired resistance. Currently, the study of protein biophysics and interaction networks is a massive undertaking that lacks high-throughput, reversible and robust assays to directly and comprehensively report on interaction specificity. The development of parallelized analytical nanodevices would resolve this, and also provide an avenue to exploit nanotechnologies for probing the function of proteins and other biomolecules.

Background: Preoperative state anxiety (PSA) occurs in approximately half of breast cancer surgery patients and is associated with several negative postoperative mental and physical health outcomes, which incur costs to both patients and the healthcare system as a whole. Despite this, few targeted and feasible PSA interventions have been developed. The most promising PSA interventions to date involve poorly feasible initiatives where patients are given the opportunity to tour operating rooms (OR) and medical wards prior to surgery, and gain information about the surgical process in a classroom setting. Immersive virtual reality (VR) is a technologically advanced interface that allows pre-emptive exposure to simulated stressful environments such as the OR, and allows for the integration of interactive artificially intelligent (AI) avatars. We aim to develop and evaluate a novel virtual reality (VR) preoperative intervention with AI avatars to reduce PSA, and ultimately mitigate poor postoperative health sequelae in breast cancer surgery patients.

Objectives:

1. Develop a novel preoperative VR simulation of the OR and test the feasibility of the 

VR platform.

a. Determine patient acceptance of the VR platform.

b. Identify a reproducible and responsive PSA measure.

c. Create a patient partner group.

2. Develop and refine the preoperative VR simulation with integration of AI avatars in collaboration with patient partners. We will specifically develop an AI educational avatar (representing the anesthesiologist) that patients can engage with and obtain information regarding the OR and their surgery while virtually immersed in the OR environment. We will conduct a randomized clinical trial (RCT) to examine whether VR with AI avatars, compared to standard care, significantly reduces levels of PSA (primary outcome) and downstream postoperative health outcomes such as pain, nausea, incident psychiatric disorders, length of stay, and delirium (secondary outcomes).

Significance: Reducing PSA and preventing poor postoperative health outcomes, such as increased length of stay and pain, using VR may have significant patient health and financial implications. This novel research will form the basis of investigating the utility of VR with AI avatars in other surgical cohorts, which may lead to broad implementation of this low cost and feasible intervention.

More than 600,000 children in Canada have a diagnosis of autism spectrum disorder (ASD) and/or attention deficit/hyperactivity disorder (ADHD). Currently, treatment for these conditions is not driven by biology; few available medications are only partially effective and have significant adverse side-effects. Although some gains have been made in treating symptoms of these disorders, long-term outcomes remain poor for many of these children. There is a clear and urgent need for new treatment approaches that target the unique needs of each child. To address this need, our project proposes a paradigm shift in the way we understand, define, and treat these prevalent conditions. Our project objectives are two-fold:

Objective 1: Examine the validity of existing diagnostic categories of ASD and ADHD with respect to having unique and distinct biology, and discover novel groupings of individuals that share biological features. To this end, we will bring together expertise from machine learning, neuroscience, medicine, and psychology to pursue a novel analytical approach: instead of comparing diagnostic groups as currently done, we will remove diagnostic labels and use an innovative data-driven approach that looks to the data to discover new groups that transcend the existing diagnostic labels. This approach can identify groups of individuals who share biology, regardless of diagnosis. To our knowledge, this will be the first application of the proposed methods to discover biologically-relevant subgroups in ASD and ADHD. We will examine various measures of brain structure, including cortical and subcortical volume, surface area, and cortical thickness obtained from four existing, open-source databases (total n=3,292).

Objective 2: Validate the new grouping discovered by examining if they align with homogeneity in other phenotypic domains and/or response to treatment. To do this, we will examine if the groups discovered on one data set will replicate on others, and examine if membership to proposed groups predicts response to treatment in four clinical trials.

The anticipated outcomes of this project are: 1) methods for cross-disorder, data-driven analysis of brain data in ASD and ADHD, 2) evidence supporting misalignment between diagnostic labels and underlying biology in ASD and ADHD. This will be a first step in moving the field from a one-label-fits-all approach to personalized medicine where each individual is cared for based on their unique biology.

Aside from its treatment complexity, a major factor contributing to the high prevalence of mental illness is the difficulty struggling people have in seeking out help. This can stem from a variety of obstacles, be it social stigma or lack of resources. We believe the pervasiveness of social media, and the recent developments in artificial intelligence (AI), provide a path for the creation of ground-breaking supporting tools that will bridge the gap between people who are suffering and mental health professionals.

The global objective of the RELAI project is to empower at-risk people, patients and practitioners to assess mental health status through AI-based analysis of online behavior. Paying special attention to the early detection of mental illness or risk thereof, we will focus on analyzing textual production as well as time use and interactions on different websites and online platforms. Leveraging the skills of our highly multidisciplinary team, the RELAI project will hence create a respectful and explainable AI-based system that will ensure privacy, transparency, and reliability to its users.

Paramount to the success of RELAI is the collection of reliable, clinically-grounded corpora, which are not currently available. The data exploration will hence begin by using information retrieval and other unsupervised techniques, such as topic extraction, to get a sense of challenges in non-clinically-grounded existing datasets from evaluation campaigns in the field. In the meantime, psychiatrists will collect instant messaging conversations and traces of online behavior from patients to compare against their level of suicidal ideation and depression severity as assessed by a clinician. These data will then allow to train learning algorithms, namely neural networks, which represent the state-of-the art in various natural language processing tasks. Once the AI model has been built, the system will make all inferences and predictions locally, so as to avoid sensitive information leaving the users' device.

Explainability, transparency and privacy requirements will be studied in detail and fulfilled incrementally  at each step of the project, implementing the team's multidisciplinary reflections on how to provide users with maximum control over their data. 

This project is highly innovative as it will set the foundation for an ethical development of user-centric AI systems to support mental health assessment. 

The declines of insects have been documented globally and have significant implications for food security and natural ecosystems. In this project, we will use an interdisciplinary, biocultural approach to investigate plant-pollinator biodiversity in Canada . This project will be a collaborative effort between academics, artists and cultural centres. We will work with pre-existing gardens created by the late Mi’kmaq artist Mike MacDonald and create new Indigenous gardens at various locations across Canada. MacDonald’s encounters with pollinators near Kitwanga, British Columbia, in an area threatened by clear-cut logging, inspired his understanding of their connection to medicine plants and healing. This was the seed of his numerous in-situ gardens created from 1995 to 2003, which he planted across the country from Vancouver to Halifax. The growing of gardens as part of contemporary art practice has burgeoned into ecological and eco-art genres, with potential for community-engaged art practices that address shared colonial histories of food, land use and medicines. MacDonald’s work bridges ecological concerns and reflects on Indigenous knowledge of plant medicines. We will use gardens as spaces for ecological research and also to create community-engaged arts programming to share knowledge of pollinators, plant medicines and land rights. The re-created gardens and other previously established Indigenous gardens will be study-sites for ecological surveys of pollinators and pollination. Additionally, this research will be supplemented with storytelling and a literature review to create a better understanding and historical context of the intricate relationships between wild pollinators, plants and people. Previous pollinator conservation research has focussed on cities and agriculture. Our novel proposal will expand pollinator research to include culturally important plants and tap into other knowledge systems. The work is significant because it aims for inclusive creation and sharing of knowledge between Indigenous knowledge holders, ecologists, social scientists, the general public, artists and students. The work will fill knowledge gaps in the pollination requirements of culturally important plants. It provides an important link between historical and contemporary environmental issues and ways of living. This research will help us understand the impact of pollinator declines on food security and the potential for Indigenous gardens to provide habitat.

Actinium-225 (Ac-225) is a radioactive isotope that shows great promise for incorporation into a radiopharmaceutical for therapy of difficult-to-treat and/or late stage metastatic cancers. Ac-225 emits 4 alpha particles in its decay, each of which is powerful enough to kill a cell. By attaching Ac-225 to a cancer-targeting molecule (i.e. biomolecule), the alpha particles would effectively and specifically kill only the targeted cancer cells. Such a drug would revolutionize cancer treatment. Despite this great potential, the chemistry of Ac-225 is virtually unexplored due to the isotope’s limited availability and difficulty with studying this highly radioactive element. Enabled by our access to the Canadian nuclear research facility TRIUMF, the objective of this project is to gain unprecedented knowledge of how to design effective Ac-225 radiopharmaceuticals by exploring the fundamental chemistry of Ac-225.

The plan consists of unconventional and truly interdisciplinary approaches ranging from theory to experiment, and fundamental chemistry to applications in nuclear medicine. We propose to use a synergistic combination of computational studies using (a) density functional theory and experimental studies using (b) beta-nuclear magnetic resonance to understand the electronic and structural preferences of actinium complexes at the molecular level. The outcomes of these studies will directly feed into (c) our search for the ideal molecule (i.e.; chelator) for binding the radioactive Ac-225 atom to a cancer-targeting agent. New chelators will be designed and synthesized, attached to established biomolecules and radiolabeled with Ac-225. Finally, we will perform (d) micro-dosimetry studies in cells, and measure cell survival and effectiveness of the drug. Our approach can ultimately be used to compare cell survival with other radiotherapies, namely radiopharmaceuticals that use other types of radiation (e.g.; Auger electron emitters, beta emitters, and external beam therapy with protons).

TRIUMF is uniquely positioned to enable this research with access to Ac-225, a plethora of other radioactive isotopes, and world-class radiochemistry facilities. The research is high-risk because so little is known about Ac-225; however, the outcome of the proposed project, novel cutting-edge and efficient actinium radiopharmaceuticals, have the potential for immense impact on the survival and quality of life of cancer patients in Canada and worldwide.

Understanding how stress shapes the brain to influence disease vulnerability is critical to tackling stress-related psychiatric disorders such as depression, which affect twice as many women as men. To develop effective treatments, we must understand both male and female brains. Animal models are essential for untangling brain mechanisms, but basic neuroscience research has almost exclusively studied male animals. Existing tools for studying behavioural stress susceptibility are based on male-specific norms, leading to incomplete or misleading results in females.

Objectives The central objective is to develop an unbiased data-driven analysis of behaviour upon which to build a model of brain function that integrates high-resolution analysis of gene activity and sex-specific behaviours to determine how chronic stress increases susceptibility to stress-related psychiatric disorders in both sexes.

Approach This proposal is from a diverse team, drawing on recent advances behavioural neuroscience, computational biophysics, computational genomics, and statistical modeling. We will develop a data-driven behavioural analysis to interrogate mechanisms of stress adaptation in male and female mice. We will apply our novel framework to generate a behaviourally rigorous, sex-specific analysis of molecular mechanisms of stress susceptibility using single-cell RNA-sequencing to measure gene activity in thousands of individual brain cells. We will then develop an integrative statistical model to understand how genes in specific cell types are influenced by stress and sex to shape behaviour.

Novelty & Significance This proposal defies established behavioural paradigms, proposing a fundamentally new approach to rigorously study both sexes. This innovation will propel an urgently needed paradigm shift, re-evaluating widely accepted, yet flawed, behavioural paradigms that do not accurately capture behavioural variability in females. Integrating concepts from disparate fields to develop new methods in behaviour, gene expression, and statistical modeling, we will generate a novel, rigorous analysis, incorporating both sexes, to tackle the question of how gene expression shapes behaviour and psychiatric risk. By systematically assessing males and females within a data-driven framework, unconstrained by pre-existing bias, this research will define a ground truth of sex-specific phenotypes that will be the benchmark for the field for years to come.

Growing urban populations and climate change are putting increased pressure on food supply to cities globally. A resilient food system- the systems and infrastructures needed for food production, processing, distribution, consumption and disposal (Pothukuchi and Kaufman, 2000) is required to ensure food security and the resiliency of cities in adapting to climate change. Working to address these concerns are scholars and practitioners in an emerging frontier called “food system planning” (Soma and Wakefield, 2011). In this field, food asset mapping (Baker, 2018) has been used to document available food infrastructures in cities. Food asset mapping conducted by planners usually consist of a spreadsheet and a web map identifying the locations of supermarkets, restaurants, and food banks. However, food asset mapping has not included ecological and cultural assets important to food system resiliency. Further, what are considered “assets” may not reflect the lived experiences of marginalized communities. In contrast, this study will apply a “citizen science” led food asset mapping involving Indigenous, racialized, and low-income communities in British Columbia. It will also combine interdisciplinary methodologies such as photovoice, statistics, storytelling, and tools from ethnobiology such as ethnographic analyses, settlement history, and floral and faunal inventories to understand keystone species and sites that are key to food system resilience (Garibaldi and Turner 2004). Further, innovative dissemination through multimedia and guided tours by citizen scientists will allow food asset mapping to move beyond two dimensional online maps, to integrate new frontiers of collective collaboration towards a more just and resilient food system. The study will answer the following questions: 1) How can a citizen science-led food asset mapping identify “hidden food infrastructures” such as spiritual, cultural, informal and ecological assets in the community? and 2) How can the inclusion of diverse perspectives and the integration of photovoice methodology improve traditional food asset maps? This study will contribute to a new area of research around ecological and food heritage planning, resulting in the development of robust data on infrastructural (both formal and informal), cultural, ecosystem and spiritual food assets, and improved policies to ensure food system resiliency in British Columbia. 

Objectives

How do our housing choices influence our sense of life satisfaction and happiness? How does urban density transform our relationship with our neighbours, our family and our community? Debates about the transformational capacity of urban design go back decades and remain a central question in our respective fields. We are scholars in architecture, planning, psychology, sociology, and economics who aim to provide novel evidence on how housing conditions may enable or obstruct wellbeing outcomes related to mental health, happiness, and social connections.

Research Approach

We propose an experimental and longitudinal study of new residents who will be offered rental contracts in the new Stadium Neighbourhood on the UBC campus. The experimental design will pair similar housing applications and then use a lottery to randomly assign households to one of two treatment conditions or a control. We will compare residents living in buildings designed for social interaction with those living in conventional buildings (experiment 1) and compare residents living in high-rise condominiums with those living in midrise units (experiment 2). This will allow us to produce unbiased estimates of how housing conditions influence wellbeing and life satisfaction indicators. Our research will include an intersectional gender approach and pay special attention to the views of women.

Novelty & Expected Significance

There is concern that Vancouver’s iconic urban form, the slender tower on podium, may have negative impacts on people’s sense of community, life satisfaction, and social connection. Our collaboration with the University planning team provides us with an exceptional opportunity to advance knowledge about the impacts of urban design on quality of life and wellbeing. We will be the first research team to use experimental methods to disentangle the complex relationship between housing condition and wellbeing. We propose a significant break from past work, which relies on observational studies rather than experimental data. We will learn about the cost-effectiveness of our design interventions and learn about the psychological and sociological mechanisms at work. We will produce a landmark dataset that will be shared with researchers around the globe for maximum impact.

Concepts That Bite Through Time is a new research project that aims to provide access to extraordinarily detailed 3D models of historical Blackfoot objects held in museums. We will leverage digital tools, art-based public engagement, and hyperlocal network technologies to improve the ability for Blackfoot people to access and interact with the historical objects and their associated knowledge.

The project aims to: create and disseminate highly detailed digital models of historical Blackfoot objects in British museum collections; provide access to the knowledge and skills embedded in those objects through virtual interfaces and live events; explore issues around access, tangibility, materiality, and value as they relate to physical objects and virtual experiences of those objects; advance efforts to decolonize online spaces and virtual worlds and promote knowledge sharing in both analytical and creative technologies; build connections between Indigenous and non-Indigenous people and perspectives; and to support call to action #67 from the Truth and Reconciliation Commission by creating best practices for art galleries and museums.

Our research approach unfolds in three phases. First, we will travel to England with Elders to image the objects in British museums with our British collaborators. The British team members have developed sophisticated techniques to produce images of objects with incredible detail. Next, we will host a gathering of the Blackfoot Confederacy to receive guidance and direction on the project. Second, we will produce web-based prototypes featuring the digital models of the objects, using spatial web technologies to re-unite the objects with their associated knowledge and culture. Finally, we disseminate the objects on the Blackfoot Digital Library (est. 2006), through localized wireless networks in areas without Internet access, and through exhibitions and public programming to engage people with the knowledge held by the objects and digital tools and techniques for re-narrating them.

This project aims to help rectify the harm colonial agents, museums, and researchers have caused by taking artifacts, knowledge, and culture from the Blackfoot people and controlling the resulting cultural capital. It will be the first of its kind to use digital imaging techniques and spatial Web technologies to provide immediate virtual access to interactive representations of historical objects stranded in museums from a Blackfoot perspective.

Challenge. As with most people in our society, persons with cognitive disabilities use technology for a variety of functions, including online banking, navigation and reminders. For them, however, technology use often serves an assistive purpose, helping them to perform tasks they would not otherwise accomplish. Nevertheless, cognitive accessibility obstacles, such as difficulties following the necessary sequence of actions to complete tasks, often limit their use of technology. The lack of cognitive accessibility (i.e., the cognitive demand is higher than the users’ cognitive abilities) leads to non-adoption, misuse or abandonment of technology. If technology developers expect to reach this fast-growing population of consumers, they must understand the factors that influence their technology adoption decisions. 

Opportunity. Our project aims to transform technology research and development (R&D) processes to be inclusive of users with cognitive disabilities, and to support the development of technologies that are accessible to them. R&D includes activities led by the private industry, the academic sector or the government to develop, test and improve technology. The objective is to evaluate an inclusive approach to R&D on a small scale, and to analyze the factors that will support a systemic transformation. Our implementation site is the Information Technology Accessibility office at Employment and Social Development Canada (Government of Canada). We have agreed on the following activities: (1) Developing and testing a protocol for evaluating the cognitive accessibility of technologies used by employees with cognitive disabilities; (2) Determining the usability and attractiveness of this protocol within and beyond the federal government; (3) Updating and evaluating mandatory diversity and accessibility training for federal employees to include cognitive accessibility. Persons with cognitive disabilities will be directly involved in these activities.

Benefits. This project has the potential to lead to disruptive thinking and practices: it may bring forward unique scientific directions in several disciplines that have yet to collaborate to solve the complex issue of the digital exclusion of persons with cognitive disabilities. It will support the implementation of the Accessible Canada Act that puts technology accessibility among the main priorities identified by Canadians with disability themselves for a Canada without barriers. 

Un défi grandissant auquel les Canadiens feront face est celui du développement durable du Nord. Alors que le Canada abandonne graduellement les combustibles fossiles au profit des énergies renouvelables, la production d’électricité et de chaleur des communautés autochtones éloignées dépend strictement du diesel, tout en étant fortement subventionnée. Face à des transformations rapides et spectaculaires en raison du changement climatique, les régions nordiques font l’objet de plusieurs initiatives de déploiement de technologies propres, mais dont la portée demeure limitée en raison de leurs sources intermittentes (solaire, éolien). Pour arriver à une implantation massive de ces technologies, il faudra résoudre la problématique du stockage énergétique longue durée en climat froid. C’est l’objectif de ce projet de recherche, qui mise sur une approche multisectorielle mise en place par une équipe inclusive pour affronter cette problématique, tant sur le plan technique que sociétal. À cette fin, des essais de démonstration seront réalisés pour faire évoluer le stade de maturité technologique du stockage thermique souterrain dans un sol gelé (pergélisol), lequel représente une solution innovante pour chauffer les bâtiments en hiver grâce à l’énergie solaire produite en excès durant la saison estivale. L’opération de systèmes de stockage thermique couplés à d’autres formes d’énergie renouvelable sera aussi analysée pour évaluer la pertinence des réseaux de chaleur à usages partagés, en tenant compte du comportement des utilisateurs. Dans l’optique d’en accélérer le déploiement, une analyse du mode d’implantation de ces technologies (individuelle, collective, municipal) et leur cadre réglementaire, sera entreprise. Ainsi, une approche multisectorielle est préconisée de manière à adapter les modes d’implantation des systèmes énergétiques aux mécanismes de développement économique préconisés par les populations autochtones, garantissant une intégration harmonieuse des technologies. Les travaux proposés sont à haut risque, car de telles stratégies de stockage d’énergie de longue durée et adaptées au contexte nordique n’ont toujours pas été mises à l’essai dans un climat polaire. Le potentiel de retombées est majeur, puisqu’avec des solutions de stockage d’énergie viables, les technologies d’énergie renouvelable pourront répondre à un plus large éventail de besoins et promouvoir un développement durable du Nord basé sur l’exploitation de ressources locales. 

This translational study will use neuroimaging and neuronal tracing to test whether prenatal BPA exposure alters neural structure and function in human children and mice.

Gestational development lays the foundation for life-long brain function. However, the fetal brain is vulnerable to environmental insults due to its immature blood-brain barrier and the sensitivity of neural progenitor cells. Prenatal exposure to environmental contaminants – such as bisphenol A (BPA), an endocrine-disrupting chemical with estrogenic properties – is increasingly associated with altered brain development. Nearly all Canadians have detectable BPA in their urine, and high prenatal BPA is associated with anxiety and depression in children. Despite this evidence, Health Canada and agencies around the world offer no guidance on prenatal BPA exposure. Convincing evidence linking prenatal BPA exposure to changes in neural structure and function is required to change policy and protect human health.

Our team showed that prenatal BPA induces precocious neurogenesis in mice, suggesting these born-too-early neurons will form abnormal brain circuits. No study has examined the effects of prenatal BPA exposure on brain circuitry in children, though our preliminary neuroimaging data shows weaker circuits measured by magnetic resonance imaging in both children and mice prenatally exposed to higher BPA.

Here, we will build on these findings and test the hypothesis that precocious neurogenesis induced by gestational BPA exposure leads to permanent structural changes across two aims:

Aim 1. Determine brain morphometry and connectivity changes associated with high prenatal exposure to BPA in children. From an existing cohort study that measured BPA in maternal urine prenatally, we will recruit 120 boys and girls with high (top 20%) or low (bottom 20%) prenatal BPA exposure. Using novel high-resolution neuroimaging techniques, we will determine alterations in brain volume and white matter connectivity at age 8-9 years.

Aim 2. Identify the phenotype of the circuits changed by BPA exposure. We will deliver matching doses of BPA (i.e., same as top 20th and bottom 20th percentiles used in Aim 1) to pregnant dams throughout gestation. We will use high resolution neuroimaging to confirm the resulting brain alterations, establishing causality and validating the mouse model. Brain regions with connectivity changes will be injected with viral tracers to map and identify the altered circuits.

Artificial intelligence (AI) has progressed tremendously over recent years, fueled by algorithmic advances and improvements in computing hardware. Yet, the physical size and energy consumption of AI computers are far larger than those of biological systems, suggesting that new computing architectures could become much more efficient than current technology. As an example of such a new architecture, we have recently achieved the world’s first demonstration of AI computing in a microelectromechanical system (MEMS) sensor. Our devices implement both the sensing and the computing functions in the mechanical degrees of freedom of a MEMS, enabling for instance a MEMS to detect sound (as a conventional microphone) and to be trained to recognize words in the sound signal (as an AI system).

Our research program targets smart sensor systems, which are built with conventional technology by integrating a discrete sensor with a general purpose computer for data processing. Our objective is to reduce both the volume and the energy consumption of smart sensors by six orders of magnitude, using our AI-MEMS. These MEMS form a dynamical system constructed using non-linear mechanical resonators, which can be trained to respond to an external stimulus (e.g. sound pressure) to implemented sophisticated AI functionalities (e.g. recognize spoken words). The proposed research will  stem from our work and create advanced AI-MEMS sensors in 3D nanostructures fabricated by STED lithography. The extension to tridimensional structures will facilitate volumetric integration, while integration of the MEMS with the processing electronics will lead to a more energy-efficient system. We will produce small and efficient smart sensors by combining methods and ideas from software-based AI, mechanical engineering, optics and nanofabrication technologies.

Such efficient AI-enabled sensors could be especially important in the future for autonomous systems  and the integration of sensors in an Internet of Things. We will demonstrate the usefulness of an AI-MEMS accelerometer in a health care application, with an ultra-miniature sensor with sufficient built-in AI capabilities to warn in real-time subjects from a frail population when they perform motion patterns presenting an injury risk. The proposed research will pave the way for highly efficient hardware implementations of AI and the co-integration of sensing and AI in a new class of devices with a large technological impact.

The ability to predict the outcome of a chemical reaction is one of the foundations of chemistry as a scientific discipline. In organic chemistry, more than a century of research has built a framework that allows us to predict the identity of the product(s) of a hypothetical chemical reaction. As a result, chemists are able to rationally plan the synthesis of complex organic molecules. This is one of the most important scientific feats in human history, leading to life-altering breakthroughs in medicine, agriculture, and materials science. These synthesis plans, however, often go awry: many attempts to make specific molecules ultimately fail because chemical reactions that should work in theory simply do not in practice. This means myriad potential new drugs, non-toxic pesticides, or materials are never created. The root of this problem is that there is currently no method to predict how fast a new chemical reaction will proceed.

The objective of our proposed research is to teach a machine the principles of organic chemistry, and use these principles to predict the rates of new chemical reactions. To achieve this goal, we will develop a completely new method in machine learning, where our algorithm will actively decide what data it needs in order to learn these organic chemistry principles as efficiently as possible. We will then use this new machine learning system to predict the rates for key organic chemistry reactions that are most commonly used to discover and manufacture new medicines.

To collect the data needed to teach our machine learning system, we will combine fundamental organic chemistry studies with state-of-the-art high-throughput experimentation to rapidly execute thousands of experiments. For example, to teach how varying the size of a molecule affects the rate it undergoes a reaction, a large set of examples will be designed to demonstrate this principle - effectively, a lesson in organic chemistry. By designing our algorithm to recognize the important similarities and differences in molecular structure that affect the rate, and determine what aspects of the reaction it wants to learn next, it will develop the ability to predict how fast a given reaction will proceed based only on the structures of the reacting molecules. Not only will this work have an immediate practical impact on the way organic chemistry is carried out in industry, it will answer fundamental questions in both organic chemistry and artificial intelligence.

Disaster response and relief is a very sensitive context that can have severe health, social and economic impacts on a community. Creativeness and adventurous ideation in such context is, thus, significantly high risk. Major incidents, natural disasters or man-made emergencies (e.g. earthquakes, tsunami, storm, fire, explosion, infrastructure failure) typically damage the built environment (e.g. buildings, underground mines, and transportation infrastructure) and can cause serious injury to people. In direct focus of this research project, people with existing or disaster-imposed mobility impairment are among the most vulnerable category of victims; they can easily be trapped in debris or be/become unable to evacuate the incident scene due to both their mobility issues as well as the existing or disaster-caused accessibility issues. Therefore, the time-efficiency of life-saving response is exceptionally critical to saving these victims. The response action involves three stages: situational assessment, search for life signs, and rescue. In this research project, we propose to bring together specialists in geomatics engineering, geographic and environmental sciences, mechanical engineering, computer science and electrical engineering to revolutionize search-and-rescue (SAR) response in damaged buildings by developing highly intelligent aerial systems that can not only carry out the tasks of assessment and search autonomously but also provide safe plans for rescue operations. Currently, robots used in SAR are heavily controlled by human operators and experts; i.e. they are remotely piloted, and their onsite view-planning is done manually through wireless controllers. The operators must spend a significant amount of time to navigate the robot and integrate the expert’s inquiries into the robot’s vision. Therefore, proposed aerial systems will be equipped with more reliable exploration capabilities to make sense of complex environments by themselves with little interventions from operators.  Currently, the experts are also inundated with overwhelming volumes of data, e.g. video streams, that they must visually interpret before making any decision. Indeed, the connectivity to the control station becomes more critical as the volume and frequency of data-streaming increases too. Therefore, smarter algorithms will be developed to control the the overflow of data by fusing and transforming disparate data into useful, concise information. 

Traditional cancer therapies such as chemotherapy and radiotherapy have serious side effects and are often ineffective. This has led to the development of more precise and non-invasive “theranostic” (therapeutic and diagnostic) techniques for imaging and treating tumors. These techniques use external agents, typically nanoparticles or small molecules, which are injected into tumors. In photoacoustic imaging, for example, light pulses are directed at the tumor. The agent absorbs the light and generates heat, causing thermoelastic expansion and the emission of ultrasonic waves that can be measured by a detector. This allows tumors to be imaged and precisely targeted with therapeutic techniques, such as photothermal and photodynamic therapies, in which the injected agent absorbs light and generates heat and oxygen, respectively, to kill nearby cells. The requirements for these theranostic agents are numerous. They must be biocompatible and stable, selectively accumulate in tumor cells, effectively absorb light and convert it to heat and sound, and effectively kill cancer cells. Ideally they could also facilitate drug delivery and other imaging techniques, but individual nanoparticles or molecules are not currently capable of performing all of these roles.

In this project, a completely new approach will be taken to develop multifunctional theranostic agents with highly controllable shape and composition. Solutions containing flakes of 2D materials that are promising theranostic agents will be irradiated using a laser. The laser will break the flakes into smaller pieces, forming 2D nanoparticles with diameters that are controlled by the irradiation time. The laser will be polarized to induce a strong, directional electric field, such that the nanoparticles can align and bond in the field to form nanorods of the 2D materials, allowing theranostic agents with different aspect ratios to be produced. Different 2D materials will be combined to produce 2D nanorod heterojunctions that have better photothermal properties, and molecules that improve biocompatibility and accumulation in tumors will be added to the solutions, such that these molecules, or portions thereof, will be incorporated into the agents. The biocompatibility, stability, cellular uptake, photothermal conversion efficiency, and in vitro anticancer activity of the nanorods will be studied as a function of their shape and composition, enabling the discovery of better theranostic agents to fight cancer.

Childhood abuse and neglect (CA&N) are a major public health problem: they play a causal role in many psychiatric disorders and are associated with the leading causes of death in adult populations. Moreover, the phenomenon of CA&N is transgenerational as infants born to maltreated parents show early neurobiological, affective and behavioural problems and are 3-times more likely to experience CA&N. After decades of research on CA&N led by scientists from social sciences, a growing body of evidence emerging from biology and health sciences shows that CA&N get embedded in stress-regulating systems and immune systems, which would contribute to the consequence of CA&N in terms of psychosocial outcomes and physical illnesses in the short and long term. Developing a prenatal intervention for survivors of CA&N to interrupt the intergenerational transmission of the social and biological effects of trauma from the mother to the foetus is therefore considered a priority to meet the 21st-century challenges related to CA&N. To date, there is no prenatal intervention designed for victims of CA&N that would efficiently reverse adverse health outcomes or interrupt the intergenerational transmission of risk. In response to this public health problem, our team developed such a multimodal intervention (STEP program). For the current proposal, we will assess the extent to which a psychosocial program can reduce the intergenerational transmission of the biological embedding of CA&N by inducing compensatory regulations that would normalize neural and physiological regulatory systems both in the mother and in the developing foetus. The proposed longitudinal study will strengthen collaborative partnerships between researchers in psychology, nursing, immunology, child psychiatry and psychoeducation. Three types of biomarkers of CA&N will be evaluated in both pregnant women and their offspring at 6-months: i) dysregulation of the immune system (plasma levels of CRP, TNF-α and IL-6), ii) dysregulation of stress-regulating systems (plasma cortisol) and iii) dysregulation of sleep (measured by actigraphy). Measures will be collected using a longitudinal pre-post intervention protocol in an experimental group receiving STEP (n = 64) and a control group (n = 64). This study will have implications for the 125 000 children born each year in Canada from mothers exposed to CA&N and may contribute to develop a new multimodal approach to prevent CA&N and mitigate their adverse effects.

Objective: Spinal manipulative therapy (SMT), defined by a high-velocity, low-amplitude force application to a specific spine region, is commonly used to treat low back pain, including lumbar disc herniation (LDH). Despite the evidence showing SMT’s effectiveness for LDH, concerns exist regarding SMT’s potential to exacerbate symptoms and further the herniation. Given that 30% of patients with chronic low back pain (who often receive SMT) present with LDH, it is crucial to determine the SMT effects to LDH patients.

Part of the concerns arise from the lack of a basic knowledge of how SMT loads are distributed within the intervertebral disc (IVD). Indeed, the IVD has been shown to be the primary load bearing spinal structure during SMT, however the SMT biomechanical effect within the IVD remains unknown. A direct quantification of IVD deformations during SMT will elucidate if SMT is beneficial or harmful for LDH patients. This will significantly improve our knowledge of SMT’s safety for LDH patients. Therefore, this project aims to quantify the IVD principal strains to elucidate the SMT biomechanical effects within different regions of the lumbar IVD in healthy and herniated discs.

Research approach: SMT vertebral movement will be quantified by optical tracking of indwelling vertebral bone pins in porcine models. Vertebral segments will be harvested, a tantalum wire grid will be inserted and peripheral markers will be attached to the IVD for stereoradiography tracking. Specimens will then be mounted in a 6-degree of freedom hexapod robot which will replicate the exact SMT vertebral displacements. X-rays will be taken with the specimen in four positions: 1) neutral position; 2) SMT pre-load position; 3) peak SMT thrust position and 4) post-SMT thrust neutral position. Deformation within different IVD regions in healthy IVD and with induced LDH will be calculated from the difference in position of the wire grid intersection points between the four positions.

Novelty and significance: This will be the first study to use the wire grid technology in LDH and during SMT interventions, significantly contributing to advancing the current knowledge of SMT effects and safety in LDH. This study will also establish the international and interdisciplinary collaboration between engineering, chiropractic and physiotherapy researchers with unique perspectives and expertise to this innovative approach to elucidate this important health-related issue that remains unclear.

This participatory project reimagines sport access and equity using intersectional, interdisciplinary, and collaborative approaches. It brings together researchers of disability sport, Indigenous health, anti-oppression education, LGBTQ sport, and program evaluation with leaders from the Canadian Paralympic Committee and Sport for Life. Research is led by: a disabled, queer, non-binary settler; an Anishinaabekwe (Anishinaabe woman) researcher; a second generation Lebanese-Muslim settler; and white gay cis-man, and a queer, white immigrant. Together, we will use our community relationships to foster new ways of thinking that will transform sport policies and practices.

Our primary objective is to co-develop novel frameworks for better understanding and removing sport barriers for those experiencing more than one form of marginalization (e.g., Indigenous women with disabilities). This is risky and challenging because Canadian sport programs are mostly structured around shared identities (e.g., women’s cycling), with inclusion programs tending to be additive and identity-focused (e.g., masters women’s cycling). What new sport inclusion policies, programs, and practices might emerge if we focused less on “kinds of people” and more on kinds of barriers, movement cultures, and movement ambitions? Our sub-objectives include: 1) identifying existing practices and needs; 2) building pedagogically accessible, policy-aware, and practitioner-focused frameworks; 3) creating and piloting training modules and self-evaluation tools. Methods include targeted literature reviews; three case studies (interviews, document analysis); five participatory focus groups at sport practitioner gatherings; and built-in workshop and tool evaluations. Should this cutting edge collaboration prove fruitful, there will be significant investment from sport leaders in collaborating on improving and customizing these tools.

By working from the expertise of the margins, thinking across disciplines, and collaborating with influential sports organizations, this project will create accessible and impactful training, policy, and evaluation. These outcomes are significant first steps in transforming the sport inclusion paradigm to one that creates more accessible, safe, equitable, and meaningful sport experiences for the millions of people who are part of multiple marginalized communities, including Indigenous peoples, people with disabilities, women, visible minorities, and LGBTQ2SI people.

Health systems in Canada and around the world are increasingly strained by growing complexity, demand, and unsustainable costs. Specifically, we have been unable to make significant shifts in the way we tackle the unsustainable burden of chronic diseases, suchas diabetes, heart disease and cancer. The co-occurrence of multiple chronic conditions, known as multimorbidity, is now the typical trajectory for patients in the health system. More than 65% of Ontario residents die with five or more chronic conditions, an increase from 39% from 1994 to 2013. The result is an acute care system that cannot keep up with the demand of patients who have increasingly complex health care needs, are taking multiple medications (polypharmacy) and have a diverse mix of medical and social needs that are not being addressed. Our health system is still largely focused on treating one disease at a time — an approach that is incompatible with the health care needs, fails to recognize interactions between diseases, medications and treatments, and results in major inefficiencies in the health care system. We will not solve these major health system problems with incremental changes. The solution requires an entirely different approach, which aligns well with this funding opportunity. Data and information are key to transforming the health system and there is now unprecedented demand for data and analytic tools to support health decision-making. To date we have not had the multidisciplinary collaboration that combines mathematics, artificial intelligence, public health and computational power to study population-level health data and  to support data-driven health system transformation. We propose a novel multidisciplinary approach to using advanced analytics for health that is radically different from our previous approaches to studying chronic diseases in the population by applying unsupervised deep learning methods (hence high-risk), which if successful could fundamentally shift the way the approach the health system in Canada (high-reward). This proposal will b ring together a multidisciplinary team that includes epidemiology, computer science, health system evaluation and financing, artificial intelligence/machine learning, mathematics and public health, in order to create a framework for studying multimorbidity using deep learning and develop optimization strategies to support health system transformation.

Indigenous cultural integrity for many communities in Canada are inextricably linked to wildlife populations. Cultural keystone species (CKS) play fundamental roles in the diets, medicines, materials, social relationships, traditions, and cultures of Indigenous peoples. Habitat loss and climate change have led to fluctuating CKS populations, jeopardizing cultural integrity. Traditional Western scientific approaches to conservation often focus on rare species (i.e., endangered species), thereby overlooking the important role that abundant populations play in order to function as CKS. To sustain or restore abundant CKS, there is a need for interdisciplinary, culturally-inclusive research that embraces multiple ways of knowing.

To help build this inclusive research space, our project goals are to:

1) Create novel, interdisciplinary research approaches that weave Indigenous and Western ways of knowing;

2) Understand how Indigenous communities are influenced by fluctuating CKS population abundance, especially in changing environments; and

3) Investigate factors related to fluctuating CKS populations using Indigenous knowledge and Western science to foster the development of research and conservation priorities.

We will build on existing relationships among the PI’s, academic collaborators, and Indigenous communities across Canada. Based on the concerns of our Indigenous community partners in ON, BC, and NS, we anticipate that our research will focus on moose (Alces alces) as a CKS, though other species will be investigated if directed so by community members. Declining across the continent, moose are vulnerable to climate change, and large-scale natural and anthropogenic disturbances. In some areas moose are considered ‘hyper-abundant’ (e.g., Cape Breton Highlands National Park) and support traditional ways of life. Variation in moose abundance across Canada creates an opportunity to understand the diverse linkages between wildlife, Indigenous cultural integrity, traditional ways of life, and wildlife conservation.

Our interdisciplinary approach will create novel linkages among early career researchers across Canada in the fields of ecology, Indigenous studies, natural resource management, and environmental law. By weaving Indigenous and Western scientific knowledge systems together, our research will further Canada’s commitment to reconcile its relationship with Indigenous people through community-led, reciprocal, and respectful research.

Despite the steady decline in cancer-related death rates for the past 30 years, cancer remains the leading cause of death in Canada, affecting nearly 1 in 2 Canadians in their lifetime. Approximately 50% of all cancer patients undergo radiation therapy as a part of their treatment, often in combination with surgery or chemotherapy. Lately, one type of radiation therapy, called hadron therapy (HT), has gained popularity. There are 86 HT centers currently in operation worldwide, with 71 more coming online. Recently, it was announced that Canada's first purpose-built HT facility will be established in Montreal, offering state-of-the-art radiation therapy.

HT is a powerful treatment technique. It delivers targeted radiation to a tumour, sparing surrounding healthy tissue. Targeting is achieved with a characteristic dose profile in tissue, with very steep dose gradients at the end of a finite range. This means that the vast majority of radiation is delivered at the end of the range in the Bragg peak and not the preceding healthy tissue. This capability is not available in other radiation-therapy modalities. Dose targeting also enables higher dose delivery to the tumour, potentially increasing treatment success. However, one of the key challenges in HT delivery is range verification: determining the correct stopping point of the beam (i.e., precise tumour location) in the human patient. Patient movement, changes in patient morphology between treatments, and other uncertainties in treatment setup or beam delivery may result in the Bragg peak missing the tumour. This error would result in substantial radiation being delivered to healthy tissue, causing unnecessary damage and reducing treatment effectiveness.

Our objective is to measure the range of the treatment beam in real time while treating human patients. Our approach combines a nuclear physics technique with medical physics and radiation oncology. We propose to use solid or solution metal markers and accumulate them in the tumour. The interaction between the beam and the marker will cause the emission of characteristic photons, which can be measured outside of the patient. The innovation of our approach is that the range of the treatment beam can be measured in real-time during treatment without any time-consuming additional imaging or simulations. The outcome of our project will greatly improve the effectiveness and safety of HT and consequently improve cancer treatment rates for hard-to-treat cancer

Background:  Exergames (i.e. technology that gamifies and promotes physical activity) have promising effects on improving engagement for older adults; however, there is minimal research examining exergaming’s effects on older adults living in long-term care (LTC). This project will build on our pilot work to further develop innovative exergaming technology, and advance current knowledge about co-creation and implementation of exergaming in LTC.

Method: A user-centered design approach (i.e. end-users are active participants throughout the study) will be applied. To optimize opportunities for clinical integration, we will actively engage stakeholders in an advisory group and on site-based consultations. Their feedback will be used to iteratively refine the exergaming technology’s hardware and software. Next, we will use evidence-based game design principles to create exergames for our technology that will motivate residents to engage physically, cognitively, and socially. Finally, we will conduct a feasibility trial  to assess its feasibility, acceptability, and efficacy to improve mobility, cognitive function, and social isolation of residents compared to usual care. We will also qualitatively explore their perspectives on barriers and facilitators to innovation translation into clinical practice.

Significance: The body of evidence regarding the validity of exergaming as an activity for older adults is outdated and features now obsolete systems. As a result, it is imperative there is ongoing, robust research and development of viable exergaming technology that support the mobility, function, and ability to age gracefully of older adults. This project serves as a model for the development of a co-created innovative exergaming technology and determines the feasibility, acceptability, and efficacy of the technology in LTC homes. This project is an excellent opportunity for scientific innovation by advancing knowledge on exergaming as a physical activity to optimize mobility, cognitive and social outcomes, and the development of a framework that can guide the co-creation and implementation of new exergaming technology, nationally and internationally. Moreover, this research project counters conventional ageist belief that residents in LTC are too technologically illiterate to engage in designing exergames, and has the potential to radically broaden our conceptualization about engage and co-design exergaming technologies for residents in LTC.

Objectives:

Promoting access to legal services

Exploring deep learning technologies to improve consistency of dispute resolution

Developing natural language reasoning models and intelligent negotiation system for small claims (pilot: severance pay calculation and negotiation)

The cost of justice and recent rapid advance in deep learning technologies such as natural language processing have yielded high-risk, high-return opportunities to expedite access to justice and legal services. Leveraging the rapid advance in computers’ ability to calculate text similarity and perform natural language inference, the Conflict Analytics Lab aims to improve consistency and accessibility in the justice system. As a starting point, we propose an AI-Powered Online Tribunal coupled with an analytics system applied at the outset of the process. The system would provide a degree of legal help as well as intelligent negotiation support for self-represented litigants. The NFRF will be used to develop the first stage of the research, that is a predictive model for severance pay and termination negotiation.

Novelty: First, the research project aims to democratize legal analytics, a technology that is, to date, only accessible to Big Law. In fact, our integrated self-help solution intends to offer legal predictions based on advanced text analytics, such as calculation of severance. Second, we are building a self-help model aimed at guiding users in finding the most suitable negotiated solution, thanks to a text-analytics system analyzing data from past negotiations. In other words, a combination of online dispute resolution and deep learning applied to law would allow litigants to develop a data-driven negotiation strategy, one based not only on legal trends but also on negotiation data, which are hard to access. This would be most significant for small claims dispute resolution insofar as small claims disputes are, in the majority of cases, resolved through settlements. From a technological perspective, causality and counterfactual reasoning are critical components of legal and negotiation language models, which, along with rapid progress in textual-similarity modeling, opens a frontier for natural-language understanding. Furthermore, the application of deep learning research to legal and negotiation texts will eventually have pertinence for AI research, notably because causality is a central element in legal reasoning.

Research Problem: The worldwide prevalence of end stage renal disease (ESRD) affects ~10% of the world’s population and more than 3 million Canadians. Hemodialysis is a life-sustaining treatment for patients with ESRD. This membrane-based therapy is an incomplete renal replacement and is associated with acute side effects, life-threatening, chronic conditions, and unacceptably high morbidity and mortality rates. Hemodialysis membrane’s efficiency is limited by two major challenging shortcomings: bio-incompatibility and poor clearance of middle molecules uremic toxins. Objectives: Our overall goal is to synthesize novel biomimetic hemodialysis membrane design towards development of an artificial wearable kidney. Our specific objectives are to: (1) create a comprehensive biocompatibility calculator to predict membrane polymer and blood interactions; (2) gain an in-depth understanding of proteomics and adsorption of plasma proteins and protein-bound molecules onto the membrane surface and correlate with the biocompatibility calculator; (3) synthesize biomimetic and bio-inspired membrane designs that offer optimum biocompatibility with natural channels and controlled chemistry; and (4) determine the membrane design with optimum performance. Approach: The proposed interdisciplinary project involves transformation modeling, simulation, design, optimization, and synthesis. We will develop and validate a prediction tool based on in vivo data. Molecular dynamic simulations will be combined with traditional computational fluid dynamics approaches for optimum clearance. Synchrotron-based X-ray imaging techniques will answer key questions regarding blood transport and interactions in hemodialysis membrane channels. We will then synthesize biomimetic and bio-inspired membrane that offers optimum biocompatibility, mimic nature, and fit the biocompatibility calculator. Significance: Hemodialysis treatment costs the Canadian health care system $70,000-$107,000 per patient per year (~$310 million/year), due to the numerous long-term chronic or acute consequences caused by membrane bio-incompatibility. The research outcome and prediction tools to be developed through the proposed project will significantly advance current knowledge of hemodialysis membranes that can be extended to various biomedical applications. This research will decrease morbidity and mortality associated with dialysis, prolong survival of world’s ESRD patients, and decrease costs to health care systems.

Objectives: With the proposed research we will explore approaches to trace and counteract the reproduction of colonialism in and through physics. Even more than other sciences, physics is a White male dominated field and, thus, a mirror of colonial patterns and social inequality. Despite this fact, physics is considered as “hard”, objective and socially independent. This narrative both constitutes and reproduces inequality such as the underrepresentation of women, PoC and Indigenous peoples in contemporary physics.

Research approach: To narrow down our research, the project will focus on light in general and on large-scale research facilities (“synchrotron” light sources) in particular, which employ light for physical research. We regard the synchrotron as prototypical paradigm for contemporary physics research, physical knowledge, and the professional culture of physics, the decolonization of which is aspired in the proposed project. For the proposed exploration, we will follow complementary approaches: engaging Indigenous ontologies and epistemologies as well as empowering Indigenous students to engage in contemporary science to attain Indigenous sovereignty. Following these approaches, we aim to explore decolonizing physics by (i) engaging Indigenous epistemologies and involving Indigenous communities in co-creating knowledge; (ii) investigating physics syllabi and curricula with regards to colonialism; (iii) training Indigenous students in physics research; (iv) investigating the impact of current physical research on Indigenous communities and on the reproduction of binaries. The outcomes of (i) and (ii) will converge into a decolonized undergraduate physics course on “Optics and Light”, those of (iii) and (iv) will result in the development of a reflective physical research approach.

Novelty and expected significance: To date, no examples of successfully established decolonized physics courses and curricula exist at Canadian universities. The key challenge of the proposed project is bringing together highly dissimilar disciplines (Physics, First Peoples Studies, Science and Technology Studies, Education) with inherently different perspectives, methodologies and terminologies (natural science, social science and humanities) to use novel approaches (decolonizing physics in teaching and research) for solving existing problems (the underrepresentation of Indigenous people and PoC in science and the reproduction of colonialism through science). 

Despite decades of research aimed at prevention, preterm birth (<37 weeks’ gestation) remains a significant leading cause of infant mortality and morbidity in Canada. Preterm neonates are at increased risk for cognitive impairments, autism and cerebral palsy. Preterm birth continues to increase and in particular, iatrogenic or medically-indicated preterm birth has increased 74%.

A novel challenge in the care of fetuses at risk for preterm birth is to optimize developmental outcomes and reduce disabilities.

Novel neuroimaging investigations are focused on antenatal predictors of preterm birth. A predictor of preterm birth in high-risk fetuses is altered functional brain connectivity as revealed by fetal magnetic resonance imaging (MRI). Altered functional connectivity may reflect ‘brain sparing’, indicative of an adaptation to placental dysfunction in growth restricted fetuses. Brain sparing results from the redirection of cerebral blood flow from frontal to brainstem regions, and is measured by a relatively increased head circumference compared to the abdominal circumference and increased brain blood flow measured by Doppler ultrasound. Brain sparing predicts poor outcome, and is an indicator for preterm delivery. Yet, current methods using Doppler ultrasound may only detect late brain sparing, when frontal regions essential for cognition may be severely impacted. We hypothesize that MRI metrics of brain development are better predictors of brain sparing requiring preterm delivery compared to Doppler ultrasound.

We will compare fetal brain connectivity determined by MRI with brain blood flow assessed with Doppler ultrasound at 32 weeks in 60 fetuses (n=30 growth restricted, n=30 with normal growth). Brain maturation will be assessed with postnatal MRI at term age (~40 weeks postmenstrual age). Cognitive and motor outcome will be determined at 12 months. Our research program in antenatal prediction of preterm birth and outcomes in high-risk fetuses will address the following objectives: 1. To determine if MRI metrics are predictive of brain sparing in comparison to Doppler ultrasound. 2. To assess whether brain sparing is associated with newborn brain maturation. 3. To determine if brain maturation predicts 12-month outcomes.

Findings will inform decisions about when to deliver pregnancies with signs of brain sparing, which will improve outcomes. Results will provide the foundation for future clinical trials aimed at preterm birth prevention.

Molecular motors are a special kind of protein responsible for the transduction of chemical energy generated by ATP (adenosine triphosphate) hydrolysis into mechanical work, which induces contraction of the cytoskeleton of a cell by pulling actin fibers (the structural backbone of a cell). This complex mechanism is responsible for important processes that involve mechanical interaction of a cell with the external environment such as (i) cell division and proliferation (cells embedded in a stiffer matrix have shown to proliferate more slowly) and (ii) cell differentiation (the fate outcomes of stem cells have shown to be influenced by matrix stiffness).

The thermodynamic efficiency of molecular motors in energy transduction is currently unknown, and this its evaluation constitutes the aim of this project. Its experimental measurement has the potential to unlock important insights into the physiological conditions of a large number of eukaryotic cells by linking their biochemical activity to their macroscopic mechanical behavior. We will pursue this via an integrated approach where predictions generated from a theoretical model capturing the relationship between molecular motors and cytoskeletal contraction developed by Bacca-Elfring will be tested experimentally, in collaboration with Zandstra-lab and Yapp-Gates-labs. The theoretical predictions in the model by Bacca are based on non-equilibrium thermodynamics and consider the energy transduction of molecular motors as an increment of the strain energy stored in the actin filaments (microstructural mechanical work), which makes them stiffer. Macroscopic contraction results once the elastic stresses in the actin filaments overcome the stresses that resist motion in the cytosol. We will carry out experiments to measure chemical energy consumption and mechanical work generation. The former will be estimated by measuring ATP depletion from observations of mitochondria activity; the latter will be evaluated by time-resolved imaging on the displacements of small molecules and metallic nanoparticles used as fiduciary markers.

The fundamental discoveries achieved here will seed future collaborative investigations, within the team, to unravel the effect of cytoskeletal energetics on cell differentiation and proliferation for the development of novel strategies for regenerative medicine and novel cancer therapies.

This interdisciplinary research project aims to repatriate 200 Indigenous children’s paintings and photographs from Indian Residential and Day Schools to the creators of the artworks and/or their descendants now residing in Anishinabe and Algonquin communities in northeastern Ontario. The objectives of this research are: 1) To create physical and intellectual spaces where IRS Survivors and/or their descendants are supported by an interdisciplinary team of community members, academics, artists, educators and museum/gallery professionals in leading discussions around the cultural tools, protocols, responsibilities and actions implemented during the repatriation efforts; 2) To develop culturally relevant and sensitive ways to care for the artwork and photography-ways that honour the items as integral parts of Anishinabeg and Algonquin cultural heritage; and, 3) To develop public exhibition opportunities and curriculum which engage the paintings, photographs in culturally meaningful ways in order to educate community about the existence of the children’s artwork and important context surrounding their creation. This research will employ an Indigenous approach to research, which is grounded in well documented theories of Anishinabe and Algonquin knowledge that encompass teachings/principles of honouring Indigenous voice and experience, relationship building, reciprocity, and accountability. The research approach is inherently participatory/collaborative and applied in nature and integrates collections and qualitative methods in a way that ensures that research done with Indigenous Peoples is for Indigenous Peoples.

This research is novel and significant because it brings together multiple disciplinary and community-based perspectives (art, anthropology, Indigenous health, Indigenous education, Indigenous social work) to contribute culturally appropriate ways to repatriate Indigenous visual/material cultural property to families and communities. This research will contribute concrete results that contribute to emerging national and international dialogue around best practices and guidelines in museums, galleries and universities that center collaboration and Indigenous values and perspectives in repatriation. Specifically it will help our society to better understand the cultural heritage and property rights of Indigenous Nations and the important role that Indigenous visual/material culture plays in ongoing healing and the work of truth and reconciliation.

Some insect species travel hundreds of kilometers crossing deserts and seas across a multi-generational migratory cycle. This high number of flying insects transfer biomass, nutrients, and genes at continental scales with major implications for the pollination of crops, the outbreaks of pests, and the dynamics of infectious disease. In a context of global environmental changes, there is an urgent need to predict the evolution of the migratory phenomenon with its benefits and risks for ecosystems and human societies. The insect migratory/dispersal behavior is a complex trait (regulated by multiple genes), for which the genetic basis is unknown. Advances in next-generation sequencing techniques have opened the door to investigate the genetic controls of migration. However, such work requires a method to quantify migratory phenotypes (i.e., a measure of traveled distance). Isotopes vary predictably across the landscape following geological and environmental conditions. These spatial isotopic patterns are transmitted to organic tissues (e.g., insect wings) allowing to fingerprint individuals provenance (e.g., region of natal origin for insects). Our overarching goal is to study the genetic basis of migration on populations of Painted Lady butterflies (Vanessa cardui) by coupling next generation sequencing with cutting-edge isotope and niche-modeling geolocation to characterize the migratory phenotype. Multi-isotope analysis of butterfly wings combined with Bayesian statistics will be used to quantify migratory distances on a macropopulation of V. cardui displaying a variety of dispersal capacity (i.e., long-distance vs. short distance migrants). Next-generation sequencing will be used to link estimated migratory distances to differential gene expression and/or selected alleles. The project is high risk because: 1) behavioral phenotypes like migration are hard to quantify, 2) it will be the first attempt at measuring migration phenotypes using geochemistry, 3) it uses novel and challenging methods in field ecology, geochemistry, genomic and statistics. This ambitious work will strongly benefit from the diverse, international and multidisciplinary scientific team committed to the project. If successful, the project will provide, for the first time, a method to associate dispersal/migratory behavioral phenotypes to genotypes with high rewards in agriculture (i.e., pollination, pest control), human health (i.e., disease transmission), and conservation.

There is an expectation that we can characterize the genetic basis of diseases by applying big-data techniques to genomic big-data, a key in achieving “precision medicine”. Machine learning (ML) is a technology that acquires knowledge by training on observed data to predict unobserved outcomes. Recently, big-data models (e.g., “deep learning”, DL) have attracted attention for their success in multiple industries. In medicine, empowered by new high-throughput instruments, researchers can generate copious data representing molecular profiles of patients, including DNA sequence (genome), RNA expression (transcriptome), DNA modification (epi-genome), and more. Each of the ‘omics contains assessments of millions of variable sites.

However, the “big” in genomic data is not the “big” in ML big-data models. DL methods in particular require large training sample sets to learn the (usually complicated) structure of models. Indeed, DL is successful in problem domains that naturally have large samples (e.g., speech/image recognition) or where they can be simulated (e.g., board games). In contrast, medical genomic studies typically involve cohorts of up to thousands of samples, limited by the prevalence of a disease or the availability of samples. Additionally, as most genetic variants reported by ‘omics experiments may not contribute to diseases, they are actually massive “noise” in the data training process. This is a critical roadblock in applying big-data techniques to genomics.

Training complicated models with smaller datasets is a longstanding issue in ML/DL. Although it looks like a next-to-impossible mission, our preliminary research shows that appropriately modeled biological and medical insights can mitigate the need for very large sample training data.  In this project, an interdisciplinary team will develop a statistical framework to systematically encode biomedical knowledge in ML models (reducing the required training set), and validate it in cardiovascular diseases (CVD) and neurodevelopmental disorders (NDD). This framework will allow researchers to utilize molecular big data, biological/medical knowledge, and statistical techniques to optimize the complexity of ML models, leading to appropriate models tailoring to specific pathology and sample sizes of a medical genomic data. This project will generate (1) predictors for CVD and NDD with experimental validation; (2) a general framework for other diseases, and (3) theoretical advancement in ML. 

Background: Bleeding is responsible for 30-40% of trauma-associated deaths. Normally, blood coagulates and adheres in wounds to halt bleeding and prevent death from exsanguination. However, during the most severe cases of hemorrhage, blood clots are often slow to form or mechanically weak, and cannot stop bleeding. Therefore, methods to augment hemostatic function are critically needed to prevent hemorrhage-related deaths.

Challenges: The field of hemostatic research is calling for new methodology and paradigm to overcome long-lasting challenges. (1) Fracture mechanics of blood clots remains largely unexplored, despite the close relevance to their function. (2) Blood clots are mechanically weak and vulnerable to failure, whereas existing methods are limited in improving their mechanical properties particularly adhesion and toughness. (3) Blood clotting is slow and the approaches to modulate clotting (e.g., administering coagulants) may involve fatal side effects.

Objectives and methodology: This project is to integrate multidisciplinary approaches to understand and engineer blood clots for hemorrhage management. Our hypothesis is that tough adhesive blood clots will dramatically improve hemostasis and promote healing. Specific objectives include (1) mechanical characterization of toughness and adhesive properties of blood clots; (2) design and refinement of tough adhesive blood clots with incorporated polysaccharide and the design of tough adhesive hydrogels; (3) strategies to control blood clotting rate via click chemistry and cellular engineering. To accomplish these objectives, this project will draw upon the expertise of leading researchers in mechanical engineering, biomaterials, hemostasis, and bioengineering. The resulting technologies are expected to promote hemostasis by enabling rapid formation of tough adhesive blood clots and preventing clot lysis and rebleeding.

Novelty and significance: This project will bring new methodology and state-of-the-art technologies into hemostatic research. It is fundamentally different from current research paradigms. This project will uncover new biomechanics of blood clots and bleeding, as the fracture mechanics of clots is not well understood. The short-term outcome will be the development of next-generation hemostatic technologies for treating severe bleeding and the long-term outcome is expected to be reduced death and related complications from uncontrolled bleeding in Canada and abroad.

Of all the scientific discoveries of the past few decades, one of the most promising — and surprising — is that of topological materials. What makes a topological material so special is that the shape of its quantum wavefunction completely determines useful properties such as its ability to transmit electrical or optical signals. Because of this, details worrisome to the engineer such as material imperfections have virtually no effect on physical properties, with obvious technological applications. Our understanding of these materials, celebrated in 2016's Nobel Prize in Physics, has been made possible through mathematics: in particular, through topology, the "science of shape".

The link between topology and physics is best understood for perfectly crystalline materials, the standard paradigm of condensed matter physics. Because of its perfect regularity, the wavefunction in a crystalline material can be easily computed, and its shape classified according to various numbers, "topological invariants". This yields a “periodic table” of crystalline topological materials. By contrast, the topological properties of strongly non-crystalline materials such as glasses and quasicrystals remain largely unknown, and for good reason: the absence of crystallinity turns the topological classification of wavefunctions into an intractable mathematical problem.

We plan to employ specialized tools from algebraic geometry and topology, yet to be exploited in condensed matter physics, to develop a profound generalization of the standard theory of crystalline materials – higher-genus band theory – which will allow us to discover radically new classes of topological materials. The key idea of our proposal is to replace crystalline lattices by hyperbolic lattices, introduced to popular culture by M.C. Escher’s intriguing patterns of interlocking motifs, whose number grows and size decreases without bound as they approach a bounding circle. We believe such lattices, which we will design and synthesize in the laboratory using nanofabrication techniques, hold the promise of generating entirely new kinds of topological invariants and physical phenomena beyond those currently predicted and observed in conventional, crystalline materials.

Based on a unique synergy between pure mathematics, physics, and nanotechnology, we plan to discover the next generation of topological materials for disruptive applications to energy-efficient technology and high-speed information transfer.

Glioblastoma is the most aggressive form of brain cancer with a survival rate of less than 5% beyond 5 years. Glioblastoma cells (GBM) can leave the tumor and infiltrate into the surrounding brain tissue, which is the main cause of treatment failure. Those cells are protected from chemotherapeutic drugs because of the blood brain barrier, whereas current radiotherapy treatments are limited due to the poor tolerance of the brain to radiation. To overcome those limitations, we are developing a cell trap composed of a porous hydrogel containing nanoparticles loaded with the chemoattractant CXCL12. This device is designed to promote a controlled release of CXCL12 that aims to attract and trap the cancer cells prior to irradiation. However, in order to optimize the trap, there is a need to develop a model that takes into account the parameters that can influence significantly the release of the chemoattractant such as the brain fluid flow. Hence, the overall aim of this project is to assess the robustness and optimize this novel GBM trap under in vitro simulated brain fluid flow. To achieve this goal, our multidisciplinary team will use a unique perfusion bioreactor, which can mimic the flow dynamics found in the brain parenchyma. The project has three main objectives. In the first objective, we will investigate and model mathematically the impact of simulated brain fluid flow on the release profile of CXCL12 from the hydrogel. This objective will provide crucial information to fine-tune the device. In the second objective, we will evaluate the effect of simulated brain fluid flow on the capacity of the device to retain GBM by monitoring their behavior and motility within the hydrogel. In the third objective, we will finally evaluate the suitability of localized irradiation to promote the death of GBM trapped within the device. This project is highly innovative as it uses an in vitro dynamic culture system to simulate the brain flow properties. It will increase our knowledge of the contribution of fluid transport in the brain for the fine-tuning of a drug delivery system, while considerably reducing animal testing. This project is an essential milestone for the development of this unconventional, yet highly ingenious therapeutic approach. In the end, the optimized device could reduce the deleterious impact of current treatments on brain functions, which would result in better patient outcomes and significant economic benefits for the healthcare system. 

Neglected tropical diseases (NTDs) due to parasitic infections are chronic, debilitating, and poverty-promoting maladies. Current treatments are failing due to the spread of resistant strains, high host toxicity, and lack of suitability for rural health systems. Among NTDs, pathogenic trypanosomatids T. cruzi (Chagas disease), Leishmania spp. and T. brucei (Human African Trypanosomiasis) are responsible for the most dramatic figures.

The gravity of the NTD situation necessitates a new mindset to provide effective therapy. Armed by new biomedical technology and a collaborative approach designed to seize upon new leads and new strategies for target validation, we propose to focus on two fundamental objectives: 1) identification of new points of intervention for therapeutic discovery. Employing promising prototypes as probes, we will characterize primary and secondary targets, binding patterns, modes of action and mechanisms of drug resistance. 2) Targeting vital parasite functions with novel molecules, we will pursue new agents to disrupt glycosome and ribosome function. Novel drugs against resistant NTDs will be developed with enhanced potential to improve potency, selectivity and drug-like properties.

Our interdisciplinary team is strategically composed of international leaders in the fields of chemistry, molecular and medical parasitology, and structural biology.  To identify and target novel points of intervention, our team has mastery of state-of-the-art approaches, including unique CRISPR-based pathway screening, ground-breaking in vitro and in vivo models, NG proteomics, RNA-mRNA foot printing, single particle cryo-EM methods to discover the molecular details underlying death or survival, whole-genome approaches for the discovery of drug resistance mechanisms, and in-house peptide and small molecule leads.

This program represents a first in-kind international effort to curtail the threat of resistant life-threatening parasites. Our fusion of medical chemistry, structural biology and parasitology offers a novel foundation for training highly qualified personnel in the identification and targeting of new points of intervention against parasites.  Fueled by our individual track records for success and our promising collaborative results, our team is positioned to pioneer discovery of new intellectual property, original tactics for controlling parasitic infection and novel therapy to relieve the socioeconomic burden of neglected tropical diseases.

Obesity and associated insulin resistance pose a significant global health threat. In addition to risks of cardiovascular disease and type 2 diabetes, obesity-associated insulin resistance leads to suboptimal vaccine responses and increased risks of severe infections and cancer. We and others recently showed that cells of the immune system express the insulin receptor (InsR), and can become insulin resistant during obesity ( Tsai et al, Cell Metabolism 2018).  Using a murine model of T cell-intrinsic insulin resistance (Lck Cre+ Insrfl/fl), we observed that InsR-deficient T cells present with metabolic defects that result in incapacitated antigen-specific immunity against severe influenza infection. Based on these findings, we hypothesize that a similar, insulin resistance-associated immune and metabolic defect contributes to increased risk of cancer, and that targeting immune cell metabolism with chemical modulators can improve vaccination-induced protection against cancer in the obese, insulin-resistant population.

Objectives:

I. Delineate the impact of insulin resistance on T cell-mediated anti-tumor response. Using Lck Cre Insrfl/fl mice, we will establish acute and chronic tumor models to test the impact of T cell-intrinsic insulin resistance on anti-tumor immunity.

II. Identify novel immunotherapeutic agents through metabolic screening. We will employ Seahorse extracellular flux (XF) metabolic analyzer (Agilent Technologies)-based metabolic screening of compound libraries to identify novel compounds capable of enhancing T cell metabolism and function.

III. Harness cellular metabolism to improve anti-tumor T cell responses. Select hits from Aim II will be tested in in vivo tumor Antigen-specific immunotherapy models.

XF-based drug screening has been used by industry for drug discovery aimed at blunting tumor cell metabolism; it has not been applied towards immune adjuvant screening.  Yet, increasing evidence emphasizes the importance of unleashing anti-tumor immune responses in the fight against cancer.  Our proposed project combines cell metabolism, drug screening, and tumor immunology research, to identify potential new drugs that can act as positive immune adjuvants and to provide a foundation for future metabolism-based antigen-specific immunotherapy design. As such, this is a high risk venture with immense potential rewards relevant across fields of cancer, infectious diseases, autoimmunity and diabetes/metabolism research.

Improving independence and quality of life for older adults can be realized by complementing human care with robotic assistive technologies. Social robots, defined as robots with a goal of providing assistance to human users through social interaction, are promising in their potential to support aging in place, and promote the cognitive health of older adults. A recent systematic review of controlled trials analyzing the impact of social robots on the well-being of older adults suggests that social robots can improve nine quality of life outcomes, including reducing loneliness, stress and anxiety. Despite these benefits, the adoption of robotics in older adult populations remains low due to concerns about technical readiness, user benefits, and immediate and long-term ethical and social impacts.

There is tremendous opportunity for innovation in the field of social robotics, as we are currently at a critical crossroad: though several technically advanced solutions already exist, including some commercially available products, new interdisciplinary development and implementation strategies are needed to improve on existing platforms and deliver “real world ready” social robots with older adult-specific functionality and emotional alignment. Recent advances in affective computing and artificial intelligence demonstrate that integrating emotionally-responsive algorithms into existing technology can lead to measurable benefits in a laboratory environment. Here we will build on these successes and integrate them into a co-design process for social robot applications that brings together expertise in health sciences, sociology, computer science, robotics engineering as well as lived experience.

The specific goal of the SOcial Co-creation of Robotic Aging TEchnologieS (SOCRATES) project is to create and test a holistic approach to social robot development that addresses key adoption barriers using an interdisciplinary, co-design methodology. Through two research aims, the SOCRATES project will involve the development of an affective social robot solutions specifically tailored to older adult needs and emotions, and will yield an evidence-based blueprint for effective and ethical technology co-creation. An innovative knowledge exchange platform will build on these deliverables and serve to ignite a conversation about the future of social robotics.

Background: Unhealthy food/brand marketing adversely affects children’s diet quality and health. In the digital age, marketers are increasingly leveraging the combined power of artificial intelligence (AI) and digital media to market unhealthy foods/brands to children in a manner that makes it difficult for children to discern their commercial intent. By contrast, researchers continue to manually audit the food industry’s marketing tactics. This failure to leverage AI precludes understanding the full extent and nature of unhealthy food/brand marketing to children on digital media, and optimal child-protective policies. Objectives: We will develop and validate the first AI system capable of comprehensively assessing the extent and nature of food/brand marketing on digital media. The AI system will subsequently be applied to assess differences in the extent and nature of digital food/brand marketing from pre- to post-implementation of new federal legislation that will prohibit marketing unhealthy foods/brands to children, and to quantify policy adherence and effectiveness. Methods: Application programming interfaces (APIs) will extract food/brand marketing data from text, images, videos and games from Canadian websites, mobile gaming applications and YouTube videos, and will classify food healthfulness. Newly developed machine learning models will determine whether marketing targets children and use of 10 marketing strategies. Domain experts will guide what the AI system should identify and conduct performance validation of the AI system. T-tests and Chi-Square tests will assess differences in frequency and proportion of unhealthy and healthy food/brand marketing that does and does not target children (extent of marketing), and proportionate use of 10 marketing strategies (nature of marketing), between 6 months pre- and 6 months post-policy. Policy adherence will be assessed according to Health Canada criteria. Significance: Development and application of this AI system will support healthy dietary behaviours in all Canadian children by providing the first evidence of the full extent and nature of unhealthy food/brand marketing to children on digital media, and the role of policy in reducing these exposures. Given the impending legislation, there is a narrow window of opportunity in which to build this AI system. The AI system will render manual audits obsolete, thereby requiring a major transformation of research paradigms and skill sets within this field.

Every year, numerous individuals develop the morbid condition of sepsis, which refers to the presence of a serious infection by a specific bacteria that correlates with systemic and uncontrolled immune activation. Patients die as a result of organ failure, as the disease elicits an exacerbated and damaging immune response. As an example, infections by N. meningitidis alone are responsible for about 380,000 death/year worldwide and are known for afflicting numerous patients with sequels such as amputation and motor/visual deficiencies. One of the most used assays in sepsis diagnosis is a positive blood culture. However, this diagnosis tool has its limitations because of the delay in the time for results, and positive blood cultures are not present in a majority of cases. To address these challenges, we propose the development of a rapid, and sensitive detection platform, for the rapid development of a tool to measure a variety of biomarkers associated with sepsis. We want to use a novel mm-size biodetector using graphene, in combination with a carefully-designed 2D molecular layer covering its surface, as the active layer in a transistor device. Differently than conventional graphene-based biodetectors, our device relies on a truly-novel 2D molecular transduction mechanism that imparts the capability of detecting individual binding events when a certain biological target attaches to an aptamer-functionalized 2D layer over graphene's surface. Such a tool could, via future clinical studies beyond this proposal, greatly facilitate the early diagnosis of sepsis, reduce the total cost of treatment (ca. 25 B$ in 2007 for the USA), and lead to improved patient outcomes. In particular, the platform nature of the proposed technology will allow us to detect not only human markers for sepsis, but also bacterial markers that will allow us to simultaneously detect the infectious agent.

Distributed acoustic sensing (DAS) is an emerging technology that uses fiber-optic cables for continuous monitoring of small, transient deformations of the Earth (seismic waves). Although geo-hazard monitoring via DAS is in its infancy, outstanding potential exists for monitoring applications with profound and wide-reaching impact. Here, we propose to deploy a DAS system with novel experimental design that is suited to monitoring of volcanoes and slopes prone to landslides. This research will create uniquely comprehensive data in a challenging environment, as well as new knowledge about complex natural hazard systems, DAS experiment design and data analysis in seismology. The system will be deployed on Mt. Meager, BC, a recently reawakened volcano that poses significant hazard concerns for the BC lower mainland but lacks seismic monitoring. This volcanic system also represents one of the highest-quality potential geothermal sites in Canada. A 4-km fiber-optic cable, configured to provide ~800 seismic sensors, will be deployed in a grid on both glacial ice and bedrock. The glacier provides unusually effective coupling by diurnal freezing. Additionally, augering will be used to install sensors in 3 spatial dimensions for improved seismic-signal resolution. While field installation and acquisition are novel and challenging, we expect to harvest an extremely rich, unprecedented data set with excellent research potential. The high sensor density overcomes the sparse-sampling limitation of traditional seismology, resulting in an unprecedented data set that will be openly available to the international community. Both seismic signals from earthquakes (including volcanic tremors) and ambient seismic noise will be considered as signals in these data. The ambient seismic noise field has been shown to contain information about Earth processes and how these processes interact. Therefore, our research will lead to new knowledge about volcanoes, slope stability, glaciers, how these complex systems interact, and new real-time monitoring technology. The research will lead to a better understanding of natural hazards and improved, informed approaches to mitigation. Potential areas of application include transportation corridors, energy infrastructure, recreation areas and communities exposed to unstable slopes.

The current focus of photovoltaics (PV) research is to develop materials that lead to superior efficiencies at a fraction of the present cost, in order to make PV modules deployment competitive in the energy market. Perovskites have recently emerged as the only viable low-cost, solution-processed candidates able to synergistically supplement crystalline Silicon solar cells, potentially reaching >30% efficiency. However, the practical deployment of 3D perovskites-based solar cells is hindered due to their reliance on Pb as their metallic core, and their inherent instability within 100 hours of operation. The main objective of our proposed research program is to simultaneously address these two challenges in an ambitious interdisciplinary approach. We will employ the 2D version of the structure, which utilizes larger hydrophobic organic cations that can act as barriers to chemical degradation and defect propagation, but they also act as insulating spacers. Our ultimate aim is to develop highly efficient, eco-friendly 2D perovskite solar cells with regenerative capabilities resulting in long-term stability.

2D perovskite structures need to be vertically oriented to allow free charge transport along the conductive layers, unobstructed by the insulating organic spacers.  There have been no reliable large-scale deposition methods reported to obtain homogeneously oriented 2D perovskite structures. Our proposed research program has three cohesive directions:

(1) Meniscus-guided deposition: We plan to engineer vertically-oriented, 2D structures that are ideal for free charge transport from one electrode of the solar cell to the other. (2) Design of organic cations: We will experiment with organic molecules that have bending and self-repair capabilities to markedly prolong the lifetimes of the solar cells. (3) Pb-free solar cells: We will design highly efficient stable Pb-free solar structures, which will bring the technology closer to commercial feasibility.

The majority of research in the field is targeted towards perfecting existing structures. However, the present strategy of incremental progress has not led to feasible solar cells. We are proposing a distinctive, innovative approach that will allow us to construct low-cost solar cells that are simultaneously efficient, chemically and mechanically stable, and environmentally friendly. This would be a game changer in the PV industry and will lead to much-needed deployment of solar modules around the world.

Today, state-of-the-art Li-ion batteries are being used in electric vehicles, despite the fact they fail to meet the long-term objectives from automotive companies. More alarmingly, Li-ion batteries fall well short of requirements for grid-scale storage capable of supporting intermittent renewable energy sources such as solar and wind. This is one of the key issues limiting the use of intermittent renewables.

In this interdisciplinary work, high-throughput experimental techniques will be combined with computer modeling in order to dramatically accelerate the design of all-solid batteries; an important emerging battery technology being targeted for grid storage. The primary challenge relates to the development of the solid electrolyte, for which a number of properties – ionic conductivity, electrochemical stability at electrodes and mechanical stability during electrochemical cycling – must all be optimized simultaneously. A number of promising candidates for the solid electrolytes have been identified including Li5.55La3Zr2Ga0.15O12, Li1.3Al0.3Ti0.7(PO4)3, and Li0.34La0.51TiO2.94. These candidates all have complex compositions that can be varied to change materials properties, but this has not been explored to any appreciable extent due to the very high number of possible compositions. The daunting task of examining such complex systems systematically only becomes possible with high-throughput experimentation such as that being developed by the McCalla group. In systems, where to date only a few samples have been studied, the McCalla group aims to make and characterize 6000 in the context of this proposal. The vast quantities of data produced in the high-throughput experiments will be utilized to further accelerate materials discovery with data-driven computational techniques developed in the Khaliullin group. Large-scale simulations augmented with modern machine learning methods will be employed to perform statistical analysis of the data and suggest improved experimental strategies for designing better materials.

Tackling the severe challenges in accelerated screening of advanced batteries is more than worth the potential pay-off in this high-risk/high-reward project given the vital importance of supporting intermittent renewables on the grid scale. The synergy between experiment and computation here will be game-changing in allowing the development of novel battery chemistries at an unprecedented rate.

In a job interview one might be asked, “why are you the best person for the job?” This is notably important with surgeons given that the safety of others is at stake. To better answer this, our project examines how psychological and physiological factors extensively described in research relate to a person's ability to learn surgical skills or their surgical trainability. The objectives of this project are guided by three research questions:

RQ1. How are psychological and physiological factors associated with surgical trainability?

RQ2. To what extent is there an association between psychological factors and surgical trainability?

RQ3. How do psychological and physiological factors influence change in surgical trainability?

In this experimental study, we will recruit medical students and have them complete a number of different personality tests. They will then be asked to complete a surgical task three times; twice supervised by an expert and once without guidance. While completing these tasks they will be recorded, their eye motions will be tracked, and their heart rates continuously monitored. Their performance will be scored using a checklist and global rating scale, and then analyzed to see if there are certain factors that give learners an ‘edge’ at learning surgery. This 'edge' will be measured as both how well they perform, as well as how well they receive feedback (i.e. change due to it).

For this project three types of measures will be used:

1. Psychological inventories (independent variables)

a. The Big Three Perfectionism Scale

b. Saucer’s Big Five-Mini Markers

d. The Resiliency Scale for Young Adults

e. Coping Inventory for Stressful Situations

2. Physiological Response (independent variables)

a. Eye-gaze metrics

b. Heart rate monitoring

3. Surgical Trainability (dependent variables)

a. Surgical performance

i. Procedure-specific checklist

ii. Ottawa Surgical Competence Operating Room Evaluation

b. Feedback receptiveness

Our study brings together an interdisciplinary team of psychologists, educators, computer scientists and surgeons to explore, for the first time, the relationship between psychological and physiological factors on surgical trainability. An understanding of these relationships may be used to enhance selection, improve learning, and ultimately impact the quality of patient care. Should these results hold promise, they may be extrapolated to any discipline.

A substantial shift in the Canadian labour market – including rising automation and digitization of jobs, increased exposure to precarious work, and growing employment in the gig and sharing economies – poses new challenges for young people seeking sustainable employment. These challenges are exacerbated among young people living with disabilities who are persistently excluded from the labour market and more likely to report underemployment and lost productivity. There is a critical need to ensure that young people with disabilities are able to meet the challenges of a changing labour market and take advantage of potential opportunities. There is also a need for research to inform the design of future-proofing strategies that can be implemented in the present to minimize shocks of the changing labour market.

Objectives are to: 1) Examine the work experiences of young people with disabilities including perceptions regarding the role of current and future labour market conditions on employment; 2) Analyze the landscape of policies and programs that support work participation, and the extent to which they are meeting the labour market needs of young people with disabilities; 3) Examine anticipated changes to the nature of work from diverse perspectives; 4) Determine opportunities and challenges that the changing nature of work poses for young people with disabilities; 5) Develop concrete recommendations to future-proof young people with disabilities.

We apply a novel strategic foresight approach to facilitate future-focused thinking to four research steps. First, we will hold focus groups with young people with disabilities to obtain insights on current and changing work conditions, and the ability to find and sustain employment. Second, we will conduct an environmental scan of existing policies and programs that support the employment of young people with disabilities. Third, we will interview employers, policymakers, educators and social innovators regarding expected changes to the labour market. Fourth, drawing on the previous steps, we will hold a strategic foresight session to obtain diverse perspectives regarding the future of work and its impact on young people with disabilities, and design future-proofing strategies for different settings.

We bring together a transdisciplinary team to develop a comprehensive picture of the positive and negative impacts of the future of work, new research directions, and innovative future-proofing strategies.

Le système de santé au Québec fait face à une augmentation accrue des besoins en soins gérontologiques due au vieillissement de la population. Parmi ces besoins en croissance, ceux liés à la démence de type d’Alzheimer (DTA) et au déclin de la qualité de vie de ces patients et de leurs proches sont particulièrement importants.  Les manifestations d’angoisse et d’agressivité observées chez plusieurs patients ont un effet significatif sur le niveau de soins requis et ont des répercussions sévères sur les personnes atteintes, leur famille, et les proches aidants.  Il a été démonté que la contemplation occasionnelle de paysages naturels est favorable à la santé et l’intellect des humains. Des chercheurs ont observé que ce contact avec la nature favorise la réduction du stress, et que la seule vue d’arbres à partir d’une chambre d’hôpital peut significativement réduire les périodes d’hospitalisation et la prise de médicaments contre la douleur après une chirurgie, et avoir des effets positifs sur des désordres psychiatriques et émotionnels, voire sur les symptômes reliés à une maladie neurodégénérative telle que la DTA.  Considérant que les patients atteints de DTA (stade avancé) manquent généralement de contact avec la nature causé par des limitations dans les capacités de déplacement, et qu’un contact accru serait bénéfique, le projet vise à utiliser des technologies actuelles en immersion virtuelle pour pallier cet état de déconnexion avec la nature et le vivant  et ainsi améliorer confort et qualité de vie des patients. L’objectif principal est donc double : développer une application de visite virtuelle immersive d’environnements forestiers naturels, et tester (mesures expérimentales) si cet outil novateur en réalité virtuelle a un effet thérapeutique sur les symptômes reliés à la DTA. Les objectifs spécifiques  sont en lien avec le développement / défi technologique de l’application de visite virtuelle immersive innovante avec les mesures expérimentales des effets qu’aura l’application sur la population cible (DTA, stade avancé). Ces objectifs prennent en compte que l’expérience de réalité virtuelle doit répondre à des critères spécifiques et composer avec plusieurs contraintes, que ce soit en rapport avec la modélisation ou en rapport avec les limitations cognitives ou physiques des personnes avec DTA.

Biodiversity is increasingly threatened as large areas of tropical forest are lost or modified, leading to increasing shared use of resources between humans and animals. The resulting increased human-wildlife interaction can have benefits, such as increased human appreciation of nature, but also carries costs to both humans and wildlife resulting from crop-raiding and increased potential for disease transmission. OBJECTIVE: Examine the nature of human-wildlife interaction using a bio-geo-cultural approach to understand the causes and consequences of perceived differences in the benefits and costs of human-wildlife interaction. METHODS: Relying on both new and existing collaborations, this research focuses on the people and primates in and around the Lewa Conservancy, a large protected area in southern Kenya, and two villages on the shores of Lake Nabugabo in neighbouring Uganda. All sites are affected by crop-raiding of small sustenance agricultural plots, with some farmers resorting to chasing, trapping and relocating, poisoning, and/or killing problem animals. However, the sites vary in the degree to which farmers are tolerant to crop-raiding, as well as in the level of direct and indirect benefits from researcher presence. To understand why people perceive human-wildlife interactions differently, especially the damage and consumption of agricultural foods by primates (i.e., crop-raiding), the proposed study will focus on bridging 1) traditional biological approaches to studying animal behaviour (e.g., scan sampling, non-invasive physiological monitoring, camera-traps), 2) geographical methods for studying animal and human land use (e.g., GIS with GPS-generated layers for animal movement, locations of schools, healthcare, and clean water, and Landsat layers for habitat characterisation), and 3) anthropological methods for studying humans (e.g., surveys to examine variation in culture and wealth). IMPACT: There is a pressing need to develop conservation strategies in response to growing human populations, shrinking habitats, and declining in wildlife populations.  Through the integration of traditional bio-geo-cultural disciplinary boundaries, this international collaboration will lead to improved understanding of the social and ecological contexts of human-wildlife interactions, which is critical to the implementation of successful conservation strategies for animals and adequate protections for humans. 

Between 2008-18, the number of biomedical engineering jobs, the third fastest-growing job sector according to the US Bureau of Labor Statistics, increased by 72% due to the surge in aging population and demand for new medical technologies. Like in many other fields, Additive Manufacturing has found its applications in the biomedical field in what is currently recognized as a subfield termed ‘3D Bioprinting’. However, major challenges have to be overcome in order to achieve success in the 3D bioprinting of soft tissue, which supports and surrounds other structures or organs and is clearly distinguishable from hard tissue such as bone.

A special category of soft tissue, such as brain and lung tissues, has a low stiffness < 10 kPa, hence termed ‘super soft’. These materials proved to be integral components in many biomedical applications and are considered perfect candidates for future research in tissue engineering and regenerative medicine. Due to their exceptionally low stiffness, they tend to collapse or deform during the printing process under their own weight. In order to circumvent this challenge, we can utilize ‘simulated zero gravity’ environment to alleviate the gravitational forces on the deposited scaffolds. This limitation complicates the process of building vascular networks to support the 3D printed structures. For tissue regeneration to occur, the simultaneous growth of a vascular network is required for mass transfer of nutrients, blood, and oxygen.

This new frontier research project is dedicated to studying the ‘simulated zero-gravity’ 3D bioprinting of super soft materials for tissue engineering and regenerative medicine. The main research challenges relate to our four themes: (i) Biomedical – To develop rigorous tests to evaluate the biological organization and functions within the 3D bioprinted materials. (ii) Engineering – To develop a 3D bioprinter for super soft materials capable of producing vascular networks. (iii) Ethics/social science – Investigating potential ethical and social implications of integrating bioprinted materials into human bodies, including questions of cognitive enhancement, human dignity, and social justice. (iv) Legal/intellectual property – To investigate the legal status or characterization of the 3D bioprinted material.

During human development, different genes are either “expressed” (used to make protein) or “silenced” (not used). Correct gene expression is essential for the right proteins to be produced at the right time, ensuring normal development. Control of gene expression is mediated in part by a chemical modification called “DNA methylation”. Some DNA methylation is added during embryonic development, but other DNA methylation is inherited from the mother or father. These patches of inherited DNA methylation are called “imprints” and regulate developmentally important genes.

Imprints are essential for normal development, and loss of imprints is a frequent feature of human disease. One in six hundred pregnancies is a “molar pregnancy”: a disorganized mass of placental cells which sometimes develop into a placental cancer called choriocarcinoma. Loss of maternal imprints is a hallmark of molar pregnancy. Loss of imprints is also frequently observed in other cancers and is linked to cancer’s rapid division. Until recently however, it was essentially impossible to add or remove imprints. We could observe the destructive impact of imprint loss in the context of complex diseases, but we could not start from healthy cells and figure out how each imprint ensures normal placental development and prevents the development of cancer. The objective of this research will be to identify which imprints are responsible for normal placental development and how they control cell division.

Dr. Pastor’s lab will use new techniques to generate placental stem cells that lack imprints. He will then use these cells to identify which imprints could be important for controlling cell division and for the formation of different types of placental cells. Dr. Serge McGraw’s lab uses technology to add or remove imprints individual, allowing us to confirm the role of these imprints in placental stem cells. Dr. Rima Slim is a leading expert on molar pregnancy who will help validate the findings in molar cells. This project employs a variety of new techniques and has the potential to rapidly and dramatically expand our understanding of the role of imprinting in human development and in preventing cancer.

Comment l’impression 3D peut-elle participer au développement durable? Afin de répondre à cette question, ce projet inédit a pour objectif général de repenser et de redéfinir le paradigme de fabrication d’objet en impression 3D ainsi que des préconceptions liées à la production et à la gestion des Résidus Industriels Forestiers (RIF, i.e. boue papetière et la cendre de bois). L’équipe interdisciplinaire de ce projet s’engage dans la réalisation des objectifs spécifiques suivants aux frontières des arts et du génie: 1) la création et la valorisation de biomatériaux nouveaux à base de RIF; 2) la reconceptualisation et le redésign d’imprimante 3D adaptée à ces nouvelles formes de matérialité à base de RIF; et 3) la création d’une œuvre inédite porteuse d’une réflexion écologique intégrant de nouveaux biomatériaux imprimés 3D fabriqués à base de RIF.

Le recyclage, l’impression et la valorisation des RIF nécessitent une approche de recherche interdisciplinaire qui s’appuie sur le partage d’expertises réunissant les arts, le génie des matériaux et le génie mécanique. Le design-thinking, une démarche pour systématiser l’innovation, permettra de relever le défi en croisant les approches de recherche-création en arts et de recherche expérimentale en génie. La recherche-création comprend la reconceptualisation des savoirs et savoir-faire d’impression 3D dans leur relation à l’art écologique et l’éco-esthétique de la mise en forme à la mise en exposition d’une œuvre. L’approche de recherche expérimentale comprend les différentes étapes de fabrication et d’impression d’objet en tenant compte des exigences structurelles, esthétiques et environnementales des disciplines des arts et génies. Elle comprend: la caractérisation des entrants (RIF et autres additifs), l’adaptation des outils d’impression 3D, l’optimisation des paramètres de fabrication, la caractérisation des prototypes et de l’œuvre produite.

Ce projet est à notre connaissance unique au Canada et dans le monde. Il appelle un changement de paradigme important en impression 3D dans le recyclage et la valorisation des RIF et promet un haut rendement interdisciplinaire: 1) en renouvelant les méthodes, technologies et démarches artistiques de fabrication d’objet en impression 3D; 2) en apportant une solution concrète et nouvelle à la production et à la gestion des RIF; et 3) en ouvrant de nouvelles perspectives socioéconomiques en impression 3D dans les secteurs des arts et de l’industrie de la construction.

The cost of fall-related injuries of older Canadians is over $2 billion per year. After a fall, regardless of fracture occurrence, individuals decrease their activity level, become socially isolated and are more likely to require residential care but men and women may experience this differently. Using a multi-disciplinary approach the proposed research will examine the complex interaction of physical impairment together with confidence related to mobility to better understand the mechanisms governing walking balance.  We will first focus on the population of stroke which is representative of a complex chronic disease with motor and cognitive challenges, and where outcomes following rehabilitation remain poor; falls occur in as many as 73% of people who regain the ability to walk after stroke; notably, people with stroke are 2–4 times more likely to fracture a hip when they fall.

Canadian Stroke Best Practices guidelines urge tasks that progressively increase challenge during rehabilitation. However, there are no objective measures to guide clinical decisions around treatment dose and intensity as it pertains to either the perceptual or actual difficulty of walking tasks. This is in sharp contrast to the retraining of endurance for which there are established measures such as heart rate to provide a metric for progressive approaches to training. Our interdisciplinary team of researchers in rehabilitation science, engineering and psychology, together with clinicians and people with stroke will develop innovative personalized rehabilitation approaches to mobility rehabilitation that will reduce falls and fractures.  This research will:

• Develop clinically useful wearable sensor technology that can measure how challenging a balance task is. This technology will provide feedback on the physical challenge (biomechanically), physical responses (e.g., balance reaction responses), together with physiological measures such as anxiety or fear of falling.

• Determine how confidence and perception of challenge impact motor control strategies and the rate of re-learning of walking.

• Using self-efficacy informed models of change in behaviour we will develop an algorithm that can determine the optimal challenge point for rehabilitation for individuals.

The proposed research will significantly advance data driven and personalized rehabilitation interventions to restore walking, balance and decrease falls in people at high risk for falls and fractures.

Cancer immunotherapies have shown great promise but remain ineffective against solid tumors due to transport barriers that prevent immunotherapeutic and cytotoxic (cancer killing) immune cells from accumulating in tumors. Transport obstacles are even more pronounced in brain and central nervous system cancers due to the blood brain barrier (BBB), which prevents transport into the brain. Glioblastoma (GBM), the most common brain cancer, has a 100% recurrence rate with median survival of only 15 months, creating an urgent need for effective treatments.

To overcome transport barriers, we will immunoengineer the brain with intracranial implants that release immune active molecules and cells by combining our expertise in materials science and cancer immunotherapy. The implants will be non-swelling, non-fouling hydrogels and hydrogel-nanoparticle composites designed to match the brain’s mechanical properties, which will prevent unwanted interactions with brain tissue and minimize pressure-induced toxicity. Directly in the brain, the hydrogel delivery vehicles will sustain the release of a bi-specific T cell engager (BiTE) and expand cytotoxic T cells. The BiTE will selectively bind GBM cells and recruit cytotoxic T cells to initiate tumor killing. Expansion of cancer killing T cells in the brain will be achieved by incorporating nanoparticles that act as artificial antigen presenting cells to mimic natural T cell expansion mechanisms. Nanoparticle shape, size and ligand density will be screened to achieve maximum activity. The BiTE will be released over several weeks to maximize the duration and magnitude of the anti-cancer response. Beyond GBM, the developed non-immunogenic materials and nanotechnology will be suitable for the safe delivery of cells and biologics for chronic diseases such as diabetes, stroke and other cancers.

Accessibility to new cancer treatments is limited by their high financial burden, potentially fatal side effects and high frequency of medical interventions, which increases patient anxiety and lowers quality of life. Local delivery will minimize systemic drug concentrations to prevent side effects. Our strategy will also decrease required dosages and medical intervention frequencies due to the local and sustained nature of delivery. Beyond improving cancer treatment efficacies, our treatment will improve mental health and quality of life by improving patient accessibility and mitigating stress from frequent appointments.

To feed a growing world population, we need to develop plant varieties that are more productive and resilient to environmental changes. Recent advances in gene editing have a huge potential to boost crop yield, by modifying plant reproduction and growth. While the genetic basis of development is extensively studied, our understanding of how gene activities control organ shape and size is still limited. Recent advances show that organ geometry emerges from the interplay between genes, hormones and physical constraints.

Flowers are critical for plant reproduction and provide a good model of plant growth. Male floral organs (stamens) are composed of a long filament supporting the anther, which contains pollen. As pollen matures in the anther, the filament elongates quickly, doubling in size each day. This fast growth pushes the anther forward, either to release pollen outside of the floral corolla or to reach the tip of the female organ during self-pollination.

Several genes are known to affect filament length and anther shape. However, the growth patterns leading to stamen morphology are completely unknown, because developing male organs are hidden inside the floral bud. Using Arabidopsis thaliana as a model system, we aim to dissect the development of stamens to understand how fine-tuning of developmental processes and mechanical constraints regulate their morphology. Our main objectives are: (1) Uncovering developmental patterns and physical processes underlying stamen shape and size; (2) Understanding how the very fast growth of filaments is regulated by molecular, mechanical, and environmental factors. We will use an interdisciplinary approach, combining advanced live microscopy, 3D image analysis, genetics, and physics-based computer simulations. For the first time, we will measure the growth of individual cells and the dynamic distribution of molecular markers in developing stamens. Using microscopy data as a template for simulations, we will compute mechanical forces within developing organs. By comparing growth, the distribution of molecular regulators of development with physical forces, we will elaborate an integrated model of stamen development. This project will help understand how stamen and pistil growth are synchronized for pollination and how it is affected by temperature. This knowledge will provide a fundamental background for crop improvement.

Canada is melting like an ice cream left on the counter and the built structures have been sinking into the thawing ground. Northern infrastructure was originally designed to rely on the properties of ice-rich frozen soil for stability. However, due to climate change, old design assumptions are no longer valid. The stability of built structures has been severely compromised by recent changes in permafrost thickness, making the current designs untenable. This calls for immediate and sound remedial actions in terms of design paradigms and rehabilitation programs.

The main objective of this research project is to develop innovative and fast-breaking solutions to predict and enhance the structural integrity of existing critical infrastructure in permafrost areas under different climate warming scenarios. In this novel approach, we will (1) develop a new geo-mechanical predictive model including the coupled effects of deformation rate and temperature change on ice-rich foundation soils subjected to permafrost degradation; (2) develop a new portal for monitoring the deformation of critical infrastructure such as embankments or railway lines as well as future construction sites in permafrost areas by integrating an innovative artificial intelligence technique involving deep learning based computer vision remote sensing framework; (3) calibrate the new geo-mechanical model by developing a deep neural network based inverse technique to optimize the model’s parameters using a pattern recognition dataset; (4) use a range of climate scenarios to predict permafrost degradation at different time intervals, and its effect on the structural integrity of civil infrastructure in Northern Canada; (5) provide climate change mitigation and adaptation strategies over the lifecycle of northern infrastructure.

The created web page will be available publically to increase public’s and stakeholders’ awareness of the adverse impacts of climate warming. The portal will provide mainly the state-of-the-art of the stability of critical northern infrastructure.

The proposed interdisciplinary research is a radical departure from what is currently done or what others have tried to tackle the adverse effects of climate warming on northern infrastructure.

The greatest reward of the proposed research is safety and reducing the vulnerability of aboriginal and northern communities to climate change.

Objective and vision:

Our proposal aims to develop a novel strategy that can revolutionize liquid biopsy. Imagine the future – taking a drug right before a blood test that helps to take a molecular snapshot of any tissue, resulting in a more accurate clinical diagnosis of health and disease.

Background and challenge:

Liquid biopsies are samples of body fluid that provide easy and quick access to disease screening and monitoring. However, the effectiveness of liquid biopsies relies on detection of unique biomarkers, which is an area of ongoing research. Some of the most promising biomarker-carriers are exosomes, a special class of nano-scaled extracellular vesicles (EVs). Exosomes (1) contain a molecular snapshot of their cellular origin; (2) are secreted by all tissues cell types and; (3) are in high concentration in body fluids. However, quantifying exosomes specific to diseases is extremely challenging. Not only are disease exosomes a small fraction of all EVs in body fluid, the lack of unique biomarkers also makes it challenging to specifically isolate disease exosomes. Hence, isolating tissue-specific exosomes is the Holy Grail in liquid biopsy.

Approach:

We have devised a “Trojan horse” strategy to specifically label disease exosomes. Using a Trojan molecular tag delivered into cells that targets exosome biogenesis pathways, we can tag only exosome and no other EVs, hence achieving exosome-specific tagging. Delivering Trojan tag specifically to disease cells will produce disease exosomes tagged with our special marker. In this way, only disease exosomes will contain our highly specific molecular tag (using peptide nucleic acid), which can be subsequently purified by affinity-based methods. This strategy does not rely on the existence of any specific endogenous biomarkers, but introduces highly unique tags to the target exosomes.

Novelty and significance:

We approach exosome isolation via a totally different strategy from conventional methods. Instead of post-purification-labelling, we tag exosomes as they are made. This strategy will significantly increase the purity and certainty of isolated exosomes to those of disease origin and no other EVs, which will substantially improve the sensitivity and specificity of disease diagnosis. This interdisciplinary collaboration requires an understanding of fundamental cell biology, development of chemical biology tags, and bioengineering of isolation devices utilizing the new tags.

Conotoxins are peptide natural products produced by marine snails that inhibit voltage gated ion channels and have been recently approved as analgesics to treat chronic pain in humans.  While all of the known natural targets for conotoxins are eukaryotic membrane-embedded ion channels, these ubiquitous transport proteins share significant sequence and structural homology with prokaryotic (bacterial) ions channels, suggesting that the latter group of enzymes could also potentially be targeted by conotoxins.  Interestingly, recent research has shown that bacterial cells growing within biofilms utilize potassium voltage gated ion channels to synchronize cell division rates, improve fitness of the colony, and to attract free-swimming planktonic cells to incorporate into the growing biofilm.  Thus, through the inhibition of these potassium gated ion channels, conotoxins may serve as a novel means to manipulate the dispersion and growth of biofilms, which often contribute to chronic human infections that resist traditional antibiotic treatments.  The proposed research will involve the use of mRNA display techniques to generate libraries of conopeptides that differ in their disulfide bonded topologies.  The disulfide topology of conotoxins is known to correlate with ion channel specificity and pharmacological properties.  These engineered conotoxin libraries will then be panned against a panel of ion channel proteins derived from biomedically-relevant bacterial species in order to identify tightly binding toxins with species selectivity. Since the interaction between conotoxins and bacterial ion channels has never before been reported, any hits derived by these screens will be thoroughly characterized with biophysical techniques to deduce molecular details and structure-function relationships.   Following the discovery of the best hits, live cell fluorescence imaging will be performed on bacterial biofilms in order to study the effects of the conotoxins on biofilm growth dynamics, dispersal, and the recruitment of new cells.  If successful, these studies could help to establish a platform for the evolution of selective peptidic inhibitors for the treatment of bacterial biofilms – a pathological state that currently has limited treatment options and that contributes significantly to human mortality and to the emergence of antimicrobial resistance.

Recent advances in virtual reality (VR) offer novel opportunities for rehabilitating cognitive impairments. The development of VR interventions that accurately simulate the real world could not only enhance cognitive abilities in individuals with brain disorders, but also promote generalization to everyday functioning. Cognition is critical as it is the mental process by which individuals think, understand and learn. Yet cognitive deficits remain largely untreated in standard care.

We propose to develop a novel adaptable intervention to treat cognitive impairments using VR, based on synergistic computer science and psychology approaches. We will first develop this project in schizophrenia, since nearly 100% of patients experience a loss of cognitive function. However, cognitive losses are observed in many other brain disorders, thus our findings have the potential of transforming care for a broad population.

AIM 1: We will design a novel semi-supervised machine learning solution to fuse sensor data and classify psychophysiological state related to user’s cognitive effort.

AIM 2: In collaboration with patients, clinicians and researchers, we will create VR training modules that represent “real-world” situations (e.g., grocery shopping, learning a new job), are adaptable based on the user’s cognitive effort and focus on strategies to improve common cognitive deficits in brain disorders (e.g., attention, memory).

AIM 3: We will test the efficacy of the VR intervention. 64 individuals with schizophrenia spectrum disorder will be randomized to either 6 weeks of personalized VR cognitive training, or active control condition where patients will play commercial VR puzzle games. The primary outcome will be the improvement in general cognitive performance on the standardized battery. The secondary outcomes will be the improvement in cognitive performance on specific tests and in everyday functioning. We will perform subgroups analyses to investigate the potential sex and gender differences on outcomes.

Our interdisciplinary team includes expertise in all relevant aspects of this project: machine learning, sensors, VR, cognitive psychology, schizophrenia, and psychiatry. The convergence of these fields offers a unique and unexplored approach to treat cognitive impairment. This study has the potential to transform the treatments offered and to have an impact on patients’ lives by reducing cognitive impairment in schizophrenia and other brain disorders.

In the past decade, immunotherapies have revolutionized cancer treatments. These breakthrough therapeutic strategies, called immune checkpoint inhibitors, block specific protein-protein interactions between cancer cells and immune cells, influencing the immune system’s ability to recognize and eliminate tumors. The initial success of immune checkpoint targeting has prompted extensive interest in exploring additional mechanisms by which cancer cells evade immune detection.

Beyond cell-surface proteins, cancers also use complex carbohydrates, or glycans, to modulate immune responses. Tumor cells have a different “sugar coating” than normal cells and many have increased surface levels of sialic acid. This hypersialylation enhances immunoevasion through interactions of sialylated glycans on tumors with glycan-binding protein receptors on immune cells. While the capacity of glycans to suppress immune cell function is now recognized, there is an absence of methods to identify, synthesize and study these complex glycan structures. Thus, our understanding of the function of glycans for immune checkpoint regulation has been greatly hindered, impeding the design of novel immunotherapies targeting this entirely distinct class of macromolecules.

The current proposal will address this deficiency through a new partnership between Dr. Capicciotti (Chemistry), an expert in glycan synthesis and chemical glycobiology, and Dr. Ormiston (Medicine), an expert in immune cell function and its relation to human disease. We will develop a high-throughput screening platform to examine the impact of specific sialylated glycan structures on tumor cell recognition and lysis by a subset of immune cells known as natural killer (NK) cells. Glycan structures will be synthesized and installed on tumor cell lines using a novel cell-surface glyco-engineering strategy. This will allow us to identify the precise structures that optimally promote NK cell inhibition and thus function to enhance tumour immunoevasion.

This interdisciplinary project will overcome major limitations in uncovering the glycan structures involved in tumor immunosuppression. It will elucidate currently unknown mechanisms of how cancer evades the immune system, driving the development of novel therapeutic strategies that are urgently needed to target aggressive cancers. Our methodology can also be applied to deepen our knowledge of glycan-mediated interactions involved in the regulation of other immune cell types.

Contaminated water and long-term boil orders are an ongoing challenge in remote First Nation communities.

Our objective is to develop solar driven, point-of-use photochemical water treatment devices for remote communities, based on broad spectrum absorbing black titanium dioxide nanowire membranes (bTiO2 NWMs). These devices will use energy up-conversion (UC) bTiO2 NWs to generate powerful oxidants capable of removing organic contaminants while degrading biological pathogens.

Research Approach

We will construct lanthanide or carbon quantum dot-doped bTiO2 NWs and study their up-conversion capabilities. Subsequently, we will fabricate membranes with the composites, and evaluate their efficacy in purifying contaminated water using several model pollutants (e.g., organic dyes, pesticide residues and bacteria), before field testing units in a local First Nation community. Nanowires have unique advantages in possessing large light absorbing surface areas with short charge diffusion distance to the surface (small wire radii) to minimize charge recombination and maximize efficiency. They are also amenable to formation of membranes through interweaving, thus facilitating their real-world applications such as filters.

Significance

Novel aspects include the development of UC bTiO2 NWs useful for water treatment. Conventional bTiO2 narrow bandgap greatly facilitates light adsorption but only generates low energy electron-hole pairs with limited applicability. However, by forming composite materials, bTiO2 NWs can be used to pump energy into neighbouring materials, exploiting the up-conversion mechanism. As long as a sufficient junction potential exists at the interface to prevent charge recombination between the materials, high energy electron-hole pairs would be generated from low energy radiation, which can subsequently be used for water treatment and many other applications. Additionally, bTiO2 NW broad-spectrum absorbance would allow for the harvesting of waste heat (infrared) for various applications and for augmenting or replacing visible light-driven water treatment during night or poor weather.

The lack of moving parts and low maintenance costs of the water-treatment devices make them readily deployed in areas where more complex water treatment systems are prone to fail due to need for local expertise to operate and maintain. The simplicity of UC bTiO2 NW membrane device may facilitate positive community health, economic, and social outcomes.

OBJECTIVES: Our recent work with Jeff Wrana and others show that cellular reprogramming is highly heterogeneous. We found that in a reprogramming population of genetically identical cells some elite cells exhibit thousand-fold higher reprogramming potential than the population average. In addition we established that early epigenetic variability might allow emergence of these elite cells.

This observation opens up a possibility of designing an optimal protocol for reprogramming, and fully harness its potential for providing a new therapeutic paradigm. To this end we will target two major objectives:

(1) Reveal the key gene regulators that propel elite cell lineages to pluripotency.

(2) Quantify and model the epigenetic-space of non-elite lineages to identify genes that limit reprogramming potential.

RESEARCH APPROACH: We hypothesize that elite cells transition via specific sequence of gene expression changes, an epigenetic reprogramming highway, which allows rapid and deterministic transition from a differentiated cell to a pluripotent cell. Such deterministic transitions are the norm for cell fate transition in a developing embryo.

To identify the key genes that propel cells onto the reprogramming highways, we will utilize single-cell RNA sequencing along with genetic barcodes to track elite lineages. We will then map out the gene expression changes in elite cell lineages using their single-cell RNA profile at different time points. The genes that change significantly in expression levels will be modeled as a stochastic process to classify them into key regulators versus slave genes.

Unlike elite cells that are poised to get on a reprogramming highway, we suspect that a non-elite cell searches through the high-dimensional gene-expression (epigenetic) space for a reprogramming highway to successfully transition. Using single cell profiles of non-elite cells we will quantify the search-statistics of these cells and utilize dynamical modeling to identify genes that delay reprogramming.

NOVELTY AND SIGNIFICANCE: This work will provide a new paradigm for understanding the cellular reprogramming, and reveal key genes that orchestrate reprogramming. Our proposal promises a novel experimental and mathematical framework for understanding cellular transitions more broadly, and opens new frontiers in cell-fate engineering and subsequently regenerative medicine.

Background & Research Objectives: This research program involves a high-risk and high-reward approach to identify new therapeutics to diminish the burden of antimicrobial resistance. Specifically, we are taking an unconventional and unexplored tactic: inhibiting bacterial host cell adhesion. The clinical need for new therapeutics is unprecedented; we are experiencing a global antibiotic resistance crisis that has threatened our ability to treat infections. Tackling this crisis requires the development of avant-garde therapies that mitigate the limitations of traditional antibacterial chemotherapy.

One approach is the attenuation of bacterial virulence to disarm a pathogens infectious capability without impacting growth. This research program is centered on the adhesin subset of virulence factors in methicillin-resistant Staphylococcus aureus (MRSA). We hypothesize interfering with adhesion will form the basis of an effective and novel class of therapeutics. We have developed an innovative high-throughput assay to quantify the adhesion of MRSA to the surface of host cells. Using this assay, we have performed the first genome-wide assessment of the genetic determinants involved in MRSA host cell adhesion. This provides a platform for the objectives described in this proposal. Objective 1 involves an interdisciplinary drug discovery campaign to identify inhibitors of MRSA host cell adhesion. Objective 2 is to investigate the in vivo efficacy of anti-adhesive targets in preclinical models of infection. Anti-adhesive inhibitor mechanism of action studies are described in Objective 3 and we will assess genetic determinants and inhibitors of adhesion in S. aureus clinical isolates in Objective 4. Overall, this research program will provide preclinical substantiation of anti-adhesive targets and inhibitors. We anticipate that our findings will be ripe for translation into therapeutically useful treatments.  

Innovation and Impact: Traditional approaches to control bacterial infections have focused on the inhibition of growth, which selects for resistance. Antibiotic use significantly contributes to the resistance crisis. It is estimated that 2% of Canadians are treated with antibiotics each day and medical care associated with antibiotic resistance cost Canadians ~$1 billion per year. This research will help position Canada at the forefront of alternative therapeutics for the treatment of bacterial infections. 

The Cascadia subduction zone is a 1000 km thrust fault that runs from northern Vancouver Island to northern California. Despite evidence of 13 past large magnitude 8-9 earthquakes in the Cascadia subduction zone (i.e. native oral histories and paleoseismic records), there are no quantitative observations of the intensity of ground shaking during these events. It is estimated that the consequences of a magnitude 9 earthquake in the Cascadia subduction zone could result in losses of $75 billion due to damage to buildings and infrastructure, resulting in hundreds of casualties and thousands of injuries. However, a detailed understanding of the expected shaking is necessary to accurately model its consequences, and to implement measures to minimize its societal impact. This proposal brings together an interdisciplinary team of researchers with the following objectives: (i) to quantify the expected shaking associated with magnitude 8-9 earthquakes in the Cascadia subduction zone, (ii) to understand how the built environment will fare, and (iii) to identify how our communities can better plan for the aftermath of such scenarios.

This research will utilize three-dimensional wave propagation computer simulations to understand ground shaking effects of magnitude 8-9 subduction zone earthquakes in Cascadia. These novel simulations are important because the unique geological conditions of the Cascadia subduction zone prevent a side-by-side comparison between a future Cascadia earthquake and past observations in other parts of the world (e.g. Japan, etc.), which form the basis of the ground motion prediction equations used presently to predict the strength of future ground shaking. The simulated earthquakes will be used to evaluate the response of buildings and infrastructure, the behaviour of liquefiable soils, and the tsunami hazard of the region. These evaluations will be used to assess community response and recovery to enable analysis of risk reduction strategies.

The novelty of this work lies in bringing together different research themes with the shared vision of reducing the catastrophic risk of a Cascadia megathrust earthquake through advanced simulation, as well as adaptive planning across the social, built and natural environments. The impact of this research will help inform policy by enabling the assessment of trade-offs between investments in mitigation, preparedness and response to the hazards posed by large magnitude earthquakes in Cascadia.

Starting from graphene, atomically thin two-dimensional (2D) materials have attracted much interest for their extraordinary physical properties. Besides importance to fundamental physics, these exceptional properties are promising for building the next generation flexible electronics and optoelectronic devices. Here we propose to develop a health monitoring application for these emergent quantum materials.

Our goal is to build a multifunctional flexible sensor based on a tunneling junction made of graphene, TMD, and hBN heterostructures. Under positive bias, the junction is a LED and can emit light in the near infrared (NIR) range. When the bias is reversed, the device becomes a photodetector and can probe the NIR reflectivity of the deep skin, which is related to the local tissue oxygenation level. Therefore, a pair of devices can help diagnose symptoms like ischemia. In parallel, since strain can alter the bandgap of TMDs and accordingly their electrical properties drastically, our device is also an extremely sensitive strain gauge.

An immediate application of our device is for preventing pressure ulcer (PU), a localized injury caused by forces acting on the skin over a long period of contact against a surface. PUs are particularly prevalent among individuals who are bedridden, wheelchair confined, or critically ill, and often lead to severe and debilitating infections. The economic burden of PUs is greater than 4 billion dollars per year in North America alone. We propose to build an array of flexible sensors and lay them underneath the patient. Our devices should be able to accurately map out the pressure and oxygenation distribution in real-time, thus providing timely guidance for repositioning patients, which is essential protection against PUs.

Our quantum enhanced approach is a bold step towards improving device performance and introducing novel functions. Compared with bulk materials, all atoms in 2D materials are confined at the surface/interface, giving rise to exceptional sensitivity. Since 2D materials are mechanically strong and flexible with no toxic or air-unstable ingredients, this architecture can be used in other healthcare applications, such as monitoring and stimulating patients with spinal cord injuries, which was recently identified as a major direction in an interdisciplinary workshop held at UBC. In the long term, our project can become a new platform for building faster, smaller, and more flexible wearable electronic devices.

This research program addresses the following research question: “How is music composition and design used to score landscapes and sacred spaces?” It investigates new forms of site-specific approaches to musical composition using decolonizing methodologies, Indigenous knowledge systems, and land-based methods to create sonic landscapes.

By sonically “remapping” coordinates from various locations, including Indigenous trail marker trees, mound sites, and trade routes this research examines ways to create sonic responses and designs based on these points. Additionally, using the geographic coordinates of sacred sites and the atomic numbers of elements which are currently being mined on traditional Indigenous territories (e.g. metals such as gold, copper, silver), this program explores musical juxtaposition through intersecting traditional knowledge systems, such as the Four Directions teachings and Seven Sacred teachings, and the geographic coordinate system.

This research is guided by exploratory, emergent approaches, including performative practice, embodied methods, decolonizing methods, and music composition. It weaves intersecting, transdisciplinary approaches to guide new forms of music composition, sonic design, and digital soundscaping, which are used to examine the implications for Indigenous expressions of spiritual sovereignty and storytelling through music. These approaches help to guide modes of experimental music creation by visually coordinating forms of soundscaping to create new musical maps of land, territories, and sacred space, resulting in a scored landscape/landscaped score. Utilizing site-specific, land-based methods to “remap” novel concepts of space and spiritual knowledge systems, this research program responds to historical and contemporary social, cultural, economic, and environmental impacts by digitally reclaiming these sites through music and sound.

This research program offers unique opportunities to engage with experimental music creation and production, and ways of teaching and learning about traditional knowledge systems through digital environments. It will also present new ways to decolonize understandings of “mapping,” while reclaiming, reenvisioning, and reimagining Indigenous knowledge systems through music composition, sonic design, and digital soundscaping.

Traumatic brain injury (TBI), especially mild TBI or concussion, is a major health concern for Canadians. One of the hallmark symptoms of patients suffering TBI is cognitive dysfunction. As local neuronal operations and integration of these local functions underlie cognition, a critical question for mild TBI/concussion emerges -- how a blow to the head disrupts intrinsic, and extrinsic, connectivity networks in the brain. We propose a pioneering research program in which we will first use biomechanical modeling to comprehensively predict how the brain’s anatomically distinct elements -- and structural networks -- are affected by traumatic forces. Then, we will conduct mathematical modeling to understand how regional variations affect entire brain function and networks. Finally, we will correlate predicted brain damage to predicted cognitive impairments and network changes.

One novelty of the proposed research is that we will develop a structural-connectivity-inspired biomechanical model. Such a biomechanical model will include hundreds of brain regions, especially axonal fiber bundles and vascular networks that will be coupled to soft brain tissues using a finite element method. Hence, this biomechanical model will have a unique capability to predict how a physical blow to the head delivers local forces/stretches to internal structural networks. With the understanding of local, cellular-level function changes to forces, we will then be able to map out disturbed structural connectivity for the entire brain.

Another novelty is built upon the structural-connectivity-inspired biomechanical model. With the biomechanical model indicating where and how nodes/links of the functional network are affected, we will then use mathematical methods to analyze what these changes mean for functional networks at a hierarchical level.

The proposed research aligns with the program and is focused on developing fundamental, novel mathematical and computational models across multiple disciplinary. Yet, these models integrate closely to help better understand mild TBI/concussion. In the long term, the proposed research will be intrinsically linked with neuroimaging for diagnosing mild TBI/concussions and can be extended to re-engineer brain networks for better recovery from brain trauma, thus promoting interdisciplinary and inter-model collaborations and leading to a high-reward program.           

The proposed research (Qfun) addresses longstanding problems in modern physics, such as “How did the universe evolve at its earliest moments?”, “How is the structure of matter inside neutron stars?” and “Why is there more matter than antimatter?”. To answer these questions, we need to dramatically advance our understanding of fundamental forces between elementary particles. The current paradigm in high energy physics (HEP) to address these problems uses numerical computer simulations that are inherently limited. The above questions cannot even be answered with future supercomputers. New emerging quantum technologies (QT) offer an exciting possibility to defy the current paradigms and to overcome the current roadblocks. Driven by this vision, Qfun will be an exploratory phase of a longer research effort to solve HEP problems with QT. Qfun will build on the first successful demonstration of a quantum simulation of a one-dimensional (1D) HEP model, that has been recognized as a breakthrough in physics in 2016. However, 1D models do not capture the essential physics of fundamental forces of nature, and thus extensions beyond 1D are urgently needed. Qfun will develop the necessary theoretical tools and provide an experimental demonstration of the first HEP quantum simulation beyond 1D using a trapped ion quantum computer. This will be the first quantum simulation with ions in Canada and a milestone for the field of QT. HEP quantum simulations beyond 1D pose outstanding difficulties for QT. To surmount this challenge, modern machine learning methods and artificial intelligence in computer science (CS) will be leveraged and integrated in a conceptually completely new framework of hybrid quantum-classical simulations. These novel tools have the potential for disruptive impact on QT and will find important applications in chemistry (CHEM). In the long run, the use of QT in CHEM can revolutionize the development of batteries, fertilizers, and drugs. Qfun brings together a diverse team of world-renowned experts of four disciplines - HEP, QT, CHEM, and CS. Together, the team members will venture into uncharted territory and define a new research direction with transformative impact for science and society.

Global warming is causing large-scale transformations of the Arctic landscape, including rapid reduction in the extent of permafrost. Permafrost thaw has wide implications for northern ecosystems and the communities who are living in this transitioning landscape. In particular, there are emerging threats to drinking water supplies in Canada’s arctic and subarctic regions because of permafrost thaw. Increasing transfers of organic matter from permafrost to surface waters result in the 'browning' of water. Links between browning of water and cyanobacterial blooms have been reported and suggest that aquatic ecosystem functions and services are at risk due to cascading physical and chemical effects not only to water quality but to the nutritional quality of the associated food webs. Furthermore, mercury (Hg) and pathogens once trapped in permafrost are now released to source water as landscape thaws. The practice of chlorinating water to reduce water-related diseases risks has both biomedical and belief-based problems; potential carcinogenic disinfectant by-products (DBPs) are created from the interaction between chlorine and dissolved organic matter, and communities in the north have differing understandings of how to ensure purity of water and are sceptical of and resistant to implementing chlorination. Current drinking water systems focus on eradicating risks from fecal contamination and are not adequate for treating emerging risks in culturally harmonized way. This trans-disciplinary project aims to investigate and measure emerging risks from threatening compounds and organisms arising from climate change effects on permafrost using an ambitious community-based participatory water quality sampling program in Northern Quebec, Nunavut, and Northwest Territories. Microfluidic tools will be developed from data collected at source water bodies to direct changes in treatment plants, water distribution and storage, and overall water policy in the North. This will lead to enhanced understanding of emerging environmental determinants, and to increased protection of individual and community health. This frontier project will provide new insights into the implications of permafrost thawing for aquatic ecosystem functioning and the access to safe drinking water in the North.

Heart-related diseases rank #1 in worldwide mortality with over 17 millions of deaths in 2016. In Canada, heart diseases are the number one cause of premature death, with about 2.4 millions of Canadian age 20+ live with diagnosed heart disease. From those, a large number, ≈600,000 people, go onto to develop heart failure (failing heart). This number increases by ~50,000/year. Conventional treatments such as drugs or cell therapies do not cure failing hearts, which need specialised healthcare, surgical interventions, and devices that cost $2.8+ billion/year to the Canadian healthcare system. Materials able to conduct electricity in the form of heart patches have proven useful for improving heart function after a heart attack in animal models. However, those “electro-conductive” heart patches are prepared in a non-customized form (i.e. not specific to the shape and size of the area in the heart that needs to heal). This makes them unpractical for use in humans where the damaged parts of the hearts will be different in each patient. In this project, we will use our gained expertise in developing novel light-activated flexible materials and “electro-conductive” fibres to produce the first customizable on-the-spot heart patch. This innovative technology will be a leap forward 3D printing in medicine and in treating failing hearts. It will combine on-the-spot delivery and formation of a heart patch directly on the damaged heart, allowing surgeons to apply the patch directly to the damaged region, independently of its size, shape, and location. Our heart patch will provide a new therapeutic tool for recovering heart function, save thousands of lives in Canada and millions of dollars in healthcare costs.

Current methods of food production are not sustainable because enormous amounts of synthetic fertilizers (mostly nitrogen) are required to grow crops to feed the burgeoning human population. The production of fertilizers is expensive and significantly contributes to greenhouse gases and water pollution. Therefore, this proposal aims to develop first-in-the-world nitrogen-fixing organelles that can replicate and fix atmospheric nitrogen inside eukaryotic recipient cells, such as yeast or plant cells. To achieve this goal, biologists will develop a method for transferring and maintaining whole bacteria in eukaryotic cells; here, the bacteria will serve as the nitrogen-fixing organelle. To speed up the process, engineers and physicists will develop microfluidic devices that will enable observation of the bacterial engulfment by and maintenance process within recipient cells. We will also have an ethics board to examine the ethical, legal and social implications of this project. Our top aims are  1 - Create a rapid screen to monitor prokaryotic cell engulfment by recipient cells; 2 - Screen a yeast mutants to identify the best lines that prolong retention of intact bacterial cells; 3 - Create dependencies required for the survival of both cellular partners.

Research approach. Dr. Karas demonstrated that a living organism could be supported transiently within a surrogate host such as yeast. Based on these observations, we ask whether the propagation of bacterial cells can be extended using yeast Saccharomyces cerevisiae as the surrogate host and Mycoplasma mycoides and Sinorhizobium meliloti as the proposed organelles. M. mycoides will be used as the donor because recently a strain was developed with superior abilities to directly transfer genomes to yeast. S. meliloti, a second donor strain, is a nitrogen-fixing symbiont of legume plants, and Dr. Karas’ team recently developed genetic tools for this species that will allow for easy engineering of this microbe.

Significance. Converting free-living bacteria into symbiotic organelles is an ambitious, but achievable, goal. In nature, such an event has occurred, resulting in the creation of organelles such as mitochondria and chloroplasts. The proposed research will revolutionize how we engineer cells and holds promise for a second green revolution where nitrogen-fixing organelles would replace fertilizers. Moreover, this method will pave the way for developing organelles with other functions.

Given the growing Indigenous demographics and maternal-child health realities, there is a need to better support healthy Indigenous mothers, babies, infants, families and communities. Indigenous maternity experiences research can help identify maternal child health strengths and resilience, as well identify gaps, barriers and needs. By engaging Indigenous women, birth partners and communities, the unique contribution of this research project is the creation of a culturally and contextually relevant Indigenous Maternity Experiences Survey (IMES).

The objectives of this project are: 1) to create a research plan and Indigenous knowledge translation framework by engaging with NWAC to discuss Indigenous women’s maternity experiences information needs, priorities and approaches; 2) hold FOUR engagement sessions (North, South, East & West) through existing NWAC structures (PTMA) to discuss ways to change and/or adapt MES questions to ensure it is culturally and contextually relevant; 3) create an online Indigenous Maternity Experiences Survey (IMES) with findings from the NWAC engagement sessions; 4) pilot the IMES through online engagement with assistance provided by each PTMA; 5) conduct an analysis of the IMES, including a culturally relevant gender-based analysis; and 6) dissemination activities to identify capacity building opportunities and KT strategies for potential Indigenous maternal-child health policy and program development and implementation.

The research approach includes Indigenous research, decolonized methodologies, community based research and quantitative population and public health approaches. The research is community based and driven by Indigenous women associated through the NWAC.

There has never been an Indigenous-created population health survey that specifically looks at Indigenous women’s maternity experiences. Through community based engagement, the research will help to identify maternal child health indicators. This research not only defies current research paradigms, but it proposes unique scientific directions by bringing together Indigenous ways of knowing with population and public health survey research. It is expected that the research will contribute to addressing social and economic marginalization of Indigenous women and maternal child health disparities. 

Breast cancer affects 1 in 8 Canadian women during her lifetime and is the 2nd leading cause of death from cancer in Canadian women. Currently, breast-conserving surgery (BCS) is a good option for women with early-stage breast cancer.  For breast cancer surgery to be successful, the right amount of normal tissue must be excised without leaving cancerous tissue behind. Society of Surgical Oncology and American Society for Radiation Oncology have recently stressed the key role of margins for BCS in consensus guideline. Unfortunately, it is not always obvious and easy to determine the edges of the tumor and currently, intraoperative pathologic methods including frozen section analysis and imprint cytology are time consuming, increased workload for pathologists and cannot be always applied in every hospital.

Biomarker discovery has exploded and combined with the progress in technology, engineering, and materials science, it opens the door for sophisticated sensors to revolutionize cancer surgery by preventing disability or greatly improving the health of persons in ways previously not possible. Electrochemical detection is a promising alternative to provide a fast, specific and low-cost methods to assist surgeons identifying the cancer cells from healthy cells. Further, there is no need to invest in specific infrastructure, or large and complex equipment to make electrochemical detection possible in operating room.

Overall goal is to engineer an electroclick probe for oncological surgeons, to allow a full image of the tumor margins in the operating room preceding incising tissue, instead of having to overestimate the tumor's margins and remove an extra portion of healthy tissue that may compromise the patient’s function.

Acrolein, glutathione and thioredoxin are 3 biomarkers related to oxidative stresses, which are highly produced in cancer cells. We will design a multi-electrochemical probe with functional coatings free of immunocompound that binds acrolein via a "click" reaction and metalloproteins via a direct electron transfer. The amperometric detection will enable to discriminate cancer cells in less than 10s. The probe will be attached to a handheld device that communicates to an external diagnostic computer system via a wireless interface.  This new electrochemical device is a cost-effective alternative to expensive and time-consuming laboratory tests to assist health care personnel with surgical decisions, to limit the rate of tumor recurrence.

Mitochondrial disease is a devastating disorder where fewer than 50% of diagnosed children survive to adulthood. Though often affecting energy demanding organs, like the brain and heart, mitochondrial disease can affect any tissue. As there is no cure, let alone an effective treatment, the most mitochondrial disease patients can hope for is simply a definitive diagnosis. Recently it was discovered that mesenchymal stem cells (MSCs) can deliver healthy mitochondria to cells with mitochondrial dysfunction. Here, we will develop novel a therapeutic approach using MSCs to treat mitochondrial disease.

As little is known about the how and why MSCs deliver mitochondria, we will use high-resolution live-cell imaging and cell biological approaches to study the basic biology underlying this process. In Aim 1, we will explore the signals that MSCs use to recognize potential recipient cells. In Aim 2, we will screen an FDA-approved drug library to identify compounds that increase the MSC mitochondrial delivery. As FDA-approved drugs have already undergone years of safety evaluation, drug repurposing offers the advantage of rapid clinical implementation. Together, these aims will provide novel mechanistic insight that will allow us to improve the ability of MSCs to deliver healthy mitochondria to cells with mitochondrial dysfunction.

Finally, in Aim 3 we will evaluate the clinical safety and efficacy of using MSCs in a mitochondrial disease patient. As MSCs are approved in Canada as a therapeutic for other diseases, they have the potential to be rapidly adopted as a treatment for mitochondrial disease. Notably, we will use a novel method we have developed, which will allow us to measure the transfer of healthy mitochondria to a mitochondrial disease patient.

We have assembled a multidisciplinary team with the requisite basic science expertise in mitochondrial cell biology and drug screening, as well clinical expertise in MSCs and mitochondrial disease. The three interdisciplinary aims spanning Biological Sciences, Basic Medicine and Life Sciences, Medical Biotechnology, and Clinical Medicine will build toward the ultimate goal of developing novel methods to deliver healthy mitochondria to mitochondrial disease patients. Importantly, mitochondrial dysfunction is increasingly recognized as having a role in a growing number of human pathologies (e.g. cardiovascular and neurological diseases), for which MSC-mediated mitochondrial delivery also has therapeutic promise.

The ability to study live cells in intact human tissues has been an elusive, yet critically needed research goal. Using advanced imaging techniques (intravital microscopy) we have been able to study many cellular processes related to inflammation, infection, cancer, and tissue repair in live animals, but we have had difficulties translating these results to humans. To address this, we propose to build and utilize infrastructure that will support the perfusion of resected human tissues within a live cell imaging facility. This approach will allow us to study living, intact, human tissues and to track cellular behaviours and interactions within these samples.

This project brings together a team of experts including surgeons (Shapiro, Beaudry), hepatologists (Coffin, Swain, Gonzalez-Abraldes), perfusionists (Menzies) and cancer researchers (Mahoney).  Additionally, in collaboration with Dr. Zania Stamataki (University of Birmingham), a world leader in ex vivo liver perfusion, we will build for the first time in Canada, a state-of-the art tissue perfusion / imaging program.

Human liver segments will be resected from explants or donor tissue surplus to clinical requirements. Liver segments retain a protective capsule and expose vasculature that is cannulated for continuous perfusion of an acellular hemoglobin-based oxygen carrier at 37oC. This supports viability of hepatocytes, biliary epithelial cells and sinusoidal endothelial cells, delays apoptosis, necrosis and intracellular reactive oxygen species. Hepatocyte cell divisions continue for up to 48 hours following perfusion. Multiple liver segment perfusions are run in parallel using a multi-channel pump to ensure compound comparison to control treatments within the same individual livers.

With this technique, we will assay macrophage function in healthy and a spectrum of diseased liver tissue (alcoholic, non-alcoholic fatty liver disease, viral hepatitis, cancer, cirrhotic). Labelled bacteria and microspheres will be perfused and Kupffer cell function (target capture, phagocytosis) will be compared to results generated in mouse models. Liver segments containing hepatocellular carcinoma will be imaged and the ability of engineered immunomodulatory viruses to infect the cancer and associated tissues will be assessed in living human tissue. For the first time, this novel imaging platform will investigate the complex interplay and behaviours of immune cells in living healthy, and diseased human liver.

Medical MRI (magnetic resonance imaging) is commonly used to image internal parts of the human body for the study and diagnosis of disease. Inhaled magnetized gases produce very strong signals in respiratory MRI, resulting in much better images that uncover otherwise undetectable phenomena. Canada leads the world in the application of this approach. Clinical trials show that it could vastly improve quantitative understanding of the effects and progress of respiratory diseases such as pulmonary cancer, cystic fibrosis, and chronic obstructive pulmonary diseases. It is a promising tool for achieving Precision Health, where optimal treatment is tailored for each patient individually. Unfortunately, current methods for gas magnetization (called hyperpolarization) are technically complex, very costly, and have limited capabilities. These disadvantages hold back the development of magnetized gas medical MRI and its widespread use.

Existing gas magnetization methods use an intermediate agent that is easy to magnetize, which in turn magnetizes the gas. This indirect process is inefficient and involves toxic materials that need to be removed before the gas is administered to a patient, often making use of cryogenics (extremely low temperatures, below -180 Celsius). Currently, about 1 litre of 50% magnetized gas can be produced in one hour.

The proposed research program will pursue a radically new approach for magnetizing gases. It will make use of a novel high-power ultraviolet laser, which will directly magnetize a gas with no intermediate agent. The magnetization rate could be as much as 100 times higher than that of existing methods. Not involving toxic materials, the new method will not require lengthy and costly separation processes or cryogenics. It will greatly increase production rates while considerably reducing operational cost and complexity.

The proposed novel method would remove a bottleneck from magnetized gas medical MRI, thus accelerating the study of disease and the development of Precision Health, as well as making this tool more accessible to physicians. Furthermore, it could permit continuous magnetization of gas as it is supplied to a patient, for continuous observation of respiratory action. A significant amount of magnetized gas atoms could then be carried to other parts of the body via blood circulation. Existing evidence suggests that this could bring the great benefits of magnetized gas MRI to imaging of the brain and kidneys.

Fluids are ubiquitous in nature, whether in the form of gases, liquids, or plasmas. Understanding how they behave is a problem that spans a wide variety of disciplines, from astrophysics to oceanography to aerospace engineering. Unfortunately, although the coupled differential equations governing fluid evolution are easy to write down, solutions to these equations are difficult to obtain for realistic physical systems. Large numerical simulations have therefore played a central role in our understanding.

Unfortunately, these simulations cannot bridge the full range of relevant length scales. Consider galaxy clusters, which are permeated by hot intracluster gas between the galaxies. Microscopically, the viscosity of the gas causes turbulent kinetic energy to be dissipated into heat, which affects the macroscopic thermodynamic balance of the galaxy cluster. This is difficult to simulate numerically ab initio from fundamental principles, because it couples the evolution of scales separated by over nine orders of magnitude. The traditional solution to this problem is to use so-called subgrid models. Essentially, one avoids resolving small-scale physical processes in simulations, instead mimicking them with simplified recipes. It is an open question as to whether such conventional sub-grid models are sufficiently accurate. Such small-scale inaccuracies can permeate to larger scales, rendering an entire simulation invalid.

Our proposed research program aims to replace sub-grid modelling with a new interdisciplinary approach combining physics and machine learning. We leverage the central idea in machine learning of learning by example. We will use small-scale, extremely high-resolution simulations to learn highly expressive models that faithfully capture the essential physics of microphysical processes. This then allows large-scale simulations to be simulated accurately and quickly without resolving the microphysics. We tackle a series of three problems of increasing sophistication: incompressible turbulence, magnetohydrodynamic turbulence, and galaxy cluster cooling.

This project represents the beginning of an ambitious program to replace subgrid models with machine learning more generally. With the former having been a crucial component of simulations for decades, our interdisciplinary work enables a fresh approach to increasing the speed and accuracy of numerical simulations, potentially impacting any field where fluid dynamics play an important role.

Our objective is to genetically engineer better bioethanol-producing yeast cells using a cancer-inspired approach. Success would have profound implications for combating anthropogenic climate change, since cheaper bioethanol would displace more fossil fuel as energy sources. Currently, bioethanol comprises only about 10% of liquid fuels in Canada, where it is produced mainly from corn or wheat, which have significant value as food crops. This limits the competitiveness of bioethanol vs. legacy fossil fuels because corn or wheat feedstocks are themselves not cheap enough. There is longstanding interest in using plant waste biomass as cheap and abundant alternative feedstocks for bioethanol production (i.e., not using food crops), but prior approaches have not yielded bioethanol-producing microbes that are productive enough to disrupt the dominance of fossil fuels.

Our approach is to specifically hypermutate key bioethanol production genes (involved in sugar metabolism, co-fermenting 5- and 6-carbon sugars) by overexpressing the cancer hypermutator enzyme APOBEC3A in yeast cells. APOBEC3A is an enzyme that targets single-strand DNA and routinely creates extensive clusters of many closely spaced mutations in cancers. We will engineer yeast cells to group several bioethanol production genes together, with a specific inducible DNA break site in between. Once we induce a break, cells generate long stretches of single-strand DNA spanning some 20,000 bases on either side of the break. The APOBEC3A will then only hypermutate the bioethanol production genes, since they are close to the break (and single-stranded) but leave the rest of the genome unmutated. We will then screen the hypermutated cell populations for mutant combinations that are especially good at producing bioethanol from processed plant waste biomass.

This will be the first time anyone has attempted to use a cancer hypermutator enzyme as a genetic engineering tool to get better, more productive bioethanol yeasts. We know from cancer genomics that hypermutation can induce all manner of novel characteristics in cancer cells. If we unleash cancer hypermutation (transiently, and only in the lab) in bioethanol yeasts, we will likely create mutant combinations that are superior to existing industrial yeasts. Since bioethanol is essentially carbon-neutral, such an advance would have an important impact for countering anthropogenic climate change, the most pressing problem that humanity currently faces.

Concussion is a common condition that can have a serious impact on health, cognition, and quality of life. However, concussion results in a complex cascade of tissue damage and cellular changes that are still not well understood, and it still has no objective diagnostic or prognostic biomarkers. In this work, we will develop an entirely new paradigm for biomarkers of concussion, and apply it to better understand concussion pathophysiology. This multidisciplinary approach will consist of both technical development and preclinical study.

Technical Development: Magnetic resonance imaging (MRI) is a powerful non-invasive imaging modality that is sensitive to various tissue properties, such as cell shape, size, and composition. However, the signal collected generally depends on multiple tissue properties and only allows measurement of empirical parameters with no direct physiological interpretation. Accordingly, to enable the estimation of physiologically relevant tissue properties such as cell density or damage, we will develop a new MRI acquisition and analysis method where several MRI acquisitions with varied parameters will inform computational models of cell microstructure. This “microstructural MRI” will allow a virtual dissection of the brain, enabling non-invasive characterization of cellular changes after a concussive injury.

Preclinical Study: Animal models provide a mechanism to study tissue damage and recovery after concussion in a controlled setting. However, the pathophysiology of concussion evolves during recovery, and the use of dissections to evaluate tissue damage do not allow observations in the same animals over time. Accordingly, to gain an unprecedented understanding of the cellular changes that occur during concussion recovery, we will perform non-invasive microstructural MRI longitudinally in a mouse model of concussion. To investigate the ability of microstructural MRI to predict outcomes, we will correlate the imaging findings to novel touch-screen based behavioural measures of cognition.

This work will define a new platform for the future investigation of how different genetic and pharmacological interventions affect cellular microstructure and recovery of cognitive function after concussion. This, in turn, will set the stage for translation of these modeling approaches and therapeutic interventions to clinical trials.

Cancer is fundamentally a metabolic disease, a phenomenon originally described in the 1920s (the “Warburg effect”), which has been re-discovered in the last decade (Wishart et al, 2016). This novel interest in the metabolic cancer phenotype has been mainly driven by vastly improved performance of high-throughput metabolomic studies and has generated strong interest in identifying small molecule biomarkers for cancer. Endogenous metabolites that either initiate or sustain tumour growth (“oncometabolites”) were identified for various cancers, including prostate cancer, leukemia, and breast cancer (Wishart et al, 2016). However, these studies were limited to individuals with an existing cancer diagnosis, while an optimal biomarker could identify disease prior to current diagnostic approaches.

Here, we propose an interdisciplinary project combining analytical biochemistry, machine learning and cancer biology to identify early biomarkers for cancer diagnosis. We will use the Canadian Partnership for Tomorrow Project (CPTP) cohort to identify novel biomarkers in pre-diagnostic individuals with hematological, pancreatic cancer and breast cancer. Our approach will use high-throughput metabolomics coupled with a novel machine-learning algorithm to identify potential biomarkers. CPTP has enrolled over 300,000 Canadians and collected blood samples as well as detailed health information in a longitudinal fashion. We have identified over 250 participants that have provided biological samples several months prior to the cancer diagnosis (cancer pooling increases study size). We will perform mass spectrometry-based high-throughput metabolomic measurements of the blood plasma samples of subjects, paired with 250 matched controls, and use novel machine learning algorithms developed in collaboration with Dr. Quaid Morris to identify and quantify putative small molecule biomarkers. We will develop a novel graph-based machine learning algorithm capable of identifying small molecules directly from a MS2 fragment ion spectrum (a challenging currently holding back many metabolomics studies). We will then identify differentially abundant analytes between healthy controls and pre-diagnostic individuals. The identified biomarker signature will then be validated on independent samples using targeted metabolomics in collaboration with Dr. Amy Caudy.

The proper organization of the genome is crucial for the regulation of genes. Despite major advances in understanding how regulatory elements contact genes on the same chromosome (intra-chromosomal) to drive gene expression, inter-chromosomal contacts between different chromosomes have remained elusive. However, these inter-chromosomal contacts represent an important layer of genome organization and gene regulation. They are crucial for development and gene regulation, and they have been implicated in disease. Determining how inter-chromosomal contacts are formed, and how they impact normal and disease states, is critical to better understand the biology and etiology of disease. To yield mechanistic insight into inter-chromosomal contacts, the applicant proposes to address this challenge by using a state-of-the-art systems biology approach. Combining genomic high-throughput techniques, bioinformatics, and confocal super-resolution live-cell imaging (biophysics) will characterize for the first time how inter-chromosomal contacts generate three-dimensional genome organization to control gene transcription programs that are pivotal for development. This novel and unique approach will direct research in the field of inter-chromosomal genome organization towards transformation. Accomplishing the aim to understand how inter-chromosomal contacts organize three-dimensional gene regulation will broaden and replace the current paradigm that these yet unexplored genomic contacts are irrelevant for cellular processes. Altogether, insights gained from these efforts will contribute to the current understanding of genome organization in living cells and explain how hubs of gene regulation are organized between different chromosomes and how they contribute to development and disease pathogenesis.

Dementia is thought to be a major manifestation of cerebrovascular disease: for instance, autopsy studies identify vascular pathology in the majority of patients with dementia (Kalaria et al., 2004). The single most widespread form of brain infarctions are cerebral microinfarcts (CMI) (Smith et al., 2012), but the mechanism by which these tiny infarcts impact cognitive function is not clear (Kapasi and Schneider, 2016). Establishing such a mechanism would require the detection of CMI during life, but since their mean diameter is smaller than achievable resolutions, there is simply no widely available method to directly and reliably image CMI noninvasively. 

Blood vessel imaging using ultrasound has undergone important improvements over the last 10 years. Most recently, a novel technique called ultrafast ultrasound localization microscopy (uULM) improved spatial resolution from hundreds to a few microns (Errico et al., 2015) via the detection of individual microbubbles injected in the blood stream at thousands of frames per second, enabling the generation of anatomical and functional vascular maps of unprecedented resolution that could be used, in principle, to image CMI in vivo in animal models. However, uULM is currently limited to 2D imaging, with a slice thickness of more than 500 microns, hence hindering its capability of detecting small infarcts in complex 3D vascular systems.

Recently, 3D ultrafast ultrasound imaging (UUI) was introduced (Provost et al., 2014), enabling the acquisition of thousands of volumes per second, and it has been leveraged to perform 3D-uULM in phantoms (Heiles et al., Accepted) with isotropic superresolution. Our objective is to translate 3D-uULM toward in vivo use in the rodent brain for the detection and quantification of microinfarcts:

SA1) Develop and optimize sequences and image formation algorithms enabling reliable and repeatable 3D uULM for the mapping of the volumetric vasculature of the rodent brain with a micrometric resolution.

SA2) Establish the minimum emboly size detectable by 3D-uULM using a fluorescent microsphere-based microocclusions rat model and a validation paradigm based on automated serial two-photon microscopy.

The world is becoming increasingly urban. More than half of the people today live in urban areas, and this is expected to grow to ~70% by 2050. Rural to urban migration (RUM) has been an integral part of this process, and central to theories of long-run economic growth. This transformation of economies has potentially dramatic yet poorly understood consequences for the environment and human health. First, as workers depart for greater opportunities in cities, the rural workforce previously engaged in planting, weeding, and harvesting, shrinks, thus promoting more mechanized and pesticide-intensive agriculture. Further, as small landholders leave, remaining agricultural land either consolidates into fewer, larger farms or transitions to natural habitat. These land use changes have potentially important repercussions for biodiversity and greenhouse gas emissions. Second, rural-urban migration leads further to a concentration of people, and potentially also pollution in cities with important implications for human health. Third, RUM is closely related to economic development leading to higher incomes, better economic opportunities for women, and therefore often lower human fertility rates. While higher incomes support more consumption per capita implying higher greenhouse gas emissions, lower fertility has the opposite effect at the population level. The net effects on greenhouse gas emissions and other environmental impacts are unclear, and still unexplored.

Understanding the implications of RUM is an inherently interdisciplinary problem, requiring insights from disparate fields. The multidimensional and multidisciplinary complexity of this challenge has thus far stymied holistic understanding of the environmental impacts of this globally relevant process. We propose to address this shortfall using new data and innovative, interdisciplinary approaches. We will evaluate the environmental impact of RUM in both the short- and in the long-term by combining household survey and census data with spatially explicit environmental data on air pollution, biodiversity and land-use change. We will explore new data sources from citizen science, satellite images, mobile phone records and social media to address general data shortages in developing countries. RUM will continue to transform economies. Understanding the environmental implications is the premise for policies to protect biodiversity, ecosystems, the climate and human health.

Like other Indigenous peoples of British Columbia, the Secwepemc have rich and diverse knowledge systems which include a variety of medicinal plant preparations and uses. However, studies of medicinal plants that profoundly engage Indigenous knowledge and maintain control of their use within the Indigenous communities are rare. Through close consultation and dialogue with the Secwepemc community, we propose to collaboratively characterize medicinal plants in interdisciplinary ways that clearly benefit Indigenous communities.

Toward this goal, we propose the following:

1) Secwepemc community elders, healers, and other knowledge keepers will be invited to participate in local, multi-site “screens-to-nature” workshops to introduce laboratory techniques and test bioactivities of medicinal plants whose identities are blinded to university researchers. “Report-back” workshops will be performed to review data, discuss what we have learned, and plan next steps.

2) Extracts from blinded Secwepemc medicinal plants plus others within the public realm will be assessed in the laboratory for efficacy against HIV, influenza, and other pathogens, among other bioactivities. Potent antiviral extracts will be characterized for detailed molecular mechanisms of action.

3) Extracts from Secwepemc and other medicinal plants will be fractionated and purified in the laboratory to identify bioactive chemical compounds.

Importantly, no Indigenous knowledge will be disclosed to university researchers during this process, as this is not required for the proposed study.

One challenge toward achieving these goals is the under-representation of Indigenous highly-qualified personnel with both community trust and self-sufficient research skills in anthropology, biology, and chemistry. This project will therefore be undertaken by recruited Indigenous postgraduate students and Secwepemc community members. The resulting training and mentorship will enable postgraduates and other knowledge keepers to independently pursue detailed studies on Indigenous medicinal plants without disclosing proprietary community information.

Results of this project will significantly advance ethical and sustainable work on Indigenous plant medicines and our mutual desire for productive community engagement, interdisciplinary study, and research excellence, while also contributing to building Indigenous community resilience and truth and reconciliation efforts.

Context:

Climate change and the loss of sea ice are creating new opportunities for vessel traffic in Arctic Canada. Traffic through the Northwest Passage has tripled over the past decade, and will continue to increase as cargo ships, cruise vessels, and pleasure craft are drawn to the region. A major challenge to the safe and sustainable development of Arctic shipping is the sparse instrument network for tracking vessels, and for reporting weather, ocean, and ice conditions. Small, mobile research labs are one tool that can help solve this problem: labs with a primary purpose to support natural science research could be outfitted and positioned to also support vessel operations. In turn, more ships in the Arctic means more potential platforms to enhance natural science research, a timely opportunity given challenges facing Canada’s fleet of research ships.

Objectives:

1.) Interview vessel operators to determine their needs for weather, ice, and ocean observations for safe and efficient operation in the Arctic.

2.) Conduct proof-of-concept testing for a mobile research station in Cambridge Bay, in support of marine biogeochemical  research.

3.) Use interview results, and experiences from the mobile lab testing, to modify lab operation and demonstrate support for vessel traffic.

4.) Interview marine scientists and vessel operators to identify the needs and possibilities for using commercial vessels for marine science.

Research Approach:

The PI and co-applicant are leads of the Canadian Arctic Shipping and Transportation Network (CASTnet), a University-led Industry/Government/Community Partnership. CASTnet has industry-wide support, and interested partners include ship and cruise tourism operators in Canada. CASTnet will provide the connections needed to engage with these industries. A mobile research lab has been built and installed (https://vimeo.com/264678242), and funds from this grant will be used to study its operation in support of shipping and natural science research.

Novelty/Significance:

This research project will combine social science and natural science approaches to determine needs of vessel operators and marine scientists.  The outcome will be identification and demonstration of mutually beneficial solutions to two major issues facing the Arctic: the lack of observational networks to support safe shipping, and the lack of research vessels to support marine science.

Bacteria derived from marine environments are excellent sources of new therapeutic agents, such as antibiotic, anti-cancer and anti-infective drugs. Currently, the most important step in discovering these new compounds is the isolation of bacteria from their natural habitats and culturing in standard laboratories. However, only 1% of bacteria from the environment can be cultured and grown in standard laboratory conditions as the physiological conditions of the bacteria’s natural habitat required for successful growth and metabolite synthesis is difficult to mimic in the laboratory. The remaining 99% of bacteria are “uncultivable” in these conditions and are lost. Thus, there is enormous untapped potential for drug candidate discovery from the vast numbers of “uncultivable” marine bacteria.

In this project, a ground-breaking technology will be developed to enable single-step growth and isolation of new bacteria from marine environment that have, thus far, resisted attempts to domesticate:

1) The bacteria samples will be isolated from branches of ocean octocorals;

2) Single isolated bacterial cells will be encapsulated in micro-beads using engineered microfluidic techniques. Each single-cell encapsulating micro-bead will act as a pure culture colony forming unit. A wide range of microfluidic chip designs and biomaterials will be tested to achieve optimal growth;

3) The micro-beads are in turn placed inside a growth chamber (uMDPod) that can be inserted back into the marine environment from which the bacteria originated. The chambers will be fabricated to have the capability to be inserted, non-invasively, and allow diffusion of nutrients and molecules across the surface area while preventing migration of bacteria cells;

4) After a period of pre-determined cultivation, the growth chambers will be collected and the bacterial colonies retrieved and isolated bacteria will be identified by phylogenetic analysis.

It is expected that the technology developed from this project will allow researchers to defy conventional microbiological practices by harnessing natural ocean environments as a laboratory for single step growth and isolation of previously “uncultivable” marine bacterial species and from which novel bioactives that may be used as anti-cancer or anti-infective drugs will be isolated and characterized.

Glaciers are melting at an alarming rate. The Canadian Arctic Archipelago (CAA) is a hotspot for such melting, and the resulting meltwater enters marine ecosystems in this region. We aim to understand the effects of glacial meltwater on CAA marine ecosystems including the humans they support. We propose a three-pronged interdisciplinary approach: 1) conduct unprecedented, high risk in-situ surveys of glacial meltwater and proximate ocean physics, chemistry and biology throughout an annual cycle; 2) develop and apply novel molecular assessments, based on plankton protein expression, to understand the impact of glacial meltwater on biological productivity; and 3) document and leverage indigenous knowledge of timing and locations of glacially-driven increases in marine productivity. In contrast to the current paradigm, we contend that different physical mechanisms are simultaneously occurring, with varying importance for ecosystem productivity at different times of the year, and that there are other biological mechanisms involving complex planktonic responses to glacier-driven changes that also play a key role. We will collaborate with the northern Inuit Hamlet of Grise Fiord to design a sampling plan and make small boat-based measurements of meltwater-ocean interactions along transects emanating from glacier termini into the ocean in all seasons. We will pair this with novel protein-based assessments of planktonic community responses to glacial meltwater. Such assessments are powerful but technically challenging, often taking years to develop and validate. Here we propose a new unproven method involving microcosm manipulations, performed in the field, that simulate glacial meltwater-driven chemical changes in surface ocean plankton. Combining these unprecedented oceanographic measurements and novel field-based molecular assessments with indigenous community perspectives will provide unique views into the role of glacier melt in sustaining Arctic marine ecosystems and the humans that depend on them. Our study region is located in the traditional hunting grounds for the citizens of Grise Fiord; the community is committed to the co-consideration of scientific and indigenous knowledge to better understand climate change impacts on the ecosystems that they depend upon. Through this collaboration, we aim to develop best practices that will empower Northern communities to direct and participate in assessing, understanding and adapting to environmental change.

Bacteriophages (phages), viruses that infect bacteria, were discovered over 100 years ago. The techniques used to detect new phages have hardly changed since, and are reliant on detection of their host’s death. This results in a bias where only the most virulent of viruses are noticed, instead of the plentiful viral ‘dark matter’ whose impact on their hosts is likely far less pernicious. Even among phages that can kill their host, we know of several alternative phage-host interaction outcomes: e.g. lysogeny, pseudolysogeny, continuous filamentous phage production.  An illustrative case is the discovery of crAssphage, present in 40% of humans and with abundances reaching a staggering 3% of gut metagenomic reads. Despite a concerted global effort to identify a host for this phage, it took four years. The reason? In liquid media crAssphage doesn’t result in detectable lysis.

With interdisciplinary collaborators in biochemistry, chemical engineering, and a company involved in microfluidic nanoparticle analysis, I will exploit three conserved features of phages to detect and enumerate them independently of host-cell lysis.

1. Phages exist extracellularly as ~100 nm-scale particles. As such, they cannot be directly detected using visible light. Advances in microfluidics and nanoparticle detection have resulted in technologies that can size and count particles in solution electrically, based on resistive pulse sensing as the particles pass through a channel.

2. Regardless of the eventual fate of the cell, phages must replicate their genetic material inside. A shift in genetic content should be measurable using C0T analysis, an annealing-based method for assessing the complexity of a genome, or by techniques aimed at quantifying the number of replication forks/rate of DNA synthesis.

3. Phages must place a metabolic burden on their host. By continuous camera monitoring of plate-based microcolony assays, paired with image analysis to generate bacterial growth curves based on integrated density, I aim to create a high-throughput manner to detect dose-dependent growth defects (up to and including lysis) in cells exposed to phages.

Independently or in combination, I expect these approaches to allow for the discovery of viruses undetectable through traditional means, and help shift the field of phage biology away from its cell-death centric dogma.

Changes in the expression levels of RNA and protein molecules characterize a large number of human diseases. Monitoring these changes can help clinicians make a diagnosis, select treatment, and monitor efficacy. Unfortunately, gene expression analysis can currently only be performed in centralized hospitals but not in any point-of-care settings such as local clinics, remote regions, and developing countries. This is because the equipment used to measure RNA levels and the computational algorithms that are needed to analyze the resulting high-dimensional dataset remain overly costly and complicated to operate at these settings. Simple and cost-efficient approaches to perform gene expression analysis will revolutionize medical practice at the point-of-care and greatly empower personalized medicine.

The long-term goal of this project is to replace the resources needed for comprehensive gene expression analysis with a “molecular computer”, operating autonomously in solution. Such a molecular computer can be arrayed onto low-cost, solid-state substrates such as paper, and upon activation, convert complex molecular expression signatures into a an easy-to-read diagnostic signal (e.g., colored patterns). This is a highly ambitious yet immensely rewarding goal, as realizing this vision will generate a new class of diagnostics that combine the analytical power of microarrays with the operating simplicity of a pregnancy test strip. The focus of this project will be to demonstrate the critical proof-of-principle that both detection and analysis of multi-gene expression patterns can be integrated into a single workflow. This will be achieved using a set of nucleic acid-regulated synthetic gene circuits as the core technology. This technology integrates cutting-edge expertise from three disciplines, namely DNA nanotechnology, synthetic biology, and computer science, to construct a system of molecular sensors that compute logic through programmed gene expression. In the proposed plan, the project will first train an in silico gene classification algorithm and demonstrate that the building blocks of this algorithm can be mapped onto a set of synthetic gene circuits, establishing the basic molecular computing framework. The second aim will apply this framework to assemble and optimize the full synthetic gene circuit. Finally, the project will test the ability of the trained gene circuit to implement the gene classification algorithm by diagnosing RNA samples.

In the late nineteenth century, Crown land grants to the Esquimalt & Nanaimo Railway (E&N) transformed a large area of unceded and collectively held Indigenous territory into one of the largest stretches of private land in British Columbia. Much of this land, which makes up approximately 20 percent of Vancouver Island, is now owned by public sector pension plans as private forest lands. The E&N lands are subject to treaty negotiations between the Crown and two Indigenous groups, the Hul’qumi’num Treaty Group and the Hupacasath First Nation. Though private land is officially excluded from the B.C. treaty process, Indigenous communities continue to assert claims to the E&N lands.

This project digs into the entanglement of private, state, and Indigenous interests in the E&N lands and their natural resources. It engages with Indigenous law in order to understand and elevate articulations of Indigenous rights and jurisdiction in relation to paradoxically unceded yet private land. We seek to: 1) clarify the content of Aboriginal title and Indigenous property rights that endure alongside fee simple in Canada; 2) contribute to the development of collaborative governance models for the exercise of Indigenous jurisdiction on private forest lands, and; 3) support B.C. Treaty negotiations through the development of scholarship and policy recommendations regarding Indigenous jurisdiction on private property.

To achieve our goals, we will: (1) work with communities to research Indigenous law in accordance with Indigenous and local legal methodologies, and; (2) facilitate collaborative workshops with Indigenous communities to develop frameworks for the governance of private B.C. forest lands. The research team includes: Estair Van Wagner, an expert in property law, resource governance, and place-based research; Sarah Morales, a Hul'qumi'num legal scholar and member of the Indigenous Law Research Unit; Michael Ekers, a geographer and an established voice on the political economy of B.C. forest lands, and; Robert Morales, a Hul'qumi'num lawyer and Chief Negotiator for the Hul'qumi'num Treaty Group.

The project responds to pressing land use issues by developing theoretical and practical frameworks to address the relationship between Indigenous legal orders and private property, and in doing so, to reimagine B.C's property relations.

BACKGROUND: Commonly referred to a ‘fracking’, unconventional oil and gas production involves the use of directional drilling and injection of large amounts of fluid into wells to extract oil and gas. Controversies over the health impacts of this process remain. 

OBJECTIVES: We propose to undertake a comprehensive assessment of fracking on human reproduction and child health/development in Alberta.

1. To determine the association between fracking and reproductive outcomes

2. To assess the impact of fracking on child health outcomes

3. To investigate the impact of fracking on child development

4. To explore the regulatory framework for locating fracking operations

METHODS: Publicly available geographic data on the location of all fracking locations in Alberta will be obtained from the Alberta Energy Regulator, while data on reproductive/child health outcomes and residential location will be obtained from Alberta Health and Alberta Health Services. For Aims 1 and 2, a difference-in-differences study design will be used to examine the impact of fracking on reproductive outcomes and child health. Outcomes before and after the introduction of fracking in affected communities and similar communities where fracking never occurred will be assessed, permitting us to calculate the proportion of the changes in outcomes attributable to fracking after controlling for temporal changes. In the exploratory Aim 3, we will recruit a sample of 100 children living in communities close to and remote from fracking locations. Cognitive function, adaptive behaviour, and social-emotional functioning will be assessed using standardized assessment measures. Children will also use personal air quality monitors to measure routine exposure to pollutants. Aim 4 will examine current legislation that guides the location of fracking sites in Alberta and will make recommendations for reform if Aims 1-3 demonstrate adverse health effects.

IMPACT: To date no population-based Canadian studies have examined the health impacts of residential proximity to fracking, and internationally, no studies have focused on children. Children may be especially susceptible to the impact of fracking as they tend to spend more time outdoors (thus having greater exposure to air and ground water pollution), breathe faster (thus being more susceptible to air pollutants), and exposures that occur during critical stages of development may have long lasting impacts.

Nobody would ever confuse a line of a computer program with a line from Hamlet. Although programming and language are distinct on the surface, they do share some similarities. Both programming and natural languages are used to communicate information. Both are combinatorial systems of symbols in which larger structures are generated from a set of smaller units (words or variables). Further, programming and language share some parallels with respect to grammar and meaning. The presence of these similarities raises a question of possible links between two domains and their instantiation in the brain. The goal of the proposed research is to test a hypothesis of reciprocal connections between programming and language. To this end, the following research questions will be explored. In Aim 1, we will explore neurocognitive mechanisms supporting programming and compare them with the mechanisms that support language. Specifically, we will examine whether linguistic and programming violations elicit similar variations in neural activity (using EEG) and whether similar brain networks are utilized to deal with these violations (using fNIRS).  In Aim 2, in a longitudinal study, we will explore whether linguistic abilities relate to the level of proficiency an individual achieves in programming. Programming requires development of computational thinking skills (e.g., decomposition, pattern recognition, abstraction, and algorithm design). We hypothesize that language use contributes to the development of these skills. A proficient language user, for example, breaks down speech into smaller units, thus, demonstrating the decomposition element of computational thinking. We predict that high level of linguistic expertise will relate to success in learning a programming language. Finally, in Aim 3, we will test the idea that intensive programming experience will shape linguistic behavior and alter underlying brain functioning. Specifically, we predict that compared to non-programmers, programmers will be more flexible in their semantic interpretations of words due to the fact that in programming a variable can take on various values. Thus, programmers are expected to flexibly discard word-meaning links existing in a language and assign new meanings to words with ease. Overall, the proposed research will illuminate underlying properties of linguistic and programming abilities and will be the first one to shed some light on the alleged link between programming and language.  

DNA is the biopolymer that stores the genetic code for cells, while the closely related RNA acts as messenger to orchestrate what proteins are built. Both are assembled through a phosphate-sugar backbone. Chemists can make short pieces, or strands, using chemical means, allowing DNA/RNA to be incorporated into useful materials in a variety of applications. This ability to make DNA/RNA has been essential in the genomic revolution, enabling personalized medicine, gene delivery, and even editing the genetic code in cells.

To fully harness the biological power of DNA/RNA requires access to significant quantities of strands. Currently, two key factors limit this ability: 1) stitching together shorter strands of synthetic DNA/RNA by enzymes only operates on small scales and 2) chemical means of stitching that can be scaled up tend to introduce unnatural alternatives to the phosphate-sugar backbone that are not biocompatible. The one exception of a non-phosphate backbone that is biocompatible is a linker introduced by a so-called ‘click’ reaction. Yet this particular click reaction has the disadvantage of a toxic copper catalyst.

We propose a new biocompatible DNA/RNA linkage that will be achieved using the SuFEX click reaction. The resulting linkage resembles the natural phosphate linkage at an atomic level, giving it a high probability of biocompatibility. Moreover, off-target lesions to the DNA/RNA are avoided by the lack of toxic catalyst, and the reaction can operate under physiological conditions. The first application will be to stitch together shorter strands of RNA using SuFEX to make a long guide RNA (gRNA) for the gene editing CRISPR-Cas9 machinery. This modular way to access gRNAs will enable us to disrupt multiple genes simultaneously, which is difficult yet greatly needed because of biological redundancy. Secondly, we will perform proximity-induced SuFEX reactions of DNA/RNA strands in cells. The ability to perform biocompatible ligations (stitching reactions) in cells will represent a new powerful approach.

This high-risk, high-reward project is rooted in chemistry but will have a profound impact in biology. Providing a new way to access DNA/RNA biopolymers will broaden the application of gene editing in research and disease treatment and open new doors for studying biological interactions in cells. These possibilities open up unforeseen ethical issues , which we are contemplating though engaged discussions with applied ethicists.

Objectives

In Canada among First Nations, lack of personal identification (PID), like birth certificates, is common and serves as a significant barrier to the social determinants of health. The lack of PID has cumulative consequences on an individual’s ability to access essential services across the lifespan. Our study explores the challenges of delayed and unregistered births and missing PID faced by First Nations people in northern Ontario. We partnered with the Kinna-aweya Legal Clinic, a nonprofit organization that holds “ID Clinics” to assist clients with getting PID. Their work indicates that missing PID is a problem with profound impact on the health and well-being of Indigenous people. Our objectives are to:

1. Identify the breadth of the problem of missing PID among Indigenous people in the region;

2. Work with communities regarding the challenges of PID and build capacity to address the barriers to obtaining PID;

3. Develop a best practices approach and toolkit for organizations that seek to develop ID clinics in the region

Research Approach

This a community-based, action oriented research project without a predetermined agenda; rather community partners will shape the research process to suit their needs. Our research practice adheres to OCAP principles. We will work collaboratively with our community partner to co-create an action research approach. To do so, we will:

1. Support four ID clinics in remote and road-access communities in northern Ontario;

2. Hold community consultations to generate advocacy tools to work towards long-term solutions for missing PID;

3. Hire a research assistant at Kinna-aweya to process PID applications and develop a best practices toolkit

Significance

To date research on PID has focused on developing nations with poor civil registration systems; research regarding the impact of PID on Indigenous people as it relates to the TRC is needed. Indigenous people disproportionately face poor health outcomes. While the causes of this issue are deeply rooted in Canada’s historical and ongoing settler colonialism, addressing the challenge of missing PID can make immediate and tangible impact on the health of Indigenous people. A lack of PID exacerbates the “invisibility” of First Nations people and ability to access services as they are denied vital services without ID and, conversely, we cannot determine what services communities need when growing numbers of people are invisible due to unregistered birth.

Approximately 300,000 Canadians live with type 1 diabetes, an autoimmune disease where the immune system attacks the insulin-producing beta cells of the pancreas. While insulin therapy is live-saving, life expectancy is significantly reduced due to complications such as heart disease. Islet transplantation is an alternative long-term treatment that eliminates the need for insulin in 70% of patients for at least 2 years. The number of patients eligible for this treatment is severely limited by the lack of access to islets from donors as well as the risks related to lifelong immune suppression. Several research groups and companies are developing methods to produce beta cells from stem cells and as well as devices to protect the graft from the immune system. So far, most of these devices have failed likely due to a lack of efficient vascularisation to provide oxygen to the graft as well as carry insulin from the graft. Direct vascularization of the islets would however be counter-productive, as blood also carries the immune cells involved in islet rejection.

The objective of this project is to engineer a new transplantation device that would protect the graft from rejection, improve graft oxygenation and be retrievable. The unique design combines strategies for short and long-term nutrient supply to the graft. The specific aims of this 2-year project are to develop a human-scale device prototype and to test device function in vitro. The device design will be based on literature and numerical modeling of expected oxygen, glucose and insulin profiles. The envisioned manufacturing approach would rely on previously developed 3D printing methods. The performance of the materials used to fabricate device prototypes will be tested in pigs due to the similarity in scale to humans. Device function will be tested in vitro by measuring glucose-responsive insulin secretion and beta cell survival.

This project has the potential to lead to the long-awaited technology required to make cell therapy a realistic option to treat type 1 diabetes. The device could also be used in type 2 diabetic patients and to treat other diseases requiring cell replacement. This technology would solve the long-standing problem of supplying nutrients to tissues of over 1 mm dimensions. The project paves the way for the engineering of human-scale tissues and organs for transplantation.

Rates of Lyme disease and other tick-borne illnesses are rapidly increasing in Canada. Despite a growing threat to human health and welfare, strategies for identifying and mitigating disease risk from tick-borne pathogens are hindered by four main limitations. First, disease risk models and mitigation strategies require better data on tick population sizes, dispersal rates, and pathogen loads. Second, new tick-borne pathogens are difficult to detect, and disease progression is poorly understood for most tick-borne pathogens. Third, testing and monitoring is focused on a single group of bacteria with less consideration of other tick-borne pathogens. A fourth and final limitation is the lack of mechanisms for quickly translating and communicating disease risk information to physicians, veterinarians, public health agencies, and the general population.

As a proof-of-principle strategy for vector-borne disease management in novel environments, we propose to address the above limitations with a multidisciplinary and integrated approach for in situ detection, characterization, risk assessment, and management of tick-borne diseases in a Canadian Lyme disease hotspot. First, we will analyze genetic structure of tick populations and the microbes they carry (i.e. their microbiome) to parameterize spatial models and improve models of disease risk. Second, we will identify matches in microbial DNA sequences between ticks and animal tissue and blood samples to identify new and emerging pathogens. Third, we will develop and test field protocols and analytical tools for in situ microbiome analysis for the identification of known and suspected pathogens in the field. Finally, georeferenced samples containing known or suspected pathogens will be uploaded to publicly accessible databases as a basis for a risk assessment tool that we will develop for medical educators, public health officials, and concerned citizens, allowing real-time updates to models of disease risk as more data become available.

If successful, this project will spark new research and applications (for future funding opportunities) in microfluidics and nanotechnology (NSERC), tick and tick microbiome ecology (NSERC), pathogen diagnosis (CIHR), public health (CIHR), and health education (SSHRC).

In 2015, the Truth and Reconciliation Commission of Canada made clear the powerful role that sport must play in restoring the country’s broader goal of reconciliation between Indigenous and non-Indigenous peoples. However, recent years have witnessed the corrosion of Indigenous sovereignty in many rural sporting communities as elite-level athletes leave home to pursue training opportunities in major urban centres. Bodies of Power, Nations of Strength will reimagine athlete training in three Indigenous hockey teams. Through lenses of Remote Presence Sporting Technologies (RPST) and Indigenous Science, Technology, and Society (Indigenous STS), this study takes as its starting point the complex roles that ice hockey—a genre of physical culture steeped in Canadian nationalism—plays in Indigenous communities. In a unique integration of scientific, social scientific, and community-based research theories and methods, we will consider how First Nations might leverage advanced exercise science and athlete-centered technologies on their own terms and in ways that support Indigenous governance. Our study, thus, contemplates the above theoretical concerns alongside the development and critique of RPST geared toward hockey development. We ask: How might Indigenous athletes living in rural/remote communities gain access to elite-level and multidisciplinary sporting expertise? What are the potential benefits and limitations of RPST in Indigenous contexts? And, how might access to advanced exercise technosciences within one’s home community support Indigenous athlete training programs? By building a novel interdisciplinary framework, we will integrate relationship-building research processes with more technical-oriented biomechanical and physiological assessments. Governed by the principles of OCAP (Indigenous ownership, control, access, and possession), all data will interface with Montréal-based servers and be co-evaluated by a team of biomechanical, exercise, and community specialists with specific expertise in ice hockey. The study’s results will shed light on RPST as a completely unexamined venue for athlete development. Grounding this research within First Nations contexts will also encourage a more complete conceptualization of RPST across cultural, racialized, and gendered lines, while centering Indigenous communities at the forefront of athlete development in Canada.

Intraventricular hemorrhage (IVH), a leading cause of brain injury in preterm infants, can result in morbidities and increased risk of death or neurodevelopmental impairment due to injury of existing as well as progenitor cells at critical stages of development.   There is no therapy for IVH or resultant injury, only symptomatic management for post-hemorrhagic ventricular dilatation (PHVD).  Stem cell (SC) therapies have been proposed to treat brain injury to repopulate damaged areas or exert indirect effects to reduce injury and enhance repair.  Animal models show neuroprotection and improved outcomes with autologous or donor SCs via many routes, including intranasal.  In mouse IVH models, SCs attenuated injury and PHVD.

Phase I infant studies for asphyxia utilized intravenous umbilical cord SCs, requiring specialized processing of a single available sample.  An innovative, easily collected, continuously produced SC source is human milk (HM).  Fresh HM contains pluripotent SCs that can form neuronal cells in vitro.  In mice, milk SCs populate pup brain tissue and can differentiate into neuronal cells.  The nares, highly vascular, close to the brain, and lacking caustic gastric enzymes, could be an ideal route for HM SC therapy in preterm infants, who are typically tube fed previously frozen HM that lacks viable SCs.  A small single centre, non-protocolized series, the sole report of intranasal HM, trended to lower short-term IVH morbidities; no long-term outcomes were collected. 

We propose a multi-centre pilot study of intranasal HM in preterm IVH patients in 3 high volume tertiary NICUs that share a protocolized approach to PHVD with intensive monitoring, early intervention, and detailed prospectively collected IVH data.  Using interprofessional lactation, nursing, and medical collaboration, preterm infants will be treated with fresh intranasal HM.  Objectives include feasibility with parent/infant separation, safety of various doses/frequencies, staff/family acceptance, outcome trends to inform for future RCTs, and HM SC quantification.  Clinical outcomes (progressive PHVD, cystic changes, need for PHVD intervention] and most importantly and novel, long-term neurodevelopmental outcomes) will be compared to the cohort 1 year prior.  A widely available, easily administered regenerative solution that improves neurodevelopmental outcomes for an injury without current treatment options would be ground-breaking for premature infants and their families.

Cholera is a diarrheal disease that kills 95,000 people annually. The rapid detection of outbreaks saves lives, but weak health systems in peri-urban areas delay detection. We hypothesize that the infamous “rice-water” consistency of cholera-induced diarrhea affects its exit characteristics (e.g., velocity). We propose to invent, validate, and deploy a latrine-based cholera sensor to:

1. Quantify diarrheal severity and detect cholera

2. Identify dominant cholera-transmission pathways

3. Demonstrate a sensor-enabled outbreak warning system

High Risk: Quantitative observations have never been made about the exit characteristics of diarrhea, let alone cholera-induced diarrhea. Additionally, sensors have never been installed inside latrine pits, where rotting feces may easily foul sensors. Finally, gathered data may fail to identify the dominant cholera transmission pathways.

High Reward: A network of cholera sensors would constitute a disruptive method of detecting outbreaks, which could reduce cholera’s 2.9 million infections annually.  Sensors may also illuminate new spatial and temporal patterns in cholera transmission. Finally, the proposed sensor could improve responses to other diarrheal diseases (which yearly kill 500,000 children) and is a step towards ‘smart’ healthcare (e.g., ‘smart’ latrines could connect sick users to healthcare providers).

Feasibility: The principle investigator is an early career researcher at the University of Toronto’s Center for Global Engineering (CGEN). CGEN has an ongoing latrine project in India, where sensors can be field-tested. The co-applicant is a postdoctoral researcher and epidemiologist at the Harvard Kennedy School of Government. Both applicants have extensive experience in developing countries working on water and sanitation projects.

Life needs energy to survive. In organisms living in oxygen-rich environments, energy is obtained by aerobic respiration, a metabolic process requiring oxygen. Deprivation of oxygen severely damages many organisms, posing a serious threat to their survival. Some microbes have solved this problem by producing a molecule called rhodoquinone (RQ) that allows the respiratory system to make energy without oxygen. By  ‘stealing’ the gene encoding RquA, an enzyme that produces RQ, these microbes have adapted to diverse low-oxygen environments distributed across the planet. Little is known about RquA, the chemical mechanism it employs to make RQ, and the impact of RQ on cellular respiration. We propose a multidisciplinary approach to determining the cellular, chemical, and structural aspects of RQ biosynthesis and function as well as the importance of RQ for the evolution of life in low-oxygen habitats and its potential biomedical applications. We aim to:

1) Determine how RquA produces rhodoquinone

In vitro studies will be carried out to determine the atomic-resolution structure of RquA and how it makes RQ. We will determine what factors are needed for an organism to use RQ for respiration.

2) Determine the effect of inhibiting RquA activity on parasites

Anaerobic gut parasites such as Blastocystis rely on RQ to carry out respiration. To develop new anti-parasitic compounds, we will chemically modify RQ and check if these analogues inhibit RquA from producing RQ. Identified inhibitors will then be tested for their ability to prevent growth of anaerobic parasites.

3) Investigate if rhodoquinone can prevent cell damage from hypoxia

When cells are deprived of oxygen (e.g. a heart attack), the respiratory system produces toxic reactive oxygen species (ROS) once oxygen is reintroduced. We hypothesize that introducing RQ into the system may allow aerobic cells to avoid the production of ROS upon oxygen exposure. We will test this by adding RQ to mouse heart muscle and monitoring ROS production and cell death upon oxygen deprivation and reintroduction.

Novelty and impact:

This is the first multi-disciplinary study that will determine how rhodoquinone is produced and may illuminate new mechanisms of enzyme catalysis. By harnessing an evolutionary solution to survival under low oxygen used by microbes, we have the potential to develop entirely new anti-microbial compounds and novel interventions to prevent damage in tissues following oxygen deprivation.

The environmental, social, and economic impacts of wildfire are increasing in Canada. A century of fire suppression and forest management have significantly altered forest fuel loads and combined with climate change have accelerated changes to fire regimes that will significantly test the resilience of communities and ecosystems. The contemporary model for wildfire management, which is embedded in European settler conceptualizations of wildfires as destructive and catastrophic events, is socially untenable. Efforts to match increasing wildfire activity with suppression efforts have either failed or become so costly that alternative solutions, such as prescribed burning, are required. However, there remains considerable social aversion to changing forest and management practices given portrayals of wildfire in contemporary media and general misunderstanding of wildfire as an ecological process. We are entering a new era of wildfire and forest management without historic precedent.

Using the Okanagan Valley, British Columbia - one of the most fire-prone landscapes in Canada - as a case study, our research will explore the ecological, cultural, and socio-economic dimensions of wildfire as a complex system, where human and ecological processes are linked across spatiotemporal scales. As we enter an unprecedented period of wildfire management, interdisciplinary approaches are required to i) understand the enculturated representations of, and attitudes towards, wildfire, ii) leverage new cutting-edge data products that can be used to understand fire behaviour, iii) develop economic and environmental scenarios to engage communities in wildfire management, and iv) comprehend and negotiate the means of effecting long-term change in social and political attitudes towards wildfire management. To address these needs, we will develop novel integrated approaches for quantifying and predicting fire risk, fuel loads, and future landscapes through spatial models, and for understanding the enculturated, gender, visual and place-based perceptions of wildfire and risk in the Okanagan. Our collaborative research program will build a participatory process that will engage the Okanagan community around the themes of wildfire, vulnerability, risk, and resilience. Translating community attitudes, visual research, and model outputs into policy, we will challenge the contemporary social and political attitudes towards wildfire management in Canada at a time of critical need. 

In a landscape of fake news and biased social media algorithms (Noble, 2018; Browne, 2015), it is increasingly difficult for scientists, community stakeholders, Indigenous communities, and other engaged participants in land-use governance in Alberta to articulate factual and rooted narratives about the pressing issues they are dealing with today in the face of cumulative pressures on their lands and watersheds from climate change, resource extraction, urban expansion, agriculture, and recreational use. Working with artists, computer programmers, scientists, Indigenous Knowledge Keepers, journalists, and other community stakeholders, we aim to develop an adaptable digital toolkit for storying pressing environmental issues in Alberta’s Bighorn Country. Starting with a case study of the decline of the bull trout (Salvelinus confluentus) in Alberta's eastern slopes in Bighorn Country, we aim to engage these diverse community members in a project that will enable them to explore dynamic skills and media to both study and communicate rapidly evolving environmental and species concerns, increase public appreciation for those species, and to foster meaningful change to policy processes regarding species at risk, watershed management, and land-use governance. This project will develop and implement an interdisciplinary, highly adaptive digital tool-kit, including both an Augmented Reality app and a series of in-depth radio documentary podcasts, for community stakeholders to employ to both collect and communicate environmental observations and concerns. Working to reclaim and unsettle the dual frontiers of new digital technologies and western scientific knowledge, we will employ intersectional and Indigenous feminist approaches to elucidate plural knowledges of environmental change in south-western Alberta.  In so doing, we aim to answer the following research question: “How can plural and intersectional perspectives on environmental governance and species recovery be expressed in the context of a polarizing socio-political landscape in the Bighorn Country, in Alberta, Canada?” 

Background: Around 86,000 Canadians live with a spinal cord injury (SCI), with 3,400 new cases per year. ‎The annual cost to Canada is $3.6B. Restoring stable walking function is the highest priority for those ‎with SCI. Although assistive technologies such as wearable exoskeletons can help, they are not widely ‎implemented in Canadian clinics mainly because their control programs are not tailored to subject-‎specific needs. These technologies are typically designed based on a few users’ data. Due to the large ‎heterogeneity of the SCI-induced neuromuscular impairments, a technology suitable for one user may be ‎inefficient or have adverse effects for others.‎

Innovation: We will identify mathematical models of impaired neuromuscular control and motor deficits ‎due to SCI and use them in the design of ‘personalized’ assistive technology. This will be achieved by ‎bringing together expertise from biomechanics, machine learning, robotics, neuro-rehabilitation, and ‎medicine through a collaboration between the University of Waterloo, University of Alberta, Toronto ‎Rehab Institute (TRI) and Glenrose Rehab Hospital (GRH). Identifying personalized models for SCI effects ‎on the sensorimotor system that enables an optimized ‘prescription’ of technology functionalities has ‎been a challenge for neuroscience and neural engineering.‎

Objective: Development and clinical evaluation of a personalized, wearable, assistive technology for ‎restoring stable locomotion for individuals with SCI.‎

Research Approach: 1) We will characterize a musculoskeletal model for individuals with SCI based on ‎biomechanical measurements. 2) We will design innovative experiments involving mechanical and ‎sensory perturbations applied during locomotion to identify the affected neuromechanics, using system ‎identification and machine learning techniques. 3) Muscular forces required during stable gait will be ‎computed based on the neuromechanical models and used for controlling a lower limb exoskeleton ‎combined with a functional electrical stimulation system. 4) We will design and implement a novel ‎adaptive controller for each user based on their identified neuromechanics. 5) Collaborating with TRI and ‎GRH, we will evaluate the clinical efficacy of this technology for individuals with SCI.‎

Impact: This research will develop new paradigms of personalized neuro-rehabilitation, significantly ‎impact the quality of life of Canadians with a disability and reduce the SCI-related costs.‎

Our team will take a community-engaged approach o advance a new area of transdisciplinary research on Indigenous agriculture. This project is high risk as it challenges current paradigms on agriculture and land tenure using a novel approach that combines oral histories, sacred geographies and community perspectives with economic and biophysical data. It is high reward as First Nations (FNs) will use outcomes to advance their own agricultural land-use planning, cognisant of community cultural values and experiences. In Saskatchewan (SK), this impacts 4 million acres of agricultural land spanning 64 FNs. We will work closely with SK FNs to co-document Indigenous oral histories and knowledge systems related to food cultivation and land and water protection methods. The narrative will be integrated with remote sensing and soil mapping methodologies to reconstruct land management histories and contextualize the contemporary status of agricultural land use on FNs.

First Nations have expressed desire to exert more control of agricultural lands - most are leased to non-Indigenous farmers - and revitalize Indigenous-led agriculture. Accounts that leases to non-Indigenous farmers are below market value are common as are concerns that leasing has resulted in ecosystem degradation. A Forum on Indigenous Agriculture held in Dec. 2018 and attended by 64 Indigenous people representing 24 SK FNs indicated demand to build capacity in order to receive greater benefits of agricultural activities, reduce environmental and financial risk, and support traditional cultural practice. Research on Indigenous agriculture in a Canadian and contemporary context is lacking.

Working with SK FNs we will: 1) reconstruct land use changes from oral history accounts in conjunction with historical soil surveys and remote sensing data; 2) learn from local Indigenous knowledge keepers about traditional horticulture, and land and water protection methods; 3) redefine agricultural land capability and land health using biophysical data with Indigenous knowledges. Biophysical data will include remote sensing information (current land use and normalized difference vegetation index) and soil data (soil type and properties, agricultural land capability). By integrating new digital soil land use maps with community-curated layers of value-laden sites, we will contribute to a new land capability classification approach that goes beyond the conventional methods.

The new Frontiers in Research Fund will enable us to engineer new electrochemical devices, capable of capturing the tremendous amount of energy available in rainfall, waves, and evaporating water. The proposed ‘hydrovoltaic’ devices are a brand-new field of research, aimed at servicing increasing energy demands with clean/green energy technology. Water covers 71% of the earth’s surface and continually absorbs tremendous amounts of energy from the sun (>1015 W globally). The total solar energy absorbed by water is more than 1000 times the global energy demand of humans (1012 W), but remains largely untapped as an energy source. In Canada in particular this is exciting, where water is one of our most abundant resources, surrounded on 3 sides by oceans and with ~9% of the surface area covered by fresh water.

Recently, it has been discovered that water evaporating off of carbon containing substrates or moving along a surface can generate electrical power - appropriately termed “hydrovoltaics”. In the ground-breaking discovery by Prof. Wanlin Guo, soot from the burning of fossil fuels was used as an electrode. Water droplets can be moved along or evaporated off of the electrode surface, in both instances generating volts of electrical potential. The current interpretation of this phenomenon is that, at the water/electrode interface, charge separation occurs; electrons are transferred from the soot to water and carried away, leaving behind unbalanced charges. The electrical charge build up is recovered by flowing current through an external circuit, generating electricity.

Soot is an ill-defined material, that is highly variable depending on the fuel source and how it is prepared. This inconsistency makes it challenging to elucidate the exact mechanism of charge separation and power generation. In collaboration with world renowned chemist Prof. Guojun Liu, we will generate well-defined nanofiber mats. The substrates will have large, porous surfaces and will be hydrophilic to maximize the adsorption of water. Hydrovoltaic devices will be fabricated by electrospinning onto conductive electrodes. This work will leverage both the existing expertise in polymer chemistry and electrospinning of the Liu group, along with the electrochemical cell fabrication of the Stamplecoskie group. Together, the team aims to rapidly take the discovery of the hydrovoltaic effect from a proof of concept to devices capable of meeting global energy demands.

Several identified incurable human diseases have been associated with alterations of the genome. The discovery of clustered regularly-interspaced short palindromic repeat (CRISPR) systems, which allow the precise and stable editing of genes, offers an unprecedented opportunity to correct some of these genetic diseases at the source. While CRISPR has garnered much attention and is extensively used to edit cells in vitro, its application in vivo has been hampered by the lack of efficient non-viral delivery methods. Nanoparticles-based methods have proven partly successful in vivo but still suffer from poor delivery. Some of the major issues are related to a lack of target cell specificity, ineffective cellular uptake of the particles, and degradation of cargo in endosomal vesicles since the direct intracellular delivery of proteins remains challenging.

To overcome these barriers, we combined our expertise in chemistry, nanotechnology, cell biology, and virology and sought to harness the power of viral glycoproteins to improve specificity, enhance uptake and allow direct delivery of their cargo to the cytoplasm via membrane fusion. We have created novel nanoparticles covered with membranes containing viral fusion proteins that we termed viral membrane-cloaked nanoparticles (VM-NPs). The novel delivery vehicles exhibited improved delivery of chemotherapeutic drugs and microRNAs in in vitro models.  Here, our goal is to test our platform for the delivery of Nuclease-guide RNA complexes to correct incurable human diseases. The specific aims of this 2-year project are to:

1)      Test and characterize the VM-NP platform to specifically knock-out genes

2)      Test and characterize the VM-NP platform to perform specific gene editing of genes.

To reach our goal, we will generate a panel of nanoparticles decorated with viral glycoproteins targeting different cell types and use fluorescent cell lines and transgenic mice to test our platform. This approach will allow the assessment of gene editing efficiency and the determination of the target cells and tissues.

This novel delivery platform has the potential to unlock the full potential of CRISPR-based technologies to cure genetic diseases that are today deemed incurable.

While computational fluid dynamics (CFD) has been a central component of engineering design for many years, the utilization of advanced CFD codes in biomedical engineering and medicine is still embryonic. Our objective is to extend the frontiers of massively parallel computing of multiphase flows on Cartesian adaptive grids and to apply it to problems related to blood flow in the human body. Blood is a complex fluid and its flowability is not yet fully understood, even less when it is seeded with artificial particles such as drug carriers. We will investigate the problem at the particle level, improve the comprehension of complex interactions between red and white blood cells, platelets, drug carriers and suspending fluid, and supply novel data in the core of blood flows.

Distributed computing of multiphase flows on 128 or 256 cores is nowadays performed routinely. We intend to develop scalable numerical models and perform computations on up to 20,000 cores, involving billions of degrees of freedom, and utilize them as genuine paradigm shifters in blood research with application to targeted drug delivery and cardiovascular diseases. The proposed research is in line with the recent upgrade of the federal supercomputing ecosystem by Compute Canada towards massively parallel computing.

At the numerical level, we will favor last generation numerical approaches implemented on dynamic Cartesian adaptive grids in order to compute all relevant length scales in the flow as particles move. To speed up the development, we will implement our models on highly scalable open source platforms: (i) an immersed boundary cut cell method in Basilisk, developed by the collaborator of the project, and (ii) a lattice-Boltzmann method in the lattice-Boltzmann solver waLBerla.

The project is meant to be disruptive in two ways. The first way combines multiphase CFD and massively parallel computing to provide medical doctors with reliable data and understanding. Novel data at the particle level also represent a building block of a multi-scale cardiovascular modelling framework used as a patient-specific clinical tool to establish new guidelines for the next generation of cancer and cardiovascular disease diagnosis and treatment. The second way equips our research group and the entire Canadian community with top of the field open source CFD models that radically extend the way multiphase CFD research is conducted in assorted fields of science and engineering.

Infertility affects 15% of the population world-wide, and even the most intensive treatments such as ICSI (intracytoplasmic sperm injection) are successful less than 50% of the time; thus, novel techniques are desperately needed. Performing ICSI involves the selection of motile sperm under 200-400x magnification and subsequent injection of the sperm into the oocyte to achieve fertilization. The ability to choose healthy sperm is critical since sperm contributes half of the genetic content to create an embryo and plays a critical role in fertilization potential, fetal development, and offspring health. Use of unhealthy sperm from men with severe male factor infertility results in significantly lower fertilization and live birth rates compared to sperm from fertile men. Assays currently available to assess the health of sperm such as DNA fragmentation, and semen analysis only provide information on the proportion of abnormal sperm or require permanent fixation of the cells to perform the assay; thus, cannot be used to direct selection of healthy sperm for clinical use. To address this critical gap, we propose to develop a novel platform capable of facilitating both genomic and molecular biologic investigations, while retaining the ability to use the results to guide selection of the healthiest sperm. This will be accomplished through utilizing high magnification image-based machine learning, and single cell multi-OMICs. Specifically, our research is comprised of three objectives. We will first compare the transcriptomic and epigenetic data of single sperm derived from fertile and infertile men, to gain insight into unique sub-populations of healthy sperm among fertile men. We will next use machine learning algorithms to identify subgroups of sperm from fertile and infertile men based upon high magnification sperm morphology. Image-based machine learning will serve as the ‘concrete linkage’ capable of reproducibly linking scientific investigation and clinical application. We will subsequently use our machine learning algorithm to identify live sperm from unique clusters, and isolate single sperm using a novel photopolymerizable polymer developed by our team, to perform single cell transcriptomic and epigenetic sequencing, linking genotype to phenotype. The results of our study have the potential to be paradigm changing in the field of reproduction, where genomic data can drive selection of the healthiest sperm to improve pregnancy rates and offspring health.

Objectives: While social accountability has been identified as a powerful paradigm shift in medical education, where programs now focus on addressing local health priorities, social accountability as an educational innovation remains under-studied and under-theorized. This study seeks better understanding of how socially accountable education (a locally embedded and globally engaged approach) may foster transformation within rural health systems.  Through a qualitative study design, our research objectives are: 1) to explore the values and meanings of socially accountable medical education; 2) to investigate how social accountability is being experienced by medical leaders, educators, and  community members; and 3) to identify novel ways of translating the impacts of social accountability.

Approach: Through narrative inquiry this research project will explore the storied accounts of social accountability. First, we will investigate international perspectives and explore to what extent, and how different medical education programs are engaging with socially accountable medical education. Data sources will include interviews and ‘rich pictures’, a visual method for eliciting meaning beyond words, with medical educators and leaders at 3 different medical schools  (Newfoundland Canada; New Mexico USA; Townsville AU). Second, we will investigate local perspectives from Northern Ontario through a case study of the Northern Ontario School of Medicine. Data sources will include interviews and rich pictures with medical educators and leaders, as well as focus groups with communities and community groups. Through this study we aim to capture a global story of place-authenticity and processes, while also delving deeply into a local story to understand the voices of those directly affected by social accountability.

Significance: Through narrative inquiry we seek to capture social accountability as a process of “becoming” at the levels of individuals, schools, and communities.  While narrative inquiry remains a marginalized theoretical lens in medicine, this research will elevate the importance of humanities-based research for understanding social accountability. Early evidence has shown that social accountability is leading medical education towards transformational change, but there is a need to understand how it works as a social change tool to help inform future educational policies and practices.

The Challenge: In UNICEF’s recent international Report Card on child well-being, Canada ranked only 25 out of 41 high income countries. Despite being the 5th most prosperous country in the world, Canada’s rankings were alarmingly low on key measures of children’s health as well as child poverty (17% of all children). These conditions have resulted in large and growing inequalities in the health and development of Canadian children.

Objective: The primary objective of our inter-disciplinary research program is to examine the social and environmental factors (and interactions amongst factors) associated with current child health disparities. We will focus on understanding the social conditions involved in “biological embedding”, by exploring the social exposome, which represents the cumulative social exposures over the life-course that influence development and health from conception onward. Specifically, we will explore how, when, and under what circumstances early life social and environmental factors become “biologically embedded” to affect neural, endocrine, and immune systems at the molecular level.

Research approach: We adopt a “society to cell” approach by exploring how children’s social environments influence their physical and psychological exposures to impact their health and development and lead to the persistent health disparities in our society. Specifically, we will link population-based data resources with biological measures to understand child development. To do this, we will build on an existing British Columbia population-level monitoring system on child development (based on teacher- and student self-report), which has been linked to birth, medical, and education records as well as family and neighborhood socio-demographic characteristics (via Population Data BC). We will link individual child health and biological measures from the Canadian Healthy Infant Longitudinal Development (CHILD) Study, which has extensive measures of pre- and postnatal environments and key biological markers, to this database.

Novelty and expected significance: This program of research is a vanguard for testing the feasibility of population-wide social exposome research and will move the promising concept of biological embedding from smaller cohort studies into a true population setting. The linkage between population and molecular data will provide an unparalleled ecosystem for understanding child development at the nexus of nature and nurture.

Imagine a near-future city, where individual buildings operate as clean energy power stations: self-sufficient energy nodes that store, recapture and produce energy.  Urban populations are increasing; requiring many tall residential buildings to be constructed globally.  Housing accounts for a large portion of the total energy consumed and residential energy consumption is rising.  Increasing urban populations, alongside increasing per capita energy consumption require multiple disciplines to work together to produce novel energy solutions. New approaches to building design and public policy transformations will be needed to address this paradigm shift. How we use and acquire energy is directly linked to some of the most significant issues facing humanity: climate change, access to clean water, adequate food supply and geopolitical stability. The built environment is the largest contributor to global greenhouse gas emissions and the largest consumer of electricity which impacts an enormous, global community. This project will leverage innovative cross-disciplinary approaches to develop real-world technological solutions to long standing problems. Tall residential buildings utilize pumps, reservoirs, and gravity storage tanks to maintain sufficient water pressure on all floors.  Currently, there is no technology to recapture this energy as waste water flows, accelerated by gravity, out of the building.  Such technology would make significant contributions to increasing energy efficiency and housing affordability in tall residential buildings. Our objectives are to develop a gravity turbine prototype concept for energy recapture in tall building waste water systems, through public consultation and with our community partners, to create a cross-disciplinary research platform across architecture, mechanical engineering and public policy, and to establish new narratives for energy efficiency in the built environment that address innovative ways to solve known problems. Researchers at Carleton will develop the turbine prototype and will investigate its scalable effects as well as its commercial viability. This research will be approached across disciplinary silos, across industry and academia, disrupt disciplinary research norms, and has the potential to greatly impact the future. Optimization tools, scenario analysis frameworks, architectural systems thinking, and public policy analysis will come to bear on outcomes.

Prostate, breast, and gynecological cancers are amongst the most common cancers in Canada. A common treatment for these conditions is brachytherapy. This procedure is a type of radiation therapy that allows physicians to deliver higher doses of radiation to more specific areas of the body, compared with the conventional external beam radiation that projects radiation from a machine outside of the patient’s body. In brachytherapy, a radiation source is placed directly inside the tumour using long needles. However, the procedure is associated with several challenges such as poor visualization of the location of the tumour and of the needle inserted into the tissue.

This project proposes a paradigm shift to the current clinical practice. Rather than using traditional ultrasound images acquired by a transducer being placed on the tissue that overlays the target organ, we postulate that needle guidance, target delineation, and tissue sampling will be more accurate and detailed if the needle itself can deliver information about the tissue directly from inside or near the tumour. We propose to develop sensorized needles that use measurements of the tissue impedance obtained from embedded electromechanical impedance sensors to characterize in real-time the stiffness of the tissue surrounding different parts of the needle. The information obtained about the electrical and mechanical impedances will be fused in real-time with conventional ultrasound images to provide both augmented ultrasound images and electrical impedance tomography mappings of the tissue, which will be more accurate than one modality alone. The proposed technologies will (a) provide accurate needle position information; (b) result in improved characterization of the tissue to better localize tumours and healthy tissue in real time, and (c) provide the clinician better control of the needle inside the tissue.

Advances in image-guided brachytherapy have the potential to improve radiation dose distribution within the prostate. In the case of gynecological brachytherapy, better visualization of the needle will reduce or eliminate the need for computed tomography imaging. More accurate needle navigation and target delineation will ensure the maximum radiation dose is given to cancerous tissues while minimizing exposure to the surrounding healthy tissue.

MOTIVATION: The Canadian Arctic is currently the largest contributor to modern sea level rise from glaciers and ice caps. This knowledge is a direct result of four glacier monitoring programs in the Canadian Arctic founded in the early 1960s. The oldest of these is the White Glacier program on Axel Heiberg Island, NU, initiated in 1959. White Glacier and McGill Arctic Research Station became a prolific hub of scientific activity in the decades that followed. To date, no avenue has existed to synthesize, analyze, and collectively communicate the uniquely linked scientific and historic significance of this program.

HIGH-RISK: This project brings together diverse perspectives from the Sciences and Humanities to: (1) Harness new scientific value from early research records, (2) Contextualize historic and contemporary perspectives in the field-research community to assess the impact on field methods and data interpretation, and (3) Update and enhance contemporary field-research practices to capitalize upon new knowledge gained through this interdisciplinary approach.

HIGH-REWARD: This initiative will provide open-access, real-time climate data for the first time in this part of the Arctic, alongside rare historic data. Detailed analysis of these data will provide new insight into the underlying mechanisms driving Arctic glacier losses and improve future projections. This collaboration will link the lived experience of the early and contemporary field practitioners and contextualize the voices of the researchers behind, and within, the research through a critical historical geography lens.

TEAM & APPROACH: Our team, including HQP, is diverse, inclusive, and gender-balanced. We will use novel techniques in historical data rescue, real-time data telemetry from one of Canada’s northernmost field stations, and big data mining. Thomson manages the White Glacier program and she is building a network of telemetric stations in the region to assess climate drivers behind glacier response (no funding requested). Nussbaumer specializes in historic records applied to glacier research and will lead communication between early researchers (in Switzerland) with Greer (Repatriation and Digitization Lab) and Cameron (Sonic Arts of Place Lab) who specialize in historic data rescue and oral histories. VanWychen, (PDC) will head digital data mining, archiving and dissemination. Larsson will lead physical archives and public engagement in a special exhibition at Redpath Museum.

Objectives of research program

We propose to revolutionize current approaches for predicting climate change effects on the biosphere. Our project aims to: 1) develop a novel mathematical framework for predicting plant microclimates from macroclimate and vegetation structure; 2) develop new mechanistic theory for “scaling up” climate-driven physiology to higher levels of organization; 3) calibrate and test our models using climate and vegetation data collected at 13 field sites located in 5 countries and arrayed across global climate gradients. Our approach will enable more accurate predictions of vegetation responses to climate change, and will inform mitigation and adaptation strategies for anticipated climate change scenarios.

Summary of research approach

Aim 1: Meteorology theories predict microclimate from macroclimate and vegetation structure, and metabolic scaling theory predicts vegetation structure from plant traits. We will synthesize these approaches to mathematically formalize how macroclimate is modified by vegetation to yield spatially complex variation in microclimate. Aim 2: A mass balance approach will integrate the carbon assimilated across all of the leaves in a canopy in order to “scale up” physiology from leaves to plants to ecosystems. Microclimate effects on leaf physiology will be characterized using a biochemical model for photosynthesis. Aim 3: To calibrate and test our models, we will collect climate and vegetation data across a network of forest monitoring sites from diverse taxa and all major biomes of the world. At each site, we will quantify macro- and microclimate data, as well as data for plant ecophysiology, diversity, growth, production and demographics.

Novelty and significance

Our approach to predicting climate change effects on vegetation stands in contrast to current approaches that are still based on rather simplistic representations of climate and vegetation. These models often use average macroclimate conditions to simulate plant responses, but these do not accurately reflect physiological responses nor do they accurately scale to larger domains. Most models also lump plants into a handful of coarse “functional types” that contain limited information about diversity and dynamics of plant traits. Our framework will address these limitations to enable more accurate predictions of the Earth system.

Traditional cinematography is limited by the two-dimensional nature of film.  Stereoscopic films (e.g., via anaglyphs or polarized glasses) create merely the illusion of depth atop a two-dimensional image, but this experience lacks all of the many other depth cues and results in nausea for some. We propose researching truly three-dimensional cinema, where each frame is a physical 3D-printed scene and frames are replaced at a rate of roughly 20 per second creating the illusion of statues come to life. To be clear, we do not propose photographing each frame using a camera (conventional, stereoscopic, or otherwise). Nor do we rely on special glasses. Instead, we propose a novel artform that will be experienced live. Rather than see projected 2D images, audience members will observe 3D-printed frames at rate fast enough to create the perception that the truly three-dimensional objects are moving.

Upon success of our technical research, we will produce the first truly 3D short film (roughly 3 minutes). This 3D film will demonstrate the use of our novel computational algorithms and human-computer interfaces to create complex camera movements and multi-take composition while ensuring that each frame is manufacturable given the constraints of 3D-printing technologies.

This proposal is high risk in respect to both computer science and art. From a technical standpoint, we are operation at an unprecedented scale. A 3D film will require not only a large amount of 3D printing, but also a large amount of digital geometry processing. Meanwhile, from an artistic standpoint, the 3D film must fit within the literally small space of the physical 3D frame. This proposal addresses these risks and describes how they in turn afford high rewards, again in computer science and art. Geometry processing at this large and physical scale requires new levels of robustness and new methods for parallel fabrication. As an artform, 3D film is a new medium that must be experienced live, in person. This artform may inspire a new wave in film that bridges a gap between cinematography and theatre.

Finally, this proposal presents a unique opportunity to equity, diversity and inclusion activities. The 3D printing resources acquired for this project will be the focal point of a Maker Day events hosted for local high school students, who will experience how art and technology merge.

People are seeking alternatives to animal protein to improve their health and the sustainability of their diet. Legume proteins could further meet this demand, if novel processes are found to improve their texture in food. Under certain conditions, proteins can self-assemble into nanofibrils (long, thin strands of 1000’s of protein molecules), with different fibril types (‘polymorphs’) formed under different conditions. Nanofibrils are of interest for a variety of biotechnology applications as they have unique structural, chemical and physical properties. This project seeks to discover novel processes for converting legume proteins into nanofibrils for use in foods as meat analogues.

OBJECTIVES: (1) Explore the variety of fibril polymorphs made under different conditions, after enzyme pre-treatment, and using ‘seeding’ reactions. (2) Characterise the assembly mechanisms (kinetics, peptide composition, structure and mechanical properties) of the various fibril polymorphs. (3) Organize nanofibrils into larger-scale materials to enhance their functionality as meat-analogues. (4) Compare the functionality of legume protein nanofibrils in model food systems, relating structure and functionality (gellation, film formation, viscosity, texture, & emulsion stability). (5) Examine the safety of plant protein nanofibrils for use in food.

APPROACH: Plant proteins and nanofibrils are complex structures, and more fundamental information is needed before we can develop novel plant protein ingredients. This project combines biophysics and food science. Biophysical approaches will be used to untangle the complex fibril formation mechanisms of plant proteins and used to inform food product development to identify legume protein nanofibrils best suited for use as meat analogues. Proteins from soy, pea, lentils & chickpea will be examined.

IMPACT: This project will define the relationships between nanofibril-forming conditions, structure and functionality, and identify the legume proteins and the processing conditions that yield protein nanofibrils most suitable for food applications. A fundamental understanding of the forces underlying protein self-assembly will be required to rationally develop plant proteins as meat analogues. The basic knowledge generated will aid the development of value-added plant protein ingredients, improve food sustainability, enhance food security, and contribute to human health by offering more appealing plant-protein alternatives.

This project investigates the potential of immersive digital environments for their capacity to stage and risk cross-cultural, interdisciplinary and cross-generational encounters.  Our research holds the potential to both transform and pioneer new digital poetics in virtual reality.  We understand Indigenous ways of knowing and practices of making as foundational to this work, and through a critical Indigenous lens we will evaluate the use of digital immersive spaces and the act of co-creation within them as opportunities to advance reconciliation. Under the leadership of Dr. Lindsay Morcom (Wikwedongkwe, Anishinaabe métis, Bear Clan), an interdisciplinary researcher working in education, Aboriginal languages, language revitalization, and linguistics, and under the guidance of Deborah St. Amant (Bezhig Waabshke Ma’iingan Gewetigaabo, Anshinaabe, Bear Clan), Elder-in-Residence and coordinator of the Aboriginal Teacher Education Program at Queen’s University, our interdisciplinary team of Indigenous and non-Indigenous scholars and award-winning visual and digital media artists will establish a network of immersive virtual reality spaces with nodes across the country dedicated to collaborative encounters and ethical co-creation.  The project also brings together Dr. Caitlin Fisher, director of York University’s Immersive Storytelling Lab, Governor-General's Award-winning visual artist Wallace Edwards, and Dr. Kate Freeman, who brings thirty years of experience working in the field of Indigenous education, concentrating on program development, delivery, and evaluation. Working together and with Indigenous and non-Indigenous children in schools across the country, our team will stage encounters and co-create knowledge, art and virtual worlds across disciplinary, generational and cultural distance. We anticipate breakthroughs in foundational assumptions around aesthetics in virtual reality, the pioneering of new directions in hardware and interface development, and an opportunity to assess the potential - to date unexplored - of these tools, methods and spaces for reconciliation.

This is a community-based, interdisciplinary research partnership between the shíshálh Nation and several universities.  Community-based approaches seek to develop questions, undertake research, conduct analysis, and disseminate results, all in close collaboration with Indigenous communities. This project examines the long-term resource management in shíshálh lands from the deep past to the present, from the sea to the sky.

The shíshálh Nation is a unique position among First Nations. They were the First Nation in Canada to achieve self-government in 1986, and have recently signed the first comprehensive reconciliation agreement. As such, this current project will be the first to operate under a formal Reconciliation framework in Canada. The agreement restores shíshálh management of key resources such as fisheries, forestry, and foreshore areas. This project will not only focus on the past utilization of these resources, as seen through archaeological analysis, but also the current efforts and impediments to management in these areas today. It will seek to establish a past baseline and at the same time analyze the current situation to provide valuable insight to the shíshálh Nation for future planning.

The geographic focus will be the northern half of shíshálh lands, near the winter village sites of xenichen and ts’unay. These areas have yet to receive any academic attention, save for a short pilot archaeological study in the summer of 2018.

This project will answer important academic research questions in archaeology, biology, geography, resource management, and geochemistry. In addition to the standard research outputs of scholarly journal articles and conference presentations, the project will produce accessible output for the shíshálh community that will include short documentary films, museum exhibits, blogs, and interactive community events.

Risk exits in two areas, as the first academic project in the formal Era of Reconciliation; there is no playbook for how to achieve success. In addition, we will attempt to produce both academic and community accessible outputs simultaneously. This will involve the commitment to explain, demonstrate, and involve the shíshálh community in all aspects of research and analysis. A task of this breadth will be daunting. However, Reconciliation is upon us and our current challenge will be commonplace in the coming years. Providing a successful way forward will benefit the broader academic community greatly.

HIGH REWARD CONTEXT: While hundreds of Canadians die waiting for organ donation yearly, 1/5 available organs are judged inadmissible for donation. In this context of urgent needs and life saving expectation from recipients, it is unacceptable to discard these precious organs and to ensure to respect the donors and its families good will. Innovative strategies for organ procurement should thus be explored and implemented. It is suggested that an intense release of inflammatory mediators (“the storm”) following brain death might be the source of organ damage impairing graft’s admission for donation and function in the recipient. Although donors are currently taken care of using untargeted drugs in regard to this storm, we propose to design an intelligent bedside device, informed by patient’s needs and adapted to suit indigenous communities’ capacity, to guide a personalized administration of drugs targeted to reduce the impact of inflammatory effectors on the organs.       

HIGH-RISK OBJECTIVES: 1- Engineer a device that will monitor inflammatory markers (at an early stage and as true effector) in a timely fashion at the donor’s bedside; 2- Create a learning algorithm that will predict the dose of immunosuppressive drugs to be administered to the donors; 3- Evaluate patients engagement in designing the device; 4- Evaluate the acceptance and feasibility of introducing this device in usual clinical care settings of indigenous communities. 

ADVANCING TECHNOLOGIES AND PATIENT’S ENGAGEMENT: An automated bedside device will be developed using a system-on-chip microfluidics approach, integrating surface plasmon resonance biosensors, which will directly draw blood from the patient’s intra-arterial line hourly, quantify the inflammatory effectors (TNF-alpha and its related microRNA’s) and feed a statistical learning algorithm, inspired by artificial intelligence techniques. By means of quantitative and qualitative methods, patients-partners and indigenous communities will be consulted throughout the process. 

RELEVANCE: Our interdisciplinary team of intensivist, immunologist, biomedical engineers, biochemist, mathematician, qualitative methodologist, nurse working with indigenous communities and patients-partners will enable the realization of a ground-breaking device that will change the management of donors in the intensive care units to improve the quality of organs provided to the recipients to ultimately increase transplantation success rate. 

This project is motivated by a central proposition: by reframing soil as a relational medium instead of a resource, we can facilitate new solutions to pressing socio-environmental problems such as soil conservation, food insecurity and environmental racism. As a "relational medium," soil is defined by the range of social and natural elements—from Indigenous agriculture to industrial farming, from wind erosion to global warming—that converge in soil in a particular location over time. Within this framework, soil is defined not only by its physical properties, but also by an ongoing history of transformation. As such, it transcends simplistic distinctions between social and natural history, and between disciplinary approaches.

To explore and advance this proposition, we develop a new methodological approach that is collaborative, interdisciplinary, and prioritizes marginalized perspectives, including indigenous, rural and northern communities. Through collaboration with soil scientists, critical theorists, and Indigenous communities, we analyze the chemical composition of soils; the geological history of soil composition; socio-political history and its local effects; and the existing and potential practices that interweave social and natural dimensions of that locale, including potential influences of global change. By doing so, our research challenges existing research paradigms, and offers a comprehensive and inclusive understanding of soil—and the wide human and non-human networks that converge in and depend upon soil.

We will apply this research at three distinct sites in Ontario, Alberta, and Yukon. Building on these ‘ground-up’ analyses, and applying theories of anthropological scale, our findings will be scaled up from local to national levels. Presenting what we find (and our process of discovery), we hope to engage a wide audience in a continuing, iterative learning cycle. In doing so, this project will achieve the following aims: improving long-term sustainability of soil networks; prioritizing benefits for communities most affected by soil degradation (including more rigorous consultation with indigenous communities regarding land and environment); and making soil research more accessible to interdisciplinary researchers, educators, and policy makers.

Gait rehabilitation strategies often focus on restoring a desired ‘normal’ or ‘healthy’ gait, and for good reason—this is typically the desire of those being rehabilitated. For example, individuals recovering from stroke often strive for a more symmetric gait. However, our recent work implies that ‘undesired’ gaits may be preferred by the nervous system because they are, in a sense, optimal—walking asymmetrically may be more energetically optimal for a person post-stroke. Traditional rehabilitation strategies directly target the desired ‘normal’ gait, coaching the individual on how to achieve it and requiring repetitive practice under the guidance of a therapist. The expected outcome is that the desired gait will eventually be adopted and energetic costs will decrease. An alternative, and untested, approach is to directly target the energetic consequences of movement, making the desired gait energetically optimal. Our hypothesis is that the desired gait will then be naturally adopted by the individual, and lead to more enduring or effective rehabilitation. We term this novel rehabilitative approach ‘energy incentivized movement therapy’. Previously, we have developed a unique research paradigm that allows us to manipulate the relationship between human gait and energy expenditure during healthy walking. To do so, we use lightweight exoskeletons to apply joint torques that reshaped the relationship between a given gait parameter and energetic cost. This creates an energetic gradient at participants’ natural preferred gait and an energetic minimum at a distinct gait. Here, we will first develop exoskeleton controllers to manipulate the relationship between symmetry and energetic cost in persons post-stroke. Next, we will test if persons post-stroke can be incentivized to walk more symmetrically when exposed to the novel cost landscapes. Finally, we will compare the effectiveness of a traditional gait retraining strategy with our energy incentivized movement therapy over the course of a multi-week intervention. This research will require an interdisciplinary team that combines expertise in fundamental human biomechanics, clinical rehabilitative medicine, and applied robotic control. Our approach, if effective, could be extended to individuals with a range of mobility impairments and has the potential to revolutionize the next generation of assistive robotics and rehabilitation strategies.

Although there is an abundance of research documenting the harmful effects of negative emotions on immune functioning, very little work has examined the potential benefits of positive emotions. Furthermore, almost nothing is known about how individual positive emotions influence immunity. This lack of knowledge is partially due to the interdisciplinary nature of this kind of work, which marries cutting-edge theories in affective science with the newest advancements in physical health. Here, I offer the first research aimed at identifying the immunological consequences of experiencing a key positive emotion—awe. Awe is defined as a combination of wonder and amazement that occurs in response to authority or the sacred or sublime. Awe arises in response to a magnificent piece of art, a beautiful sunset, or the feats of an exceptional person. Although awe has featured prominently in philosophy, art, and religion, only recently has it become a focus within psychology.

In my recent work I identified a powerful relationship between awe and immune functioning (Stellar, et al., 2015). Compared to six other positive emotions, awe showed the strongest negative correlation to circulating levels of a pro-inflammatory cytokine, called interleukin-6, in a healthy population. Though pro-inflammatory cytokines are adaptive in response to infection, illness, or injury, when chronically elevated they have been implicated in the onset and progression of diabetes, cardiovascular disease, and depression (e.g., Cesari et al., 2003). This initial finding challenged the commonly held assumption that positive emotions fail to have the same importance for physical health as negative emotions.

To conduct the experimental work necessary to make causal claims about awe’s impact on immunity I will take an interdisciplinary approach that combines affective science and immunological processes with the visual arts.  This proposal outlines three studies that examine the effects of inducing awe on pro-inflammatory cytokines in the laboratory and the field. In the field, I am collaborating with the Royal Ontario Museum to examine how visual art, through inducing awe, may impact pro-inflammatory cytokines. This work will have a significant impact on our understanding of inflammatory processes and how they can be impacted through positive emotions like awe, and the mediums such as visual art, that elicit awe.

Eyesight is used throughout daily life, from business and education, to navigating social relationships. It is unsurprising then that large resources are leveraged to mitigate eye diseases. This is especially true as we age–almost all eye diseases, including retinal detachment, cataracts, glaucoma, uveitis, and age-related macular degeneration (AMD) increase with age. A limitation of visual impairment research is the availability of high-quality, medically-relevant samples, with corresponding measures of visual function that will reveal impacts of age and genomic background on eye health. As an expert in primate visual systems, I have recently been extended a time-sensitive opportunity to work with an unprecedented biological dataset. My aim is to spearhead a new line of ambitious, multidisciplinary, and collaborative research investigating the genetic and anatomical underpinnings of age-related changes in visual function in the premier non-human primate model of human health. The proposed project, conducted together with with co-applicant Dr. James Higham (New York University), and collaborator Dr. Nalisha Mohamed, OD, FAAO (Optometrist for Alberta Eye MD) will capitalize on a unique, large-scale population reduction of free-ranging rhesus monkeys occurring on Cayo Santiago, Puerto Rico. (Please note, these decisions are being made by the Caribbean Primate Research Center; we seek to maximize the scientific gain from this unfortunate situation.) Each year ca. 200 animals, from juveniles to advanced aged individuals, will be removed from the population and humanely euthanized. Prior to this, we will undertake customized behavioural tests using a looking time paradigm developed by Dr. Higham (Winters et al. 2015) to assess the acuity, contrast sensitivity, and colour vision of each monkey. While monkeys are under anaesthesia, we will test for glaucoma, (ocular pressure), AMD (fundus images), uveitis, and cataracts (visual examination with a slit lamp). Following euthanasia, we will examine changes in retinal function using differential gene expression profiles of retinas. This population is fully pedigreed and our research will facilitate future analyses of disease heritability and specific risk factors using genome-wide data. Overall, we will provide an unprecedented study linking behavioural assessments of visual function with anatomical and gene expression profiles, and  major progress in uncovering the genetic basis of age-related visual impairment.

One of the grand challenges in statistics is understanding the relationship between Bayesian and frequentist inference, the two dominant approaches and philosophies of statistical inference. Progress on this problem could have dramatic consequences for statistical practice, which plays an important role in society today.

It is our view that many of the roadblocks that have arisen in the pursuit of this grand challenge are due to Kolmogorov’s countably additive axiomatization of probability theory, which provides the mathematical foundation of modern Bayesian analysis. In short, our proposal is to rebuild the mathematical foundations of Bayesian statistics, using tools from mathematical logic that were unavailable at the time Bayesian analysis was formalized. In recent work, replacing the standard model of countably additive probability theory with a nonstandard model allowed us to settle the longstanding open problem of deriving a Bayesian characterization of frequentist extended admissibility. We believe that rapid progress on the grand challenge can be achieved by committing additional resources to this unconventional approach.

Unfortunately, there are only a handful of researchers with the requisite expertise in both statistics and mathematical logic to carry out even the basic aspects of the research program we are proposing, and so an interdisciplinary team must be assembled to pursue this research, and junior researchers must be trained. The problems we are studying are also closely related to problems in game theory (a subject with microeconomics). Our approach also relates to a sizable body of work in philosophy that studies the implications of finitely additive, countably additivity, and nonstandard probabilities for the philosophical foundations of Bayesian statistics. It is essential that our solutions not run into known incoherence results identified by philosophers and statisticians. The proposed research is atypical of work pursued within mathematical logic, statistics, microeconomics, and philosophy: expertise in any one of these fields is insufficient to evaluate this work. This represents one of the high risks we face. The interdiscplinary nature of this work also means that it is unlikely to be funded by any one of the three granting agencies.

This project ("In the Words of our Ancestors: Inspiring Contemporary Indigenous Language Research by Critically Engaging with Linguistic Archives") aims to build Indigenous research capacity and explore new approaches in Indigenous language learning for learners with advanced proficiency. The purpose of this research is to collect and critically analyze linguistic archival data as a means to inform language learning generally, and specifically to inform mastery level language learning for Kanien’kéha (Mohawk language) learners in the community of Kahnawà:ke. The objectives are: 1) To train ten community-based language researchers in archival data collection and analysis (e.g., textual and thematic analysis of archival linguistic documents); 2) To consult with Elders and mentors as part of the analysis process (i.e., discussion circles/focus group sessions); 3) To share research findings with the Indigenous community using traditional Indigenous knowledge transmission methods (i.e., formal oration and storytelling); and 4) To produce and distribute a report and resource guide that will help advance learners achieve proficiency at a master level. This research project is guided by Indigenous and decolonizing methodologies and is grounded in theories of postcolonialism, decolonization, Indigenization, and critical Indigenous theory. This research reflects a novel approach to critically engage in linguistic archive-based research as a means to re-purpose data to ultimately inform master level learning of the Kanien’kéha language. The research has inherent risks, such as analyzing particular archival document sources of a sensitive nature, exercising “data sovereignty," and re-visiting and re-establishing relationships between researchers and Indigenous peoples. At the same time, the research offers considerable rewards. Effective teaching of the language to future generations and eventual resumption of intergenerational transmission depends on a critical mass of highly fluent speakers across the age range from younger to older adults. This research holds the power to build Indigenous research capacity and produce positive and significant change for members of the Mohawk Territory of Kahnawà:ke as they work to revitalize their heritage language and have it thrive at a mastery level.