Titulaires de subvention – Exploration 2019

Neurodegenerative diseases (NDs) are incurable debilitating conditions that result in progressive degeneration and/or death of neurons. Alzheimer’s (AD), Multiple Sclerosis (MS) and Parkinson’s (PD) diseases are examples of neurological disorder that are characterized by progressive problems with movement, or mental functioning that significantly impairs the patients’ daily life. The etiology of these disorders has been associated to multiple and distinct genetic factors but the mechanisms of disease are still unclear.

Emerging evidence suggests that changes in diet and alteration of the microbiota influence the metabolic and inflammatory status of the neurons that is linked to NDs insurgence and progression.

Peroxisomes are metabolic organelles that contribute to maintain the healthy metabolic status of the cell. In the last years dysfunction of peroxisomes has been linked to the development of NDs. Our team demonstrated that the peroxisome is essential for the metabolic status of the organism, to regulate inflammation during microbial infection and in brain development and to maintain host-commensal interactions. Considering the importance that all the aforementioned factors play in the insurgence and progression of NDs, we believe that the study of peroxisomes in NDs development will shed light on both genetic and environmental factors (e.g. microbiota-nutritional metabolic factors) that controls the brain health.

We propose a systems biology (transcriptomics, metabolomics, and proteomics) approach to define the peroxisome-dependent metabolites and genetic networks that control the microbiota-gut-brain axis in health and disease using the fruit fly as a fast and genetically sophisticated model organism. The results obtained from the fruit fly study will be verified in cells of the murine brain engineered mimicking human neuropathies and in samples from patients with NDs (e.g. MS). We will apply biophysical analyses to determine the effects of local and distant metabolites that are produced by peroxisomes on neuronal myelination and inflammation. Our multiscreen research approach is high risk but if successful will have the high reward to establish: 1) how dietary- and microbiota-derived metabolites control brain health; and 2) how peroxisome activity affect microbiota-gut-brain axis in patients with NDs such as MS, opening the possibility to identify new disease markers or new targets for therapeutic intervention in these devastating diseases.

As the Truth and Reconciliation Commission calls for a commitment to mutual respect between Indigenous and non-Indigenous Peoples, there is growing recognition that research has and can play a role in supporting long term reconciliation given its’ capacity to inform how Canadian society can mitigate intercultural conflicts, strengthen civic trust, and build social capacity. Critical to supporting this process in science and long term monitoring in Nunavut is recognizing the value of Inuit Qaujimajatuqangit (IQ). Inuit stress that IQ is more than knowledge to be extracted by researchers, it is a worldview supported by principles that guide our interactions with each other and the land. Appropriate use of IQ occurs by embedding certain attitudes and behaviors and actions that are respectful of these principles into all aspects of research. In the Ikaarvik Position Paper 'Meaning Engagement of Northern Indigenous Communities', a concept called ScIQ was proposed by our youth co-applicants (CP; IK) to describe a more functional middle ground between science and IQ.  Inuit youth are uniquely qualified to explore these issues as they often hold dual identities at the intersection of Western and Indigenous worldviews. They are also chronically underrepresented in environmental research and monitoring in Nunavut, where older and more experienced hunters and trappers are often favored. Given that 60% of Nunavut’s population is under age 30, this suggests a gap in research capacity development with almost half of the northern population. The next generation of Inuit scientists, leaders, and resource managers is not being fostered and trained within many current research efforts. This project will foster Inuit youth leadership in environmental research and monitoring in Nunavut using a novel youth-led participatory and highly interdisciplinary approach facilitated by the research team. Inuit youth researchers will operationalize their vision of ScIQ by designing and implementing an environmental monitoring program with the tools and technologies of modern science as well as IQ. This project will provide a tangible path forward in conducting environmental research that values and respects different worldviews while responding to scientific and community research needs. We will measure youth capacity building, local and scientific outcomes using co-designed indicators including self-confidence levels, leadership skill attainment, ScIQ literacy and scientific rigor.

The proposed project will be done in collaboration with the Nisga’a Lisms Government, the Nisga’a Village Government of  Lax̱galts’ap and Simon Fraser University. Traditionally, one type of pts’aan (totem pole) was carved and raised to tell the adaawak (story) of ownership, jurisdiction, title and place names of each of the four Nisga’a tribes and subsequent houses (family groups). Most pre-contact Nisga’a house pts’aan were destroyed by missionaries or stolen and relocated to international museums due to colonialism. The loss of these poles leaves many Nisga’a Peoples unfamiliar with the stories, history and traditional place names that are associated with our visual archive that serves as a form of sovereignty and is connected to Nisga’a cultural identity. In addition, the Nisga’a language is considered critically endangered with approximately 5% of Nisga’a people who are fluent speakers. Significant efforts in the last fourty years have been made to revitalize our language; and a revival of the Nisga’a carving tradition has begun. However, there remains a great need to expand work in these areas. Research objectives include: 1) Use Nisga’a philosophical and pedagogical practices to increase engagement with Nisga’a knowledge, tribe and house adaawak, and the traditional skills needed to carve three new Nisga’a House pts’aan; 2) Expand intergenerational knowledge and awareness of traditional uses of the red cedar tree, place names, and seasonal cycles that are depicted in the poles through the Nisga’a language among Nisga’a children, Elders, families and teachers.This work is based on Indigenous methodologies, with particular attention to the application of a Sayt-k’iĺim-goot (one mind, one heart, one Nation) methodology which is embedded in Nisga’a epistemology and ontology. The research question is: In what ways can the integration of Nisga’a traditional carving knowledge, Nisga’a language revitalization, and land based education contribute towards wholistic well-being for the Nisga’a Peoples? Mixed methods to gather data include: A Nisga’a advisory committee, talking circles, land based walking interviews, museum visits to view ancient house pts’aan, document analysis, video taping, story based research notes, photo voice and community meetings. The proposed research will be the first educational study to ever be conducted on the philosophical and pedagogical practices of the Nisga’a carving tradition, language revitalization and land based education.

Current preclinical therapy-screening approaches, including those employing monolayer cell cultures and animal models, analyse drug-induced molecular, morphological, and/or behavioral changes as the read-out for putative therapeutic efficacy. However, such conventional methods still pose limitations with respect to direct translation to the in vivo response in humans. In order to enhance the physiological relevance of in vitro studies and lessen our dependency on animal studies during preclinical testing, it is thus critical to capitalize on translational approaches and generate tools that provide accurate predictive data on pathophysiological processes. In this context, in vitro strategies founded on the use of 3D cell-based constructs are poised to generate progressively more accurate predictive and diagnostic data on therapeutic efficacy. As ~80% of therapeutic candidates fail due to their underperformance in the human body and/or toxicity effects, these new strategies to develop and screen pharmaceutical compounds for Parkinson’s disease (PD) during preclinical tests will reduce clinical rejection rates. It is now well documented that the bursting activity of basal ganglia neurons is abnormally increased in PD, and that this disease-associated electrophysiologic signature is linked to the loss of dopaminergic input from the substantia nigra (SN). We therefore hypothesize that the bursting pattern of striatal neurons can be exploited as a read-out of the efficacy of prospective PD therapeutics in terms of restoring and maintaining normal electrophysiological behavior after dopaminergic denervation. To this end, we propose an original approach to create a flexible in vitro platform for preclinical drug screening to identify the most effective pharmaceutical compounds prior to clinical trials. In particular, we will synergistically combine microfabrication techniques, multi-electrode arrays (MEAs), 3D neuronal and stem cells cultures to ultimately create a biomimetic system to test, in real-time and in a patient-specific context, the potential of candidate therapeutics to correct the electrophysiological consequences of nigrostriatal denervation. This new approach will ultimately provide crucial data on the ability of therapeutics to offset the degeneration of dopamine neurones in the nigrostriatal pathway, creating an innovative and flexible in vitro platform to safely and rapidly screen compounds to treat PD.

Soil-dwelling bacteria synthesize specialized organic molecules for diverse functions: chemical defense, communication, and chelation of metal ions. Among bacterially-produced natural products, molecules with nitrogen-nitrogen (N-N) bonds are a group of rarely isolated but highly bioactive drug molecules. However, the role of N-N bond-containing molecules in ecological interactions is unexplored.

We identified candidate biosynthetic gene clusters likely to encode enzymes for construction of N-N-bond-containing molecules in a wide suite of plant-associated nitrogen-fixing bacteria. However, little is known about the corresponding molecules themselves or their biological roles.

Hypothesis: N-N bond-containing molecules have the potential to play key biological roles in symbiosis, thus explaining why genes for their assembly are found in many plant-associated symbiotic bacteria and are overexpressed during symbiosis.

Goal: To exploit advances in biosynthesis to understand the structures and biological roles of N-N bond-containing molecules.

This two year, interdisciplinary project has the following objectives:

1. Isolation of N-N bond-containing molecules

We will target a gene cluster in Bradyrhizobium japonicum and use newly developed 15N-NMR experiments with putative biosynthetic precursors to track the molecule during purification and then determine its structure by NMR and X-ray crystallography.

2. In vitro reconstitution of a five-enzyme pathway

We will use purified enzymes to unravel the complete biosynthetic pathway to the unknown N-N bond-containing molecules, and provide an independent determination of their structures.

3. Determine biological function

We will use imaging mass spectrometry of the wild-type bacteria in different conditions, compared to a deletion mutant control, to identify the location of this molecule during symbiosis with plants.

Novelty and Significance: Nothing is known about the function of N-N bond-containing molecules in the natural world. This project, only possible through our highly interdisciplinary team with expertise in Biological Sciences/Biochemistry/Enzymes and Chemical Sciences/Organic Chemistry/ Natural Products Chemistry, will elucidate the structures, biological assembly, and locations of these overlooked metabolites, setting the stage for understanding new aspects of bacterial-plant symbiosis. This high-risk, high-reward project could open up a new chapter in symbiosis-related research.

A team of multidisciplinary researchers has proposed a new mechanism to trap ions for quantum computing and quantum information processing. Traditionally, laser-cooled trapped-ions are used to demonstrate quantum superposition and entanglement, where scalability is often a challenge. Inspired by naturally occurring water channels, i.e., aquaporins, the proposed system will have ions that are trapped inside an artificial one-dimensional (1D) water channel by maintaining the spacing between ions through single-file water molecules, thereby achieving multi-qubit with desired fidelity and coherence. The main objectives of the proposed research program are: (a) to fabricate a fluidic chip that trap desired ions (Cesium and Sodium ions); (b) to characterize the trapped-ion system using high resolution microscopy and spectroscopy techniques. The ions are first extracted from an electrolyte using electroosmotic flow within hybrid silicon nitride–silicon–glass microchannel. In addition, it utilizes van der Waals assembly by sandwiching an atomically flat hexagonal Boron Nitride spacer between two cleaved graphite, thereby obtaining precise angstrom-order channel height to trap ions. The distance between the trapped-ions is manipulated, by introducing water molecules as spacer within 1D nanofluidic channel. This allows us to engineer the ion-ion interactions as an essential component for state initialization and error correcting schemes in future. The characterization of the proposed platform will be performed using high-resolution imaging systems, i.e., Nion UltraSTEM (scanning transmission electron microscopy). Towards the development of scalable trapped-ion quantum hardware, experiments will be performed that determine the system’s viability and feasibility as a promising candidate. For example, we map atomic energy levels via high-resolution spectroscopy to assess the atomic level lifetimes and potential atomic transitions as a qubit. This novel framework brings together fundamentals of micro- and nanofluidics and the state-of-the-art nanofabrication with quantum physics. Finally, this system is a substantial advancement from the traditional linear Paul or 2D Penning traps in the mainstream of trapped-ion quantum hardware. Our proposed program would propel Canada as a global leader in delivering solutions for multi-qubit trapped-ion systems.

Substances addressing the opioid receptor system are widely used pharmaceuticals for the treatment of chronic pain and addictive disorders. Prescription opioid narcotics produce analgesia and side effects through activation of a member of the opioid receptor family the mu-opioid receptor (mu-OR). The misuse of opioids is a serious national crisis due to addiction and life-threatening side effects, such as respiratory depression, convulsions, and seizures. As stated by the Public Health Agency of Canada: “Canada is facing a national opioid crisis. The growing number of overdoses and deaths caused by opioids, including fentanyl, is a public health emergency’’. Strategies for addressing this national problem must occur on multiple fronts, including the development of safer analgesics. The Giguere-Beauchemin labs are addressing this problem by using a multidisciplinary approach specifically designed to achieve our main goal of developing safer analgesics. The proposed research aims to bring to another level our findings that some Na+-channel inhibitors interact with the Na+-pocket of the mu-OR with high affinity. Preliminary data confirm the feasibility of generating small-molecule drugs that would stabilize the Na+-cavity, hence biasing the receptor activation toward more medically meaningful pathways. Interestingly, those Na+ channel inhibitors have chemotype similarity with NAV1.7 and 5-HT3R modulators.  Inhibition of 5-HT3R was found to reduce the reinforcing effects of drugs of abuses. Another important route for pain sensation was recently uncovered by the discovery of a rare genetic disorder involving the sodium-channel Nav1.7. Genetic inactivation of this gene leads to complete inability to feel pain. Despite major advances and drug development, it was found that partial inhibition of Nav1.7 with blocker had poor clinical effectiveness, BUT, combining Nav1.7 blocker with a very low dose of opioids, produced dramatic pain relief. We are thus proposing to generate and optimize the activity of hybrid bifunctional ligands that will act as selective bias agonist at the mu-OR AND blocker at Nav1.7 and/or 5-HT3R. The main hypothesis is that synergistic action will lead to a designer drug with polypharmacological action acting as an analgesic that will alleviate the risk of addiction, respiratory depression, and constipation. Based on key literature reports and preliminary results, we are convinced of the feasibility of such hybrid ligand at mu-OR.

The paradox of model species – representing general conditions, while often being highly specialized – remains a challenge in fields with a comparative foundation. The problem is acute in studies of evolutionary transitions, across which drastic modifications of anatomy coincide with radical ecological or developmental shifts. Amphibians are uniquely positioned at the interface of a key transition in vertebrate history: the water to land transition. However, long-standing model species, Xenopus and the axolotl, are both are highly specialized aquatic species and failure to integrate fossil data with these disparate models has impacted advances in different fields.

As such, the objective of our proposed research is to synergize the fields of experimental developmental biology and paleontology, with input from ecology and computational imaging technology, to add clarity to outstanding questions concerning the origin and evolution of vertebrate form across the water to land transition. To achieve this objective, we will: a) cultivate new model species to facilitate broad, comparative research in vertebrate evolution and development; and b) expand techniques applied to the fossil record utilizing computational and radiation scanning tools resulting in 3D data, refining an analytical pipeline using morphometrics and network analysis.

We will target two living amphibians: Eleutherodactylus coqui (coqui frog) and Plethodon spp. (lungless salamanders) – both terrestrial, direct developers (i.e., no aquatic larval phase). We will establish breeding colonies and develop cutting-edge, molecular tools (CRISPR, transgenics) and experimental systems (embryo manipulation), making these species and tools readily available to a broad research community.

We anticipate our experimental results will fill a conspicuous gap in our knowledge of vertebrate development. Integration of these results with novel data from the fossil record will lead to better understanding aspects of complex vertebrate transitions, such as terrestrialization, as well as aspects of developmental processes underlying major ecological shifts. This interdisciplinary framework – herein, eco-evo-devo-paleo – will allow fundamental questions to be addressed, such as: whether these living amphibians parallel events in early vertebrate terrestrialization; how different life histories influence the diversity of form; and how development coordinates ecological, morphological, and evolutionary changes.

Untreated oral conditions affect 3.5 billion people worldwide. In Canada, oral diseases, including caries, are the second highest direct cost for treatment (estimated economic burden of $11B in 2011). Ideally, safe antimicrobial agents should be present intra-orally to assist with the control of biofilm-dependent diseases. Despite a significant need for mercury-free, safe and affordable alternatives to replace dental amalgam (WHO: The Minamata Convention on Mercury, 2013), not much has been accomplished. Current restorative dental materials do not decrease the incidence of dental caries and the need for scientific efforts on the development of dental materials able to modulate oral pathogenic biofilm is pressing.

The proposed research focus on the development of a novel dental resin able of continuously control oral biofilm attachment and growth. The global hypothesis is that novel metal-doped, photosensitive methacrylate-based dental materials can control oral pathogenic biofilm, immediately and in long-term, without compromising mechanical, chemical and physical properties. The overarching aim is to develop antimicrobial materials that can be periodically reactivated in photodynamic chemotherapy using blue light, safely delivered in any dental office or in light trays at home. Specific aims: 1) Develop a novel metal-modified acrylate co-monomer, sensitive to blue light, to be incorporated into dental resins blends to inhibit oral pathogenic microorganisms (S. mutans and C. albicans); 2) Explore the use of large photosensitive metallic nanoparticles (~200nm) as antimicrobial compounds for dental formulations; 3) Explore synergistic effects of multifunctional formulations containing metal-modified acrylate co-monomers combined with photosensitive nanoparticles to achieve an optimal, non-toxic, low-cost, resin-based antimicrobial dental material.

The expected outcome will be the development of novel resin-based materials with effective long-term antimicrobial activity and equivalent or superior mechanical, chemical and physical properties. The social impact will be significant, especially for populations more susceptible to chronic oral diseases (elderly, hospitalized, frail populations) and for those with limited access to dental care (low income, rural, indigenous populations). The exploratory steps towards the innovative material presents great potential in significantly lower the costs associated with the disease, estimated in $545B in 2015.

The prevalence of food allergy is increasing worldwide. In Canada alone, >2.5 million people suffer from food allergy, which imposes a great economic burden on the healthcare system. Certain food allergies, such as allergy to peanuts, are lifelong in most patients (~80%), and strict avoidance is the only treatment. Despite the patients’ efforts to avoid the offending allergen, the rate of accidental exposures is exceedingly high (33% of peanut-allergic patients affected yearly). Accidental exposures result in allergic reactions, of which anaphylaxis is the most severe. It requires systemic access of the allergen and is life-threatening. Importantly, peanut is the major culprit of food-induced anaphylaxis; this is attributed to its stability on oro-gastrointestinal digestion, which allows high quantities of peanut to enter the bloodstream. Indeed, the major peanut allergens (Ara h 2 and 6) are known to be resistant to mammalian digestive enzymes. We have shown that human intestinal microbiota, the complex and dynamic population of microorganisms that inhabit the oro-gastrointestinal tract, metabolize dietary antigens. However, metabolic processing of peanut allergens by human microbiota, and how this influences its ability to access the bloodstream, has yet to be elucidated. Therefore, we propose bacterial metabolism as a novel target for the prevention of peanut-induced anaphylaxis.

We will apply our expertise in microbiology, immunology, gastroenterology, allergology, and biochemistry to:

1. Characterize the oral and intestinal microbiota of healthy and peanut-allergic individuals, and their capacity to metabolize peanut allergens.

2. Isolate specific bacteria with a strong ability to metabolize Ara h 2 and 6 and diminish their immunogenicity.

3. Assess the ability of the selected bacteria to prevent systemic access of peanut allergens administered orally to germ-free and gnotobiotic mice.

4. Evaluate the protective capacity of selected bacteria in a well-established model of peanut allergy and anaphylaxis.

We expect to discover a combination of bacteria with a protective metabolic signature clinically relevant to peanut-allergic patients. This microbiota would increase the threshold of clinical reactivity to peanuts, thus decreasing anaphylaxis risk and positively impacting patient’s quality of life. If successful, this strategy might be applied to other food allergies highly associated with anaphylaxis.

Mitochondria are central to production of adenosine triphosphate (ATP)—the body’s energy currency. They regulate and mediate key biochemical pathways, impacting most cell biology and medicine. The first demonstrated involvement of mitochondrial DNA variation as a cause of disease was in 1988. Multiple pathogenic mtDNA mutations have since been associated with common chronic diseases, e.g. diabetes, cardiovascular disease, and Alzheimers. Treatments for mitochondrial dysfunction include antioxidants and compounds targeting specific mitochondrial proteins, with underwhelming outcomes. An emerging approach is transplantation of freshly-isolated mitochondria to injury sites, started in 1982 with the demonstration that “isolated mitochondrial can be incorporated into mammalian”. For some time, no published studies replicated the method or explored mechanisms of mitochondrial internalization by cells. In 2000, the scientific community became interested in furthering understanding of mitochondrial transformation and its mechanism, leading to successful mitochondrial transplant in pediatric patients with ischemic heart disease.

Still in its early stages, clinical mitochondrial transplant is a natural fit for treatment of mitochondrial disease. To date, no studies have evaluated the potential of mitochondrial transplantation for mitochondrial disease. Use of mitochondrial transplants in inherited mitochondrial disease presents challenges, including the need to identify autologous mitochondrial with low (or absent) levels of mtDNA mutation and ensuring that no novel mitochondrial DNA mutations are developed.

Thus, the overall objective of this study is to use mitochondrial transplant to decrease or stabilize heteroplasmy in mitochondrial disease. To achieve this we will: (1) define the best method to shift mtDNA heteroplasmy in patient-derived iPSCs; (2) establish an efficient and stable mitochondrial delivery method; and (3) validate selection and autologous transplant efficiency using mouse models of the disease. Ultimately, the project will lead to testing the efficacy of mitochondrial transplant in patients with mitochondrial disease.

Our group is best positioned to establish Canada this field’s leader with our already-developed technologies: (1) iPSCs that maintain heterogenic levels; (2) genetic methods to shift in hetoroplasmy; and (3) a hydrogel matrix with potential to properly deliver mitochondrial to tissues.

Optical (and microwave) microscopy suffers from a fundamental resolution limitation arising from the diffractive nature of light.  This translates to an optimum resolution in the order of half wavelength multiplied by the numerical aperture of the imaging lens (i.e. hundreds of nanometers for light). Current solutions to sub-diffraction optical microscopy are limited by the need for placing the object in the extreme near field of the lens (few nanometres), fluorescent-molecule labelling with shaped light illumination and slow/fine-scanning operations. To overcome these limitations, we are proposing to leverage established antenna-array theory to focus electromagnetic waves beyond the diffraction limit using superoscillations combined with advanced computational imaging techniques.  Our goal is the development of high-risk/high-reward imaging and focusing apparatus in two distinct parts of the electromagnetic spectrum---optical and microwave.

Superoscillations make it possible to generate extremely fast local field variations beyond the Fourier-transform limit. We will use this property to develop an advanced optical super-microscope (AOSM): a microscope with sub-diffraction resolution which can operate in the far-field, does not require fluorescent labelling and can take real-time images. To achieve this, our planned AOSM will rely on a programmable spatial light modulator (SLM) that weighs the propagating spectrum of light, thereby yielding a super-oscillation optical transfer function (SO-OTF) that can be modified on the fly in real time. In this way, advanced computational imaging techniques are enabled.  To this end, our focus will be on the development of computational imaging techniques tailor-made for the AOSM in order to obtain the best-resolved image. Specific directions will include (1) designing optimal coding schemes for controlling the OSM’s spatial light modulator to get the sharpest possible SO-OTF, (2) end-to-end optimization of the SO-OTF and the computational image post-processing algorithm, and (3) development of optimized multi-image acquisition techniques for enhancing resolution even further, by first acquiring images with an appropriate sequence of SO-OTFs and then jointly post-processing them with an optimized multi-image decoding algorithm.

In addition, we will develop a system to produce sub-wavelength focused microwave spots for biomedical therapy/imaging applications.

Since the 1970s, there has been a perceived increase in the pace of films and television programs addressed to children. While researchers have attempted to study the impact of this “intensification” on children, results have been inconclusive. Concurrently, increasing screen time in children starting at a young age has developed into a high parental concern, with regards to impact on cognitive development and bio-psycho-social factors, such as the risk of developing attention deficits. Research on this subject tends to be discipline-specific, and thus governed by competencies that belong to a given field. An example is the obvious disagreement on what constitutes “ audiovisual pace” which cannot be defined objectively even when consensus exists on the question of intensification. Audiovisual pace is not reducible to a single parameter. Spectators simultaneously receive many inputs: visual aesthetics (camera movements, shot scales, editing), sound effects, music, dialogue, and images, each of which a spectator pieces together to construct a narrative. Secondly, the inputs are received within the context of a story which impacts the perception of pace. The objective and subjective perception of pace may then not coincide. Thirdly, the formal features of an audiovisual story typically apply techniques intended to render the formal features invisible to attention such that editing is nearly imperceptible to the average viewer. Likewise, it is difficult to define parameters for establishing areas of the brain or the mind that are affected. This project proposes to combine the efforts of two research labs from different fields, Laboratoire CinéMédias and the Neuroscience of Early Development (NED) Lab, with support from an expert in artificial intelligence, by designing new stimulations and experiments intended to address these questions. In order to define parameters linked to the experience of audiovisual pace, we will use electroencephalographic (EEG) activity as an objective outcome measure, suggesting that brain activity resonates with pace perception. Further, we will develop and validate questionnaires to assess the subjective audience perception of audiovisual pace in different age groups. Thirdly, artificial intelligence will be used for evaluating high and low paced audiovisual content in order to develop baseline criteria for discriminating these two categories of stimulation and comparing these results with those of the other two studies.

High-profile research on radiotherapeutic methods like radioimmunotherapy, targeted alpha particle therapy and associated imaging techniques is hampered by the limited availability of rare and relatively short-lived isotopes like 209,211At, 225Ac, 223,224Ra, 213Bi or 212Pb. A promising production method for these and a variety of other rare isotopes is the irradiation of Th targets with high-energy proton beams.

The production rates are large enough to provide sufficient quantities for clinical research. The challenge – and the motivation for this proposal – is the efficient and timely separation and preparation of pure radiopharmaceuticals from rare isotopes with half-lives in the range of hours or days.

We propose investigations of a set of element and isotope separation techniques:

1. The development of a thermo-chromatographic pre-separation process to extract volatile species from a refractory target material.

2. The chemical processing of fractions from stage 1.

3. The separation of isotopes of specific elements via resonance ionization mass spectrometry (RIMS).

The benefits compared to chemical processing of the whole target or “isotope separation on-line” are:

- simplified processing of smaller quantities (lower activities, fewer species, higher purity)

- quick separation of relatively short-lived, but volatile species such as 209,211At and 211Rn

- reduction of radioactive waste (less wet chemistry required, no further processing of a re-usable target

- removal of any contaminants and radiological hazards via element and isotope-selective RIMS

Some elements, such as actinium, require very high temperatures to be efficiently driven out of the production target. Therefore, the development of a target material that is stable up to a temperature of at least 2000 °C is an essential condition for this approach. The only compound with the right properties is thorium carbide (ThC) which is also pyrophoric and a safety hazard. It has been demonstrated on UC, which is somewhat less pyrophoric than ThC, that it is possible to render the material sufficiently inert by adjusting its carbon content, particle size and sintering. Whether it will be possible to develop a ThC material that is sufficiently inert to obtain safety approval for the operation of isotope production targets is a major risk for the complete success of the project. Regardless, the separation techniques proposed above could be adapted for other targets.

Non-deterministic polynomial time (NP-complete) problems are relevant to many applications, such as resource allocation, cryptography, circuit design, and protein folding. The time required to solve these problems increases exponentially with the problem size, making them intractable for conventional, sequentially-operating electronic computers, for which the computing time and energy consumption increase exponentially with the size of the problem.

Several approaches for these problems are proposed, but all face dramatic challenges. Quantum computing is a strong challenger, but the question remains if quantum multiplicity is enough to completely explore the large solution space of NP-complete problems, against the fundamental noisy nature of quantum computing, requiring large redundancies, and the finite number of qubits. Alternatively, DNA computing attempts to solve NP-complete problems by generating an enormous number of different DNA strands. However, because the sequences comprise all possible base combinations, rather than only those representing the possible solutions (a much smaller population), DNA computing requires large amounts of DNA (tons).

Recently, the PI proposed the use of self-propelled cytoskeletal filaments as computing agents exploring, in a massive-parallel manner, molecular motors-functionalized planar microfluidic networks, which encode an NP-complete (Subset Sum) problem. This approach scales well in energy consumption, and the large number of computing agents exploring tree-like networks make the computing time grow only polynomially with the size of the problem. However, while the computation itself is very quick, all agents must pass sequentially through a single entry, making the ‘booting’ of the computer, and the overall computing time, inordinately long.

The project proposes the use of computing agents, such as bacteria, or splittable cytoskeletal filaments, that divide during the exploration of microfluidic networks encoding an NP-complete problem. This is equivalent with the increase of the number of ‘computer’s CPUs’ during the computing process, in line with the size of the problem. Additionally, the agents will be light-activable when passing logical gates, thus being able to report their calculation history at the end of calculation (as opposed to the present post processing of trajectories). The project requires expertise in mathematics, computer science, micro- and nano-fabrication and molecular and micro-biology.

The hippocampus is a specialized region of the brain important for the acquisition, storage, and retrieval of memories over the life-time of an animal.  For example, bilateral removal of the hippocampus in the patient H.M. lead to the inability to form new long-term memories.  The hippocampus is also one of the first regions negatively impacted in Alzheimer’s disease.   Closed-loop experimental interference in hippocampal dynamics also negatively impacts performance in memory-based tasks.  These findings all point to the fact that interfering with hippocampal dynamics somehow leads to memory deficits, as if the “hard drive” of the brain has become corrupted or disabled. 

In fact, we hypothesize that hippocampus is operating explicitly as a biological implementation of a Hard Disk Drive (HDD).  To that end, we have constructed a mathematical model where hippocampal rhythms and functions concretely map to those of an HDD.  For example, the hippocampal theta oscillation maps to a disk read/write speed, while hippocampal sharp-wave-ripples map to disk rotations. 

We refer to our mathematical model as the Biological Disk Drive (BDD) model of the hippocampus.  Since the time of Jon von Neumann, mathematicians and computer scientists have used loosely defined brain-computer analogies.  However, the BDD model is the first mathematical model to concretely link the functions, structures, and dynamics of a neural circuit to a computer device.   

The objectives of this research are three-fold:

1. Construct spiking-neural-network computer simulations that implement the mathematical BDD model in the lab of Prof. Wilten Nicola (University of Calgary).

2. Test the BDD spiking models experimentally in mice performing novel behavioural paradigms while simultaneously recording (multi-electrode) in the hippocampus in the experimental lab of Prof. David Dupret (Oxford University).

3. To reverse the analogy and construct a Neuromorphic Disk Drive (NDD) by implementing the BDD model on neuromorphic chip.

The BDD model would yield a new understanding of how memories are encoded and lead to novel strategies for treating memory-related disorders by treating them as repairable malfunctions of an HDD.  Further, the BDD model yields a novel computer architecture, the NDD, for storing information.  The NDD would have a wide-ranging impact on society given our effortless ability to store, catalogue, replay, and compress information over a life-time. 

The Intergovernmental Panel for Climate Change (IPCC) has identified photovoltaics (PV), among other renewable energy sources, as having the largest mitigation potential for meeting the Paris Climate Agreement emission targets. To guarantee the widespread distribution of solar energy conversion technologies, however, cost competitiveness and solar intermittency must be addressed. Solar fuels based on the photoelectrochemical (PEC) conversion of CO2 can store electrical energy from solar PV while offering a potential solution for controlling greenhouse gases. By replacing state-of-the-art manufacturing techniques for PEC devices with low-cost solution-based methods, cost-competitive alternatives for fossil-based resources can be obtained. Canada has the potential to be a leader in this important new field of research, creating new jobs in the energy sector, satisfying the increasing energy needs for transportation and off-grid communities, and contributing to a clean and sustainable energy solution for the future.

The proposed project targets the development of novel low-cost deposition methods for catalyst thin film layers that are at the core of the CO2 reduction reaction in PEC devices (PECs). It will focus on the use of benign and abundant reagents to fabricate both solution-processed metal oxide and metal chalcogenide thin films of high material quality, stoichiometric and morphological control, and reproducibility. Films will be evaluated on their activity and energetic efficiency, product selectivity, rate of conversion, overall processing costs, scalability, and stability in operation. The project further aims to design and realize operational PECs for CO2 reduction by driving electrolysis reactions with solution-processed single- or tandem thin film solar cells. Inspired by photosynthesis, the development of efficient and low-cost solution-processed PECs could ultimately pave the road to transition from conventional fossil-based resources to renewable and carbon-neutral solar fuels. The project will build on Prof. Uhl’s extensive expertise in solution-processed semiconductors and inorganic thin film PV as well as Prof. Berlinguette’s excellent facilities and renowned expertise in water and CO2 catalysis and dye-sensitized solar cells.

MOTIVATION: Many neurodegenerative diseases involve aggregates of misfolded proteins that propagate by converting their normally folded counterparts into toxic forms. Therapies targeting misfolded proteins have failed, in part because there can be multiple misfolded structures or ‘strains’ and these strains can adapt to drugs: targeting one structure simply allows other, resistant strains to dominate. Despite the importance of such strain adaptation to therapeutic development, it is poorly understood mechanistically. We will investigate strain adaptation in misfolded proteins using the hallmark protein misfolding disease—prion disease, caused by the protein PrP—where strains have been best characterised.

GOAL: Most prion strains selectively convert PrP molecules with a specific pattern of sugars (glycans) attached to the protein. How glycans influence protein misfolding is key to understanding strain adaptation but remains unclear, because natural glycan patterns are too variable for controlled study: specific glycans at specific locations are needed. Our solution is to attach glycans chemically to recombinant PrP, generating specific glycoforms for controlled experiments to decipher the molecular basis for strain adaptation.

APPROACH: We will enzymatically trim natural PrP glycans to a uniform stub, to which we will attach glycans of different size and charge. The mechanisms of strain adaptation will then be studied, by first seeding solutions of specific PrP glycoforms with different prion strains to test which strains each can propagate and then repeating these assays using drugs that select against certain strains, to see how each glycoform contributes to strain adaptation. Finally, we will use laser tweezers to measure how the glycans change the folding/misfolding dynamics of single PrP molecules, thereby relating the dynamic effects to the strain adaptation abilities of each glycoform.

NOVELTY: Native-like chemical glycosylation of PrP has never been done because it is technically challenging. We propose the first systematic study of how glycans affect strain adaptation, and protein folding more generally at the single-molecule level, to close critical gaps in our understanding of the effects of glycans on protein biology. The project impact will go beyond prion diseases to prion-like diseases (e.g. Alzheimer’s, Parkinson’s, tauopathies), where strain selection is also important and an improved mechanistic understanding will aid drug development.

Globally, chronic non-communicable diseases (NCDs) including obesity and heart disease kill 38 million people per year. Canada is no exception with over  50% of Canadians overweight or obese and more than 18% of adolescents living with one or more chronic conditions before they finish highschool. The Developmental Origins of Health and Disease (DOHaD) concept provides a new lens through which to prevent NCDs and reduce health inequalities. Studies show that prenatal adversity changes the way a fetus develops and increases later risk of NCDs. Critically, NCD risk are transmitted from parents to children and grandchildren, perpetuating health deficits. Therefore the window just before and  during pregnancy give us new opportunities for interventions to have transgenerational impacts. But, to shift policies for addressing inequity and NCDs and to break this cycle of disadvantage, we must effectively translate early life origins concepts to policymakers, healthcare professionals and to the public, in a supportive and productive manner.

Overall Goal: With the Art Gallery of Hamilton (AGH), we will create an interactive art-based education program, to translate the new science of “early origins” to the community, particularly to those who would not normally have access to this science. Working in collaboration with local artists we will create visual representations of the importance of the early developmental environment through photography and film. We will create interactive art installations within public spaces that will engage, inspire and educate the public, conveying messages of the importance of periconceptional health, in a manner that will enable us to collect health behavioural data.

The Art of Creation Project (ACP) will be co-developed with members of  community, health organizations, pregnant and postpartum women, and local artists. It will be accessible and appealing for people across all socio-demographic spectrums, and will convey messages of the importance of a healthy start to life to reduce NCDs. The ACP will be easily scalable to any community, city or country. Arts-based education can be a powerful tool to inspire, motivate, and empower change.  It can challenge cultural narratives, shift imagery and inspire emotions in a way that other traditional methods of learning rarely do. Using interactive art installations, we will shift community and health policy perceptions on how to improve health and reduce disease risk.

Background: Galectin-9 (Gal-9) is a sugar-binding protein belonging to the family of galectins. It exhibits a wide range of immunomodulatory functions, mainly anti-inflammatory, by inducing apoptosis of activated T cells and promoting the differentiation of regulatory T cells. Gal-9 reduces rheumatoid arthritis, autoimmune encephalomyelitis and ameliorates lupus in animal models. It also reduces organ transplant rejection. Recent studies have demonstrated that Gal-9 offers anti-proliferative capability on cancer cells, as Gal-9 expression loss has been reported in association with metastatic progression.

We have recently shown that soluble Gal-9 prevents HIV infection. Another report indicated that Gal-9 reactivates HIV latency and may be exploited to prevent HIV acquisition and/or to eradicate the latent HIV reservoir. Therefore, Gal-9 has a broad range of biological and immunological functions targeting autoimmune diseases, Inflammatory bowel disease (IBD), asthma, transplantation, cancer and infections such as HIV.

Hypothesis: We hypothesize that engineering a commensal bacterium to secrete human Gal-9 when administered to the mucosal surfaces (orally, vaginally or as a rectal suppository) would be a novel and versatile platform with a wide range of clinical applications.

Objectives: 1) To engineer a commensal bacterium with Gal-9 secretion capability. 2) To determine the biological/immunological functions of recombinant Gal-9 secreted by the engineered commensal bacteria. 3) To design optimum drug delivery methods for Gal-9 producing bacteria for topical and systemic applications.

Methodology: Our methodology will combine state-of-the-art methods from immunology, molecular biology, biochemistry, pharmacology and chemical/material engineering. We are already in the possession of a Gal-9 construct in Escherichia coli that will be transformed into commensal bacteria. We will use Lactococcus lactis, a widely used and safe commensal bacteria as our delivery system. The activity of secreted Gal-9 by L. lactis will be confirmed by various biochemical and immunological assays. Finally, the validated Gal-9 secreting bacteria will be incorporated in our optimized biomaterials for delivery.

Significance: Our proposal will pave the way toward developing first-in-class, live and versatile immunomodulatory drug.

Cells are the fundamental unit of life, capable of self-replication and adaptation. The information necessary to perform these tasks is encoded in the genome. Cells have evolved diverse strategies for compacting the genome into a small volume while maintaining access for replication, transcription and repair. For example, eukaryotes use highly-conserved histone proteins to wrap DNA into nucleosomes and assemble chromatin. The only known exceptions to this rule are dinoflagellates, a diverse group of primary producers. Dinoflagellates use a set of basic proteins termed Dinoflagellate Viral Nuclear Proteins (DVNPs) to package their large genomes into constitutively condensed liquid crystalline arrays. This remarkable chromosome morphology was first observed over fifty years ago but the underlying physical and molecular mechanisms are still unknown.

Liquid-liquid phase separation has emerged recently as a novel mechanism for genome organization. Like oil droplets in water, transcriptionally silent heterochromatin domains separate from transcriptionally active euchromatin. Despite our growing knowledge of the mechanisms that spatially organize genomes, it remains unclear how higher-order chromatin organization governs cellular function.

Here, we will exploit the dinoflagellate Symbiodinium, which naturally switches between free-living and symbiotic states, to directly compare changes in genome organization and cellular function in two distinct environments. We will integrate four complementary approaches to identify the physical principles and biological processes that condense genomes into liquid crystals and to determine how they regulate genome function. First, we will map the locations of DVNPs, histones and open chromatin across the genome to compare genome structure to transcriptional output in free-living and symbiotic cells. Second, we will characterize and perturb the dynamics of DVNPs and histones in free-living and symbiotic cells to assess the impact on genome organization. Third, we will reconstitute chromatin in vitro to characterize the role of DVNPs and histones in liquid crystal assembly. Fourth, we will develop an analytical model and numerical simulations of phase separation to directly compare theoretical predictions with in vivo locus-tracking. Ultimately, our work will reveal how cells throughout the tree of life exploit simple physical laws to drive adaptation, evolution and thus biodiversity.

Background: Neoadjuvant (i.e. pre-operative) chemotherapy (NAC) is used to treat patients with high-risk breast cancer. The benefits of NAC for high-risk patients include early treatment of potential micrometastatic disease and the ability to monitor in vivo the clinical response to the NAC regimen and enables pathologic evaluation of tumor response post-operatively. Patients who achieve a pathological complete response (pCR) after receiving NAC, have a significantly lower risk of breast cancer recurrence and better disease-free survival (DFS) compared to patients who have residual disease (Cortazar et al., 2014; Von Minckwitz et al., 2012). Currently, we are unable to ascertain which women will achieve a pCR to neoadjuvant chemotherapy. There is a need to predict which women treated with NAC will achieve a pCR, so that additional (adjuvant) treatments can be targeted appropriately to those at greatest risk; while sparing those who do not benefit from NAC, the toxicities of ineffective treatment.

Objectives and Methods: To identify clinicopathomic biomarkers that predict pCR upfront among high-risk, breast cancer patients treated with NAC. The pre-treatment digitized core biopsies of the tumor will be used for computational biomarker analysis. This work will build a computational oncology and pathology platform to predict NAC response in breast cancer. Data analysis will be carried out in breast cancer patients who did not achieve a pCR (with partial pathologic response [pPR]) and for those who demonstrated a pCR. Digital pathology of the core tumor biopsy and lymph node specimens will be analyzed and pathomic biomarkers from each will be used for analysis and model-building using artificial intelligence algorithms. We will apply deep learning models to characterize tumor nuclear architecture, as well as tumor infiltrating lymphocytes (TILs), within the tumor to identify aggressive or chemoresistant disease (Wang et al., 2017). Machine learning classifiers, such as k-NN, naïve Bayes and SVM classifiers will use clinicopathomic features to predict the response to NAC. We will compare the performance of the clinicopathomic score to the standard RCBI (as assessed after NAC) by running two logistic regression models and then doing a test of correlated ROC curves.

This highly interdisciplinary project connects ecology and climatology (biological and earth sciences), art theory and practice (fine arts), mental health and social wellbeing (health sciences), and learning theory (social science) towards producing materials and knowledge that will support the development of visual and linguistic vocabularies and rituals for understanding thoughts and emotions associated with “climate grief”.  Climate grief is a general term used to encapsulate negative emotions such as cognitive dissonance, sadness, and other forms of pain that people feel when experiencing loss associated with a changing climate. The vocabularies and rituals around experiencing climate grief are insufficiently developed, however, and there is a pressing need for community spaces to discuss, visualize, and process feelings associated with loss. There is also a lack of understanding of how the effects of climate change are transforming artistic practice and the notion of artistic legacy.

Our interdisciplinary team will engage in a high-risk research collaboration at the volatile and often uncomfortable intersection of fields that produce different types of knowledge. This tension will be used to fuel an artistic process that will bind the different forms of knowledge and build expanded vocabularies and rituals for climate grief. We will explore the following objectives: (1) Create a forum for cross-disciplinary exchange of knowledge, vocabularies and practice and assess which parts of the emotional, artistic, and ecological landscape of climate grief are currently under-described, poorly understood, and/or difficult to articulate; (2) Generate art works that respond to, and explore climate grief, and create spaces for public discourse and emotional response; (3) Explore artists’ and the public’s thoughts and emotions around climate grief through engaging with art practice and experience.

Our methodology involves different phases of knowledge production, art creation, community engagement, and analyses of the emerging vocabularies and rituals of climate grief through engagement with multiple ways of knowing (artistic, scientific, emotional). The vocabularies and rituals for climate grief will engage with the environments and publics of key Canadian ecoregions already feeling the effects of climate change and will contribute to multiple settings that support mental health, overall wellbeing, human resilience and environmental sustainability.

Over the past ten years, a novel approach to combat bacterial food contamination has emerged, and this approach employs nanostructure geometry to deliver lethal mechanical forces causing bacterial cell death. A series of nanofabrication techniques (etching, sputtering, templating, etc.) and materials (black silicon, graphene, etc.) have been employed to prepare the mechano-bactericidal nanostructures. Electrospinning is a simple and inexpensive method to produce fine fibers with high aspect ratio and large surface area. To date, electrospinning has been used to fabricate nanofibrous ‘mats’ that prevent bacterial adhesion via superhydrophobicity but have not yet proven to be mechanically bactericidal. Commercial cellulose acetate has been widely applied in the fabrication of electrospun fibers. The obtained non-woven fabrics are stable in water and can be converted into pure cellulose by deacetylation. Cellulose nanocrystals have a needle like shape (diameter: about 10 nm; length: 100-1500 nm) and are very rigid. The preparation of cellulose-based biodegradable mechano-bactericidal nanostructures has never been reported. The overall goal of this research is to utilize cellulose acetate and cellulose nanocrystals to build the mechano-bactericidal nanostructures. Co-axial electrospinning will be used to fabricate ultra-fine fibers with core-sheath structure. Hydrophobic plant protein will be added in the sheath layer, so it will shrink in water or be partially dissolved in ethanol/water to expose the needle-shaped cellulose nanocrystals, which will act as nanopillars to damage bacterial membrane. This will be the first attempt to combine this nanostructure (needle-shaped rigid cellulose nanocrystals) with a cost effective technique (electrospinning) to fabricate a biodegradable mechano-bactericidal material. Various types of antimicrobial products will be fabricated, including food packaging materials, and filtration membranes. These novel materials will mechanically destroy microbial cells, thus improving food safety and extending shelf-life, while still maintaining a "clean-label" food product. The expected significance of the work will be filling a knowledge gap: using natural polymers and electrospinning to prepare a mechano-bactericidal nanostructure, and producing value added products with a desirable anti-microbial property.

Congenital fetal anomalies occur during pregnancy and is either diagnosed before or after birth. Abnormal organ development induced by gene defects, multifactorial inheritance, or environmental teratogens leads to perinatal mortality or severe lifelong morbidity. Therapy using microRNA, which are small non-coding RNAs that regulate gene expression through mRNA stability and translation, can guard against this detrimental condition but currently lacks the adequate delivery system. We will explore the potential of nanotechnology for targeted fetal delivery of microRNA during pregnancy while maintaining restricted maternal exposure.

Herein, we propose novel technologies to rescue abnormal lung development of babies with congenital diaphragmatic hernia (CDH). With no current cure, CDH accounts for 1-2% of infant deaths and exhibits a disproportionate socio-economic burden in Canada to those affected by CDH and their families. A multidisciplinary team consisting of Dr. Hagar Labouta; a nanotechnologist with expertise in nanoparticle (NP) design and in vitro assessment and Dr. Richard Keijzer, a pediatric surgeon and leading authority of CDH in Canada will drive the development and elucidate the clinical potential of these innovative technologies. Dr. Keijzer has demonstrated the potential of a pre-natal micro-RNA therapy, namely miR-200b, in rescuing abnormal lung development in an animal model of CDH.

Our current understanding of the key determinants of placental transport of NPs is rudimentary. The goal of this project is to study and develop NPs that can selectively cross the placental barrier to deliver miR-200b to the fetus while mitigating maternal off-target effects. This hypothesis will be evaluated at the in vitro and in vivo level through a systematic approach to a) optimize antibody-functionalized NPs with high loading efficiency of miR-200b using microfluidics; b) assess the transport of NPs across the placental barrier in vitro under flow conditions simulating the dynamic environment in vivo; and c) assess miR-200b therapy in a rat model of CDH. Successful development of this effective and novel therapy has the potential to rescue abnormal lung development for babies with CDH before they are born with this devastating disease. This would decrease the healthcare burden and improve the quality of life of infants in Canada and globally. This will serve as a catalyst in the development of fetal therapies to correct for congenital anomalies.

Dogs do it. Parasites do it. We do it. Fertilization is an essential biological process that requires the fusion of sperm and egg membranes. Given the success of in vitro fertilization, one would think that the mechanisms of fertilization would be well understood. However, the molecular players involved and mechanisms of sperm-egg fusion are still unknown and remain one of the biggest mysteries in reproductive biology.

Our group previously demonstrated that sperm IZUMO1 and egg JUNO are necessary for gamete recognition, but not fusion (Aydin et al 2016 Nature). We now have preliminary data that indicate that the sperm proteins SPACA6 and ADAM20 are also critical for human fertilization. Knockout of SPACA6 in mice results in male sterility. A mutation in ADAM20, first observed in an infertile patient, results in a buildup of sperm in the perivitelline space, suggesting a failure in fusion. Moreover, ADAM20 contains a putative viral-like hydrophobic fusion peptide. We hypothesize that IZUMO1, JUNO and SPACA6 interact to recruit ADAM20 to mediate sperm-egg fusion.

We plan to use a very non-traditional approach to unravel the molecular underpinnings of sperm-egg fusion. We will uniquely combine leading expertise in structural virology with reproductive biology to:

AIM 1. Visualize and decipher the molecular steps involved in human fertilization. Traditional structural biology approaches study proteins in isolation and not in the native context. Cryo-electron tomography (cryoET) is transforming how we view and value proteins in their intact cellular environment. We will use our expertise in crystallography and cryoET, gained by studies of viral entry into host cells, to visualize in situ the function of SPACA6, ADAM20 and its relationship to IUZMO1-JUNO. Moreover, in vitro biochemical assays and in vivo genetic mouse models will be used to further elucidate the roles of these proteins.

This high risk-high reward project is designed to resolve a longstanding debate regarding the bonafide human sperm-egg fusogen and mechanism of fertilization. This research will significantly advance fundamental knowledge and ultimately have applications across the animal kingdom. Our plan brings together multiple disciplines to study fertilization with a new lens, applying the techniques and principles developed from viral entry to fertilization. Our work on IZUMO1-JUNO proves that lessons learned from viruses can be used to take a fresh look at fertilization.

Wearable sensor systems present a unique opportunity for the continual monitoring of vital signs and health status of an individual. These systems can be integrated into common items such as clothing, contact lenses, bandages, and watches to detect and quantify analytes from mucosal membranes or biological fluids.   One major challenge to fully realize these systems is the development of platforms that allow for reagent-free analysis of complex biomolecules such as proteins, nucleic acids, and metabolites in real time. Electrochemical sensors are a powerful platform for environmental or biological monitoring based on inexpensive instrumentation and straightforward measurements of electrical currents. As small (nA) currents can be reliably measured, low detection thresholds are feasible. Several challenges remain for its implementation in practical devices and generalized for all types of protein analytes. The development of enzyme-free and reagent-free reporter systems that exhibit levels of sensitivity suitable for analysis of real-world samples has not as yet been realized.   In this project we will design, fabricate, and validate a novel reagent-free electrochemical assay capable of rapid quantification of protein biomarkers. Using both purified analytes and in vivo models we will demonstrate utility of this approach to detect a panel of markers including those linked to stress response and cardiac function. To achieve these goals, we have assembled a team with expertise in development of ultrasensitive multi-analyte electrochemical sensors, electrical engineering, model systems, and biochemistry. Together, this team will develop new technologies with the potential to monitor biochemical and physiological parameters with high levels of sensitivity. The project deliverables will have a significant impact on the Canadian population with potential applications in monitoring the health of employees in hazardous professions and providing continual biomarker monitoring in healthcare.

Despite recent advances in anticancer therapies, children who develop certain brain cancers have a 95% mortality rate within 2 years of diagnosis. It is well known that anticancer therapies must match an individual tumour’s genetic mutations in order to work, but between different patients, the brain cancer mutations are highly variable and also continue to change over time. Furthermore, it is difficult to safely biopsy the cancer cells in a tumour that naturally forms deep in the brainstem of a child. Today, following radiation therapy, children are eligible for experimental therapies, which are hampered by a lack of tumour genetic information.  Otherwise, the children are managed palliatively.

The objective of this proposed research program is to develop a safe, yet highly effective, non-invasive method to physically sample pediatric brain cancer cells, such that therapies can be customized to the exact genetic makeup of a patient’s tumour. This research approach will combine what is known about the physics of interactions of ultrasound with matter and the latest advances in pediatric brain cancer treatments. We will design a new ultrasound-activated bubble with size, stiffness and composition such that it can be remotely activated by ultrasound with control in both space and time as guided by magnetic resonance imaging. From outside the patient, after the tiny bubbles are injected into the bloodstream, ultrasound energy will first cause the bubbles to break, initiating the release of sample genetic material from the brain tumour, known as biomarkers, into the bloodstream. After biomarker release, the bubble fragments will be designed to then reform into a new particle that can trap the newly released tumour biomarkers. These particles containing the biomarkers can then be collected from a blood sample downstream from the tumour to provide a non-invasive way to perform a liquid-based biopsy of brain tumours.

This novel ultrasound-activated material can allow clinicians to remotely acquire previously unattainable genetic information from a child’s brain tumour such that new combinations of different potential cancer therapies can be tailored to treat each child. This non-invasive approach can also permit dynamic adaptation of the therapy regime during the therapy course as the tumour mutates over time. This approach can lead to increased survival of pediatric brain cancer patients who otherwise are clinically considered virtually untreatable today.

In 2015, the Mental Health Commission of Canada (MHCC) reported that at least 75% of mental health problems and illnesses appear in childhood and adolescence. Approximately 5% of male youth and 12% of female youth, aged 12 to 19, have experienced a major depressive episode, and only a ratio of 1/6 of them receive the needed mental health services (MHS) from a ratio of 15-20% of diagnosed cases. A crying need for strategies to improve MHS for youth with mental illnesses has been established in health services research. The lack of availability and active knowledge for providers has been reported to be a visible gap at all levels in the MHS. The fragmentation between the stakeholders and the service sector has created significant challenges to develop an efficient and effective MHS system which considers the unique characteristics of patients together with other aspects of the health. The surge in the availability of health-related data coupled with advancements in Machine Learning and Analytics tools have brought some promising solutions to improve health services. In this proposal, we intend to systematically use data and related business insights developed through applied analytical disciplines (e.g., statistical, contextual, quantitative, predictive, cognitive, other models) to drive fact-based decision making for planning, management, measurement and learning for the MHS for youth. Specifically, we will utilize and integrate numerous sources of qualitative and quantitative youth mental health data collected over the last half decade. We will identify key factors and determine what role they play in a patient’s decision-making process, enhancing the understanding of characteristics of patients, and dependency among care services offered. We will next examine the information and data available in administrative databases to catalogue services assessed, cost, and demand associated using Machine Learning tools. Finally, we will use Analytics tools including simulation and queuing optimization to investigate all possible strategies to improve the patient outcomes. The impact on the MHS will be assessed and analyzed. Our work will make an important contribution to the delivery of care services by predicting patient behavior given the existing system and recommending mechanisms to improve them.

Mastitis is an inflammatory process of mammary glands, which is caused by the invasion of the gland by microbial pathogens. This is one of the most costly and highly prevalent diseases of dairy industry, which results in considerable economic losses to dairy industry, decreased quality and quantity of milk production and loss of animal. Treatment of mastitis is usually carried out by using antibiotics. However, their efficacy is governed by the type of pathogen causing the infection and by the severity of the disease. There is evidence that poor antibiotic stewardship practices have induced the emergence of bacteria resistant to commonly used antibiotics to treat intramammary infections. With growing concerns on antimicrobial resistance to existing antibiotics, antimicrobial peptides (AMPs) are being recognized as potential and safe alternatives to cure drug resistant microbes. The presence of different cationic peptides such as beta defensins in mammary gland of cows are an example of naturally occurring host defense peptides to treat mastitis. However, natural anti-inflammatory responses initiated by the animal are generally not sufficient to cure the infected tissue. Hence, the research is focused on the discovery of new antimicrobial peptides and their potential applications to over come drug resistant and intracellular pathogens in mammary gland of cows. Some of the pressing issues with successful antimicrobial therapy to treat mastitis are following: 1) Limited efficacies of AMPs in vivo and capability to initiate complex immune response, which allows progression of pathogens inside the host cells 2) limited retention time in mammary gland and their inaction on microbes residing inside the host cells and 3) surface functionalization of peptides on a scaffold to improve retention time in blood or tissue often render them inactive. To solve these issues, we propose the synthesis of a dual delivery system for A) sustained release of antimicrobial peptides to provide continuous supply of AMPs in infected tissue and B) modulating the immune response of infected tissue to maintain the antibacterial activities of AMPs in vivo. To achieve this, we will be working on following objectives:

1.Synthesis of mesoporous silica microparticles embedded hydrogel patch for dual loading of AMPs and pro-inflammatory molecules

2.Evaluation of controlled release of peptides and pro-inflammatory molecules in vitro

3. Evaluation of in vivo efficacies of hydrogel patch

We live in a matter dominated world, but where did all the antimatter go? This is just one mystery in understanding the evolution of the universe, a key endeavour of modern physics. Subatomic ghostly particles called neutrinos, which pervade our universe, may be a critical piece of this puzzle. A strange phenomenon called neutrino oscillation, where a neutrino appears to change types, was observed in 1998 and garnered the 2015 Nobel Prize in Physics. We can now explore whether these oscillations behave differently between neutrinos and antineutrinos, shedding light on this mystery.

Measuring neutrinos requires massive detectors built by international collaborations. Super-Kamiokande, the current generation based in Japan, consists of a 50 kilotonne water tank surrounded by over 11,000 single-photon sensors providing detailed images of light from particles produced in the complicated neutrino interactions occurring within. Teasing out the small neutrino/antineutrino difference will require unprecedented precision provided by the next-generation detector, Hyper-Kamiokande, coming online within the next 8 years. In the interim, significant research and development across multiple disciplines is required to fully exploit its capabilities towards success.

An incomplete understanding of the complexity of the images that emerge and the uncertainties in the detector construction limit the precision of the final measurement, which can mean the difference between a discovery or not. To address these issues, this proposal develops two cross-disciplinary approaches: machine learning and photogrammetry, both currently minimally applied in this detector field. The former has significant potential for improvement over traditional algorithms to deduce the information in these complex images. The latter will be able to pinpoint the position of each photosensor, removing confusion that arises from detector distortions.

A successful implementation of these two approaches will alter the way this type of detector is calibrated and analysed, for both current and future generations. This is expected to enhance our understanding of multiple topics in physics, from neutrino oscillations to other phenomena such as proton decay, supernovae and other multi-messenger astronomical events, and dark matter.

For over 200 years, biologists have known that the cell is the unit of life, but how the collective behavior of cells forms a functional morphology (morphogenesis) remains unclear. Our overarching goal is to understand animal morphogenesis by taking advantage of the resemblance of living tissue to liquid crystal.

Liquid crystal is a state of matter that has both liquid and crystal properties. When a liquid crystal consists of rod-shaped molecules, the orientation of one molecule affects that of another, resulting in the emergence of orientational order (nematic phase) in the field. Also, when the established nematic phases are different among domains in the field, the singularities in the orientational fields are called topological defects. These characteristics are also prevalent in living tissue containing rod-shaped biological units such as epithelial cells and the cytoskeleton. Surprisingly, emerging evidence suggests that topological defects in the tissue regulate morphogenesis, but the underlying mechanisms are largely unexplored.

Our highly interdisciplinary team with expertise in animal development, mathematics, and fluid dynamics will dissect this new frontier in developmental biology through the following Aims:

1. Couple live-imaging, machine learning, and mathematical analysis to develop tools to systematically characterize the nematic phase and topological defects during embryogenesis of the nematode Caenorhabditis elegans. We will perform genetic screening to identify the molecular players involved in the formation of the in vivo nematic phase.

2. Identify the roles of topological defects in morphogenesis by manipulating them using laser-induced control of cytoskeletal dynamics and cell killing.

3. Fluid dynamics is both the origin and consequence of nematic phase. We will analyze fluid kinematics using 4D nanoparticle tracking and use mathematical models to understand how fluid dynamics controls developmental events.

This novel program will analyze the developing embryo as an active liquid crystal. By taking advantage of decades of theory in liquid crystal science, our multiscale analysis will uncover the fundamental rules that explain how micron scale dynamics controls centimeter scale tissue organization. The knowledge and tools developed will be widely applicable to understanding development and disease. Manipulation of the nematic phase has the potential to be a novel therapeutic strategy to mitigate developmental

The inhabitants of the rural areas of Northern Ontario lack reliable Internet access and are subject to the digital divide. Furthermore, these communities lag behind provincial averages in terms of quality healthcare. Connectivity is a key enabler for providing smart healthcare by monitoring and managing physical/mental health conditions and addiction trends. The aim of this research is to address both the urban-rural digital and healthcare gaps in an interdisciplinary manner. First, to tackle the digital divide issue, this research envisions a robust communication infrastructure by leveraging Unmanned Aerial Vehicles (UAVs) such as drones, equipped with communication and energy harvesting modules as well as robotic arms, to form an agile mesh network. The drones will be deployed to the hotspot areas of indigenous communities to either establish an affordable primary communication infrastructure or to complement the existing satellite technology in case of service outage due to harsh weather, disasters or maintenance. Resiliency is a high-risk factor in this research as drones may be lost due to animal attacks, forest fire, wind, and so forth. To address this risk, drones, capable of transforming into dockable access points by using robotic arms to clutch onto reliable anchoring points such as rooftops or tree-trunks, will be used. Field experiments will be conducted to perform deep learning-based smart and dynamic distribution and management of drones by scheduling flight/docking modes and recharging aiming to maximize network capacity and coverage. Second, to address the healthcare gap in northern Ontario, the drone aided network, coupled with cost-effective Device-to-Device (D2D) relays composed of user smartphones, will offload the health/addiction-related data collected by Internet of Things (IoT) and wearable devices deployed at the remote communities. The acquired data will be both locally and centrally processed and analyzed to discover health irregularities so that caregivers can make early decisions on patient-appointments and interventions. Also, some drones can be scheduled to collect lab samples and deliver them to the local caregiving facility. If the associated high risks can be addressed, the interdisciplinary approach, to connect users and offload health data, can save both patients and caregivers the hardship and cost of frequent traveling and bring high reward by bridging the urban-rural digital and healthcare gaps in northern Ontario.

Heart valve diseases really are a matter of life and death. They gain in prevalence and are a substantial cause of illness and death in industrialized countries. Although there are many options available for valve replacement, they present various important drawbacks, the most significant being the requirement for patients to take lifelong medication (anticoagulant and/or immuno-suppressors). Biological valves that would be produced with a patient’s own cells constitute an attractive, yet to be solved, objective to overcome these problems. In the case of pediatric patients, such a valve would have the ability to grow with the child, thus avoiding costly and traumatizing repeated operations. The proposed project aims at the production of a living, autologous heart valve substitute by tissue engineering. The aortic valve is chosen for this project but the technique could be applied to other heart valves as well. The approach uses sugar glass tridimensional (3D) printing, a cutting-edge technology, to produce a biocompatible sugar mold into which a mixture of alginate (a natural polymer) and human cells is poured and cast into the mold presenting the complex shape of an aortic valve. Different cell types will be considered and studied. Upon gelling of the alginate scaffold, the sugar mold is dissolved, and the valve is placed in a specially-designed bioreactor able to apply progressive flow conditions promoting cell activity and the maturation of a living biological substitute as the alginate resorbs. The bioreactor that will be used in this project was developed by our team and is able to reproduce with great accuracy a wide range of physiological flow conditions. In addition to the conditioning and maturation of the valve substitutes, the bioreactor will allow extensive testing of the valves under sterile conditions. 3D printing of the complex sugar mold required to cast the valve is very ambitious. The use of an alginate-based substrate for a shape as complex as the aortic valve is new and represents a great tissue engineering endeavor for the production of a biological substitute populated with human cells. The proposed team is uniquely positioned to address this challenge with expertise in cell-based tissue engineering, medicine, pediatric and adult cardiac surgery, molecular biology and mechanical engineering.

Each year 70000 Canadians suffer a heart attack resulting in 16000 deaths and the majority of the 50000 new cases of heart failure diagnosed annually. A heart attack leaves behind a region of non-functional scar (or dead) tissue, often resulting in a poorly functioning heart. Unfortunately, the cells that are lost cannot be regenerated. The ability to repopulate the scar by transplanting new functional heart cells represents a revolutionary new therapy for these patients. However, a number of critical barriers must still be overcome to ensure the success of cell therapy, including optimizing the route of delivery and ensuring the maximal retention and survival of the implanted cells. Open-chest surgical delivery is direct but highly invasive, unable to see scar (“blind”) and cannot access all heart regions. Intracoronary delivery offers very low retention rates to offer any benefit. Other catheter-based methods suffer from ionizing radiation (X-ray) or poor spatial precision. None of these can visualize the success of delivery. Magnetic Resonance Imaging (MRI) is the gold standard modality for evaluating heart scar and function, and it overcomes all the preceding limitations. Hence, the goal of our project is to develop a unique MRI guidance and visualization system to offer an optimal solution for cell delivery and tracking, retention and response assessment post-therapy.

The core components of our framework will include: a) a trackable MRI-compatible injection catheter; b) visualization system for real time catheter positioning and 3D scar fusion; c) catheter-compatible hydrogel biomaterial to promote cell survival/retention; d) MRI contrast agents to visualize media distribution; and e) MRI sequences to verify injection success and assess response. First, we will establish the hardware and software components of the system and test maneuverability of the injection catheter. We will design the catheter to enable safe passage of cells co-delivered with the hydrogel vehicle. Next, we will deploy the system in a large animal model of a heart attack. Targeting accuracy and media distribution will be examined both under MRI and histology using magneto-fluorescent labels.

The proposed imaging technology is directly translatable to humans and will greatly facilitate the successful translation of promising cell therapies to the large heart failure patient population for whom a minimally-invasive, closed-chest radiation-free intervention would be desirable.

Approximately 50% of the energy consumed by industrialized countries is lost in the environment as waste heat and only a fraction (<0.2%) of this heat is converted back to electrical power. Portable modules that could be mounted directly on a hot surface (e.g., in engines, industrial ovens) would be an ideal universal solution for recycling this waste heat into electricity. Unfortunately, whereas large-scale heat-to-electricity conversion technologies are mature and widely used (e.g., boiler, turbines), their smaller solid-state counterparts (e.g., thermoelectrics generators) are not up to the task due to high cost and poor performances.

Our goal is to create new portable heat-to-electricity recycling modules by uniting recent breakthrough work on (1) precision mechanics, (2) solar cells and (3) heat transfer research. All objects, when heated up, emit light (e.g. think of a glowing element in a toaster oven). This physical process is described by well-known, century-old physical laws on “blackbody radiation”. At almost any temperature encountered on earth, this radiation phenomenon is weak and is not of great interest in energy conversion applications. However, in recent breakthrough work, it was demonstrated that when objects are placed in extreme proximity, these law can be broken and light emission becomes much stronger than usually predicted. In essence, this transforms large quantities of heat into light, which can then be converted to electricity using modified solar cells (i.e. cells modified for harvesting heat rather than sunlight).

Despite strong interest from the research community, no functional demonstration of this technology exist due to a broad spectrum of risks spanning across three traditionally different disciplines: precision mechanics, solar cells research, and advanced radiation process simulations. This funding will allow us, for the first time, to gather a multidisciplinary team of researchers with the complete set of skills required for tackling these challenges. (1) specialized solar cells will be fabricated and characterized Karin Hinzer’s group at uOttawa. (2) Precision micro-mechanical systems for achieving the required extremely small separation will be developed by R. St-Gelais at uOttawa. (3) Finally, simulation and optimization of the radiation process will be performed by Alejandro Rodriguez’s group in Princeton.

Neurodegenerative diseases (NDD) are difficult to diagnose and treat. Take amyotrophic lateral sclerosis (ALS) as an example. Nearly all ALS patients show no specific clinical symptoms until disease onset, but their condition progresses from good health to death in 2-3 years or shorter. Currently ALS is a disease that has no known causes, does not have a diagnostic test, and cannot be cured. That is why ALS is a fatal, perhaps the most feared, NDD. However, early detection can prolong survival and improve quality of life, as there are methods to control symptoms and prevent complications, which make it easier to live with the disease.

Creating a diagnostic test requires disease biomarkers.  The objective of this project is to pursue an unconventional approach to identifying biomarkers characterizing a given NDD, with a primary focus on ALS. With a belief that distinct ALS biomarkers exist in the blood of ALS patients, we have conceptualized an innovative method to find them. The method models after "American Idol", wherein a large pool of molecular contestants (specifically, ~1,000,000,000,000,000 different synthetic DNA sequences) will be put to an iterative process to compete for their talents in finding ALS biomarkers. In each cycle, they will see the blood from healthy people (control group 1), other neurological disease patients (control group 2), and ALS patients (ALS group). The molecular contestants that report a positive signal with the ALS group will be "saved and copied" for next round of competition. Repeating this process 10-20 times will produce winners that will be used as the "fishing hooks" to identify ALS biomarkers using an analytical method called Mass Spectrometry.

Our idea is risky for two reasons. First, it is possible that there are no specific biomarkers that characterize ALS. Second, it is also possible that there are biomarkers, but they are also present in other NDD patients and the differences are not significant. However, if our research succeeds, the impact will be enormous. It will revolutionize the care for ALS patients because they can be treated by available methods in a timely fashion. Moreover, the discovery of specific ALS biomarkers will come with a golden opportunity to develop a curing drug for this incurable disease. Finally, the same method can be extended to other NDD like Parkinson's disease and Alzheimer's disease that are also hard to diagnose and treat, with the same conceptual advantage and impact.

Background: Cortical visual impairment (CVI) arises from damage to primary visual cortex (V1) and affects ~20 million people worldwide. As V1 is retinotopically organized, with different spatial locations representing distinct parts of the visual field, damage to a given region of V1 (the lesion-area) results in a blind spot in a corresponding part of the visual field (the lesion-field). This also leads to retrograde degeneration of the thalamic (dLGN) inputs that relay visual signals from the retina to V1. In contrast, lesion-field dLGN neurons that project to non-V1 visual (extrastriate) areas survive V1 damage. Recent clinical work has shown that training patients to view images on the edge of their lesion-field can decrease blind spot area, and this is thought to arise by engaging extrastriate visual circuits. However, training is slow and results in only minor benefits, likely because it does not optimally leverage brain plasticity mechanisms. Properly engaging spike timing dependent plasticity (STDP) – strengthening connections between neurons when they spike in near-synchrony – could greatly increase therapeutic outcomes. To test this, we will take advantage of recent technical developments in mice to design a closed-loop brain stimulation system to increase connectivity between lesion-field dLGN neurons and extrastriate visual cortex (V2).

Aim 1: Develop a closed-loop stimulation system to drive activity in V2 based on activity in dLGN. We will 1) lesion a portion of V1, 2) implant an electrode in dLGN and record light-evoked spikes from neurons within the lesion-field, 3) use adeno-associated viruses to drive the opsin ChR2 in lesion-field V2 neurons (anterolateral visual area), and 4) place a fibre-optic cable over V2.

Aim 2: Does strengthening dLGN-V2 connectivity reduces blind spot size? After establishing our closed loop brain stimulation technique (Aim 1), we will present animals with visual stimuli and use the timing of lesion-field dLGN spikes to optogenetically activate ChR2-expressing V2 neurons. After a week of closed-loop experiments we will perform behavioral tests to see if the blind spot area is decreased.

Outcomes: This will be the first project to combine optogenetics, electrophysiology, and behavioral testing along with a closed-loop brain stimulation method focused on ameliorating therapies for CVI patients. Our results in mice will guide future experiments in non-human primates, and possibly lead to a clinical trial.

This collaborative and interdisciplinary research values and embraces Indigenous ways of reading and viewing the western world.

Scholars have brought Foucault and other western critics and their approaches to understanding the aesthetic or intellectual value of Indigenous cultural and artistic production. The normative way of performing research up to now usually relies upon western, often masculinist interpretations of the textual and visual material under study. These research approaches were designed for western-settler audiences and scholars. Certainly, the canon’s design was greatly influenced by primarily white male scholars. In both a literary and visual sense, especially before the twentieth century, the canon remains white and masculine in terms of the authors and artists under study. It is thus not surprising that Indigenous literature and visual creations tend to reside outside of the western canons because the assessment of their quality depends upon western ways of assessing and interpreting them.

The Truth and Reconciliation Commission’s Calls for Action, as well as scholarly and public discourse after 2015, have aroused a consciousness within settler scholars about the importance of acting upon the TRC’s recommendations. For settler scholars whose work does not normally intersect with Native American and Indigenous Studies (NAIS), however, understanding one’s place, standing, and ability to contribute to the longer-term project of indigenizing the academy is challenging. Other scholars, furthermore, struggle to see how their specialized area might be indigenized, particularly when their disciplines have little apparent connection with Canada or the Americas or predate the European invasion and colonization of the Americas. And other scholars are convinced that this work, and/or NAIS-related inquiries, should be completed by Indigenous scholars alone.

The proposed project boldly pursues two critical outcomes: 

1. By exploring Indigenous approaches to the western literary and visual canons--an Anishinaabe critical interpretation of Chaucer, for example--we will provide scholars of all backgrounds with means of indigenizing their discipline, whether that is medieval studies or Picasso’s works.

2. By asking new questions of the western canons, they become unsettled, our values shifted, and ideally the academy will re-assess what it studies and why, and make room for Indigenous authors and artists in the canon.

Despite recent legislation mandating inclusion and the development of accommodation policies and programs, learners with disabilities (LWD) have low enrolment in higher education, have high dropout rates, and require twice as much time as non-disabled peers to complete their programs. In health and human service (HHS) education, which requires demonstrated competencies in both academia and practicum, barriers to full participation by LWD include stigma, disabling discourses, discriminatory program design, and oppressive interactions. Because HHS professions are practice-oriented, having an “able body” is often associated with safe practice. While the literature focuses on learners’ feeling excluded from clinical environments, few educators, clinicians, or HHS employers understand the barriers LWD face or the supports they need, especially during practicum.

This 2-year project will develop transformative accessibility practices that create more inclusive learning environments for LWD, advance equity and promote diversity in HHS programs in Canada. This project aims to:

1. Identify challenges and opportunities of current practices for supporting LWD in practicum across HHS programs;

2. Identify practice competencies required for licensing that create barriers for LWD; and

3. Pilot the effectiveness of unique processes, tools, and resources for educators and LWD seeking accommodations in HHS education.

An interdisciplinary team of disability studies and HHS scholars, with and without lived experience, will apply a critical lens to a mixed-method design, including surveys and focus groups with diverse stakeholder groups (educators, learners, supervisors, licensing bodies) at HHS across Canada. The data generated will inform our understanding of strengths/weaknesses of current practices. We will develop and trial best practice guidelines, tools and other resources.

This will be the first interprofessional Canadian study at this scale on this topic. Inclusive HHS programs will enable the student body to better represent the diversity of the populations they serve, including those with disabilities. Results will inform curriculum developers and policymakers nationwide to provide strategies for increasing diversity, equity, and accessibility in HHS practicum education. Our model of pedagogical accessibility will provide a foundation for programs with similar components of practicum, emphasizing Canada’s role as a leader in this initiative.

Objective:

In this project, we will take advantage of our newly discovered room-temperature photo-reduction of nitrogen into ammonia by ultra-small ruthenium clusters on the surfaces of GaN nanowires (NWs).  This proposal will combine the expertise of Prof. Li (chemical synthesis), Prof. Mi (nanocatalysts), and Prof. Guo (theoretical calculation of nanomaterials) to develop sustainable nitrogen-fixation with solar light by using theoretical and experimental means.

Research Plan:

We will establish a fundamental understanding on the unprecedented catalysis at the atomic first principles level, predict and design nanocatlysts with high performance for photo-reduction of nitrogen into ammonia. All proposed and ongoing work are solidly based on our extensive experience in first principles modeling of chemical reactions and processes on semiconductor surfaces and will support and possibly providing new avenues for experimental work throughout this project.  Specific deliverables are:

a) decipher the fundamental understanding behind the unprecedented catalysis;

b) preparing nanocatalysts to validate the theoretical calculations;

c) identify and prepare new nanocatalysts to this reaction based on the calculations;

d) develop new nanocatalysts functions under solar light

Novelty and Significance:

A fundamental component of protein, nitrogen is the most common pure element on Earth, making up nearly 80 percent of our atmosphere. Yet despite its abundance, atmospheric nitrogen cannot enter the food chain without first being converted into a form that can be used by plants.

In modern agriculture, the tried-and-true way to do this is to turn nitrogen into ammonia. In 2018, the UN Food and Agriculture Organization expects global demand for ammonia for fertilizers will exceed 115 million tonnes. However, the industrial ammonia synthesis process requires high temperatures (500-600 oC) and pressures (20-50 MPa) to overcome the activation energy barrier of N2, and consumes more than 1% of the world’s annual energy supply. To achieve an energy-efficient production, the development of sustainable nitrogen fixation strategy under mild conditions has become one of the greatest sustainable challenges facing us today.

The microenvironments in which tumour cells reside are highly specialized, with gradients of nutrients (oxygen, glucose) and biophysical properties (matrix stiffness) that give rise to heterogeneous cell populations and niches. While conventional radiation and chemotherapies are reasonably effective at shrinking tumours, a small population of cancer cells, some of which possess stem cell-like properties, are capable of altering their phenotypes to evade therapies, leading to relapse. Existing in vitro platforms cannot faithfully capture the heterogeneous cell population and niches founds in patient-derived tumours (PDT), therefore the gold-standard for predicting the fate of “real” tumours and to assess therapeutic efficacy is to grow PDT cells in immunodeficient rodents to generate patient-derived xenografts (PDX). Unfortunately, only a small number of PDT (< 20%) can be propagated in a PDX model. Moreover, a PDX model may misrepresent the true diversity and behaviour of corresponding PDT. These challenges limit our ability to understand the multicellular dynamics during tumour growth and to develop personalized and targeted therapies. This project will address these challenges by creating methods that can preserve the cellular diversity of patient biopsy samples in vitro while simultaneously tracking their growth and responses over time in the presence of antitumour agents. We will achieve this goal by completing two successive aims. The first aim is to combine microfabrication and aqueous two-phase bioprinting techniques to culture PDT cells in a sandwiched culture platform. Explanted and minimally processed PDT microtissue (<100 micron dia.) will be evenly deposited over a layer of stromal cells and placed under a barrier layer to impose transport limitation which generates 3D-like microenvironment over the bioprinted construct independent of the PDT geometry. Compared to PDX models, we will have the opportunity here to use a minimal number of PDT cells without the need for expansion to measure and explore emergent properties of tumours relative to their complexities, including growth kinetics, metabolic profiles, cell motility and self-organization. In the second aim, we will construct a multiparametric deep learning neural network to generate PDT tumour profiles. The goal here is to recognise and classify cell- and tissue-level phenotypic patterns as a way to predict binary responses (e.g. susceptible vs resistance) and improve therapeutic efficacy.

The objective of the research is to investigate a potential modifiable risk factor, exposure to environmental copper, for incidence and progression of amyotrophic lateral sclerosis (ALS). Since the survival time from diagnosis of ALS patients is short, about 30 months, it is possible to study both incidence and progression in the proposed study. We hypothesize that ALS patients will have excess biochemical activity of copper. 

The blood copper levels of ALS patients would be screened 4 times over a 12 months period (every 3 months) and compared to levels in sex and age matched controls from a non-neurological outpatient clinic and to normal levels. The two main ALS clinics (at MUHC and CHUM) serving the Greater Montreal Area, with a population of 4 million, will be contacted to recruit the ALS patients. Family medicine clinics will be contacted to recruit the sex and age matched controls.

S. Gaskin, a civil engineer, has experience in leading research in the areas of water resources and water quality. K. Mann and J. Gaskin have expertise on the effects of metal toxicity (arsenic, tungsten and mercury) on cellular processes and on the population health benefits of screening programs, respectively. A. Avan is a clinical researcher of ALS and other neurological disorders. As a senior investigator at the Jewish General Hospital, K. Mann has the experience to direct clinical trials. The proposed blood tests are standard blood tests in Canada.

Currently, the cause of ALS is unknown; there are no effective treatments and no known cures.  ALS is an adult-onset, progressive and fatal neurodegenerative disorder; 50% of patients die within 30 months of diagnosis, while 10% of patients may survive for more than a decade. Although there have been preliminary investigations of the association between several heavy metals (mostly zenobiotics) with ALS, copper has not yet been either identified or excluded as an environmental risk factor.  The significance of identifying copper exposure as a risk factor for progression of ALS is that individuals with elevated copper levels can be safely, albeit slowly, treated to reduce the body copper load, leading to improvement in neurologic symptoms.  The significance of identifying copper exposure as a risk factor for incidence of ALS is that a population health risk assessment could quantify the burden of ALS associated with copper exposure and possible strategies to reduce environmental copper exposure could be investigated.

The development of antimicrobial resistance in bacterial and fungal pathogens is one of the greatest threats to global health. Mechanisms of resistance are currently being explored; however, the limited discovery of novel antimicrobials over the past two decades confirms the urgency behind our need to discover and develop novel therapeutics to combat an array of diseases. Currently, antimicrobial resistance is commonly profiled from the pathogen’s perspective, investigating evolution of resistance over time. However, an in-depth analysis of resistance during the interplay between pathogen and host from both experiments in a single experiment is lacking. In addition, analysis of resistance is typically explored at a single molecular level (e.g., protein, RNA, DNA), whereas regulation among levels is proving to be a highly valuable approach to studying systems biology. Moreover, analysis is generally limited to the most abundant cells, resulting in a bias in data collection and processing and an inability to profile infection and immunity with a holistic view. We hypothesize that integrating datasets from multiple molecular levels will reveal novel mechanisms to combat antimicrobial resistance from both the pathogen and host perspectives in a single experiment. Here, we will develop a high-throughput, multi-dimensional platform for simultaneous multi-OMICs profiling to measure and correlate global changes during infection. Out three short-term aims: 1) Design a contactless dielectrophoresis microfluidics chamber for selection and enrichment of mammalian and microbial cells; 2) Develop a multi-OMICs platform for simultaneous multi-OMICs profiling of genome, transcriptome, proteome, metabolome, and lipidome changes; and 3) Characterize novel mechanisms of resistance displayed by pathogen and host cells during infection. To achieve our objectives, we have coordinated an internationally-renowned interdisciplinary team from microbiology, immunology, biochemistry, biophysics, nanotechnology, statistics, and bioinformatics. Using the information gleaned from this research project, our long-term goal is to develop novel therapeutics, such as anti-virulence compounds, to reduce the occurrence and effect of antimicrobial resistance on a global scale.

Nature provides many examples of superhydrophobic materials; using biomimicry to reverse engineer these novel designs, which include the small-scale hierarchical structures found everywhere from lotus leaves to aquatic insects, offers the possibility of significant technological breakthroughs in materials research. Superhydrophobic surfaces may also diminish drag in hydrodynamic applications (e.g. pipe flow, underwater vehicles). Drag reduction occurs as a result of the air bubble that coats submerged surfaces, which are themselves characterized by hierarchical microstructure.

Whereas surface attached bubbles play a key role in diminishing the transfer of momentum from liquid to solid, their impact in reducing the transfer of heat has received almost no attention. This knowledge gap is remarkable because bubbles are known to be used as thermal insulators by ephydrid flies and water shrews, which respectively dive in very hot and cold water. Moreover, there are numerous industrial scenarios where it may be helpful to use superhydrophobic surfaces as thermal insulators. For instance by applying a superhydrophobic coating to the interior of a water pipeline, it may be possible to insulate from the inside-out thus eliminating the need for exterior insulation. Bubble-based insulation may also prove beneficial in lab-on-a-chip devices where exothermic reactions might lead to large thermal stresses.

In view of the above, the research objectives are to (i) survey the biological literature to better understand the biological adaptations used to exploit bubbles for insulation, and, (ii) investigate the efficacy of superhydrophobic surfaces as thermal insulators either in connection with, or distinct from, their drag reduction function. To achieve our objectives, we will first investigate the connection between habitat and biological form/function, e.g. by systematically characterizing how insect integument and shrew pelage vary according to environment and the severity of the imposed thermal stress. This knowledge will inform the development of complementary mathematical models. Model development will be the focal point of our research and is meant to unveil the connection between micro- and nanoscale surface properties, the stability of surface attached bubbles and the degree of thermal insulation. In turn, model predictions will be validated by comparison with lab experiments using e.g. polydimethylsiloxane surfaces having various micro-features.

The response to the threat posed by antimicrobial resistance (AMR) has concentrated on reducing antibiotic use and developing new drugs. Recent work suggests it is imperative to understand the complex interactions between biological and social pathways of emergence and spread of AMR if control efforts are to succeed.

If selective pressure drives adaptation, promotes genetic mutations and favors transfer of resistance genes, then bacterial molecular sequences serve as archives of social and historical events that exert these selective pressures. Phylogenetic analyses map transmission events within microbial communities. Combining oral history and ethnography with resistome phylogenies illuminates the multi-dimensional interactions that participate in the emergence and spread of AMR.

Our primary objective is to bridge the gaps between field and laboratory studies in order to better understand the drivers of AMR. To do so, we will focus on multidrug-resistant Acinetobacter baumannii (MDR-AB) as a case study, retracing its emergence and spread in Lebanon. We chose MDR-AB and Lebanon for the following four reasons: i) the World Health Organization (WHO) recently identified MDR-AB as one of its top three critical pathogens for which research is urgently needed; ii) MDR-AB has been recognized as an important transmitter of AMR genes; iii) one of the earliest nosocomial outbreaks of MDR-AB was reported at the American University of Beirut Medical Center (AUBMC), in Lebanon, in the 1980s, with numerous other outbreaks since; and iv), the AUBMC houses a unique collection of approximately 2,000 A. baumannii clinical isolates gathered between the 1960s and the present day. This repository also contains important epidemiological and social data in archived patient records.

Stored MDR-AB strains will undergo whole genome sequencing. The genetic environment of resistance genes will serve as the basis for building phylogenetic trees. Phylogenies will then be contextualized using oral history, ethnography and epidemiological data, such as, but not limited to: availability of antibiotics and their consumption patterns; timing and specifics of military conflicts; demographic data of migratory flows.

The results from this interdisciplinary approach have the potential to be highly significant by providing novel insights into underrecognized social and biological processes involved in AMR emergence and spread, and inform and redirect efforts to contain this threat.

Quantum information science allows us to create tools that are not possible in the classical world. With quantum tools we can engineer a probe that is sensitive to the presence of specific structures in their entirety. Biology is rich with elaborate structures that span lengths from nm to mm: quantum measurements can be tuned to be selective for and sensitive to these biological signatures. For example, we can tailor spatial profiles of light’s polarization to match a biological feature of interest. The traditional characterization methods of biological structure require us to image the sample and then to perform image analysis. With quantum engineering even a single photon can reveal the features of a complex structure. This enables characterization with direct measurements. Quantum tools are the most effective tools when the existence of organized structures are of interest. One important example is the macula in the human eye which possesses azimuthally ordered birefringent fibers over 100 μm, and whose health with aging is an important clinical concern. This structure is very well suited to quantum probing via structured light beams. The need for prospective monitoring of the macula’s health provides an excellent test of our ability to engineer quantum devices tailored towards health needs. It also provides a unique opportunity to build a physics/engineering/vision science collaborative team to deliver a clinical application. Our objective is to place a programable structured light interferometer into a clinic and use it to explore the power of quantum states for studying disorders and diseases of the human eye. The first target will be to macular degeneration. This is the leading cause of blindness among people over the age of 60. We expect this to lead to other applications in visual sciences. This project is a partnership between Institute of Quantum Computing which focuses on quantum information, the (CFREF) Transformative Quantum Technologies program which focuses on quantum technology applications, and the School of Optometry and Vision Science with an onsite public clinic. It brings together quantum scientists and engineers with vision scientists and eye health care providers. Quantum technology is broadly recognized as delivering the ultimate efficiencies allowed by nature for sensing and characterization. This potential is well realized in physics labs but it has been challenging to move to other centers where it can have societal impact.    

Annually, more than 1000 Canadians are added to transplant lists and approximately 260 people die waiting. Transplant improves pressing physical, quality of life and economic impacts of organ failure, but graft failure and challenges adhering to complex post-transplant care carry risks. As medical assistance in dying (MAiD) has entered into Canadian legislation and culture, individuals experiencing graft failure are also amongst those requesting access, defying the curative intent of transplant. "Frictions of Futurity and Cure in Transplant Medicine" reconceptualizes three central challenges extending across the transplant process and organ sites: (1) organ procurement and waitlisting of transplant recipients (2) recipient adherence to medical care (3) the experience and sequelae of graft failure. We argue that the three challenges are interrelated and can be radically transformed through critical disability ("crip") studies and feminist science and technology studies (STS), scholarship that is rarely in conversation with transplant medicine. Our project mobilizes feminist/crip STS to recast deeply held assumptions, standard practices and foundational principles of transplant medicine.

Using an interdisciplinary qualitative approach based on narrative, ethnographic methods and arts epistemologies, we will trace interrelated aspects of the three challenges through heart, liver and kidney transplant sites. Bringing together observational data, longitudinal interviews, discourse analysis and arts-based participant-driven knowledge translation, we aim to:

1. Characterize and communicate experiences of transplant recipients to inform the development of feminist/crip materialist understandings of key concepts shaping the three central challenges, including liminality, friction, failure, and risk;

2. Mobilize these concepts to inform practices and policies within the transplant setting, e.g. (a) assessments of adherence and strategies for engagement in clinical care (b) communication relating to consent to surgery, risks/benefits of transplant and options for end of life care (c) organ transplant advocacy, fundraising and research strategies.

This innovative project contrasts with conventional methods and opens possibilities for transplant medicine and transplant recipients by asking what new futures might materialize, if transplant medicine is imbricated with a critical stance that questions presuppositions about cure, futurity, livability and thriving.

Recognized as an urgent global health crisis, antibiotic resistance is often associated with the rise of drug tolerant bacteria; however, it is increasingly clear that many chronic infections are actually the result of “persister” cells.  Common to all bacterial species, persister cells are a subpopulation of infectious cells that grow slowly and show a transient tolerance to antibiotics. Able to exist in the persistent state for long periods of time, these cells can wait out an antibiotic treatment, then sporadically switch back to an infectious state.

A tragic example of bacterial persistence is seen in Tuberculosis (TB), a contagious infection caused by the pathogenic bacteria M. tuberculosis, and one of the top 10 causes of death worldwide. Due to the presence of persister cells, TB is currently treated by the long-term administration of antibiotics with a typical regime lasting for approximately 6 months! Understanding and combatting these persister cells is ultimately the key to eradicating TB.

Unfortunately, a limited number of methods for killing persisters have been discovered, all of which rely upon affecting cellular metabolism. Metabolism plays a critical role in the entry, maintenance, and exit of bacteria from the persister phenotype. In fact, all antibiotics are expected to affect bacterial metabolism, yet tools to assess their metabolic impact are lacking. Antibiotics induce redox- related physiological responses in bacteria by dynamically altering cellular respiration and elevating levels of toxic reactive oxygen species (ROS). M. tuberculosis, for example, is able to evade the lethality of antibiotics, in part, due to an ability of persister cells to survive the toxicity of ROS.

Together, we will develop a system for long-term, single-cell tracking of the metabolic/redox state in M. smegmatis, a non-pathogenic relative of M. tuberculosis, based on a combination of microfluidics, time-lapse microscopy, and new genetically encoded biosensors. Our platform will provide a continuous real-time readout of intracellular ROS levels with tight control of the nutrient supply, spatial dimensions, and environmental conditions. This will enable us to perform single-cell tracking of intracellular ROS levels in live bacteria exposed to antibiotics over the course of multiple generations.  In combination with automated microscopy, the platform could eventually serve as a high-throughput screening tool for antimicrobial drug discovery.

While the global incidence of type 1 diabetes (T1D) continues to rise, it is now clear that transplantation of human pancreatic islets of Langerhans, into the patients’ liver, can successfully restore glycemic control. Despite marked progress in clinical islet transplantation, transplant approaches are limited to those with life-threatening hypoglycemic unawareness. The major obstacles that hinder the more inclusive use of beta cell replacement with human islets are the need for life-long toxic immunosuppression to overcome the fierce immune attack that occurs after transplantation and lack of sufficient human donors. The objective of this application seeks to test a highly innovative and multidisciplinary approach to tackle these vital roadblocks that plague the broad-spectrum application of this curative beta cell-based therapy.

Our research approach will attenuate the immunological and organ donor limitations associated beta cell transplantation. Our aim is to develop and test a cutting-edge minimally invasive transplant platform that combines a micro-and nano-porous thin film immune-isolating device, implanted under the skin, together with genetically altered immunomodulatory A20 islets to prevent immune destruction; eliminating the need for immunosuppression. To overcome the human organ donor supply, islets will be sourced from pigs serving as a ubiquitous islet supply. The following aims will aid in accomplishing this objective:

1) Optimize micro-and nanoporous device fabrication and genetic engineering of A20 expressing porcine islets,

2) Utilize our ‘immunosuppression free’ combination islet transplant approach in murine islet transplant model, and

3) Scale-up and test our ‘immunosuppression free’ combination islet transplant platform in a large animal porcine study. 

This application leverages the specific expertise (clinical islet transplantation, biomaterial and genetic engineering, immunology, and commercialization) of our international team in a new, innovative and synergistic project. By subverting the immune response to an islet transplant with a combination of a retrievable, biocompatible, scalable encapsulation device with genetically engineered immunomodulating porcine islets, our results will increase the prevalence of insulin independence, led to long-term durable graft function, eliminated recipient complications associated with systemic immunosuppression and broaden the spectrum of T1D patients eligible to receive a curative

Objectives: The proposed research program is a multidisciplinary innovation for improving our capability of suicide prevention at the population and health system levels. Our objectives are to:

1) develop tools for predicting suicide risk at the population level and identifying communities that are at high risk. The tools will enable policy and decision makers to mobilize resources in advance to mitigate population risk.

2) Determine the formats of presentation (visualization) of the tools, that facilitate communication with and uptake by health policy and decision makers.

3) Identify the barriers and facilitators of implementation, as well as the ethical and privacy issues, of the risk predictive tools.

Our approach: We will take a multidisciplinary and cross-sectoral approach, and bring together academic researchers, mental health policy and decision makers, service planners, IT developers, and people with lived experience, spanning the disciplines of risk predictive analytics, artificial intelligence/machine learning, psychiatry, mental health services, sociology, ethics, health administrative data, data visualization and implementation science. We will develop the first multivariable risk predictive algorithms (MVRP) for suicide by linking vital statistics, Quebec health administrative data and Canadian Urban Environmental Health Research (CANUE) data. We will take an explicit sex perspective by developing sex-specific MVRPs, because men are more likely to die by suicide than women. We will engage policy and decision makers, clinicians, computer scientists and IT programmers to determine the appropriate formats of data presentation, that are acceptable to policy and decision makers. We will involve all stakeholders to identify the potential ethical and privacy issues and mitigation strategies for implementing the risk predictive tools.

Novelty and significance: We know that suicide is influenced by many factors including individual, health system, and neighbourhood and community characteristics. Traditionally, mental health services are planned based on historical information that happened in the past. The proposed research aims to develop a set of risk predictive tools assisting policy and decision makers to prevent suicide proactively, using existing and readily accessible data. If successful, the tools can greatly enhance decision makers’ capability of forecasting population suicide and mobilizing mental health services precisely.

Recent joint advances in microscopy and algorithms, applied to cryo-electron microscopy (cryo-EM), have led to the discovery of a significant number of protein and molecular structures, initiating a revolution in the field of structural biology. While this technology has become capable of imaging an increasing range of proteins at unprecedented resolution, cryo-EM reconstruction remains very challenging in the vast majority of cases, especially with proteins of low molecular weight, and conformational continuous transitions. To address this conformational heterogeneity problem, new methods need to be designed, to not only determine the structure, but also to visualize and interpret the conformational space and transition pathways from high dimensional cryo-EM image datasets.

The main objective of this proposal is hence to design new methods and algorithms in machine learning in the context of cryo-EM data, to 1) characterize the conformational space of the imaged molecule, 2) characterize transition pathways, and 3) apply these methods in structural studies of membrane receptors. This work is feasible through our unique strongly interdisciplinary team, including applied mathematicians and computer scientists, in charge of developing and implementing the methods, with biochemists providing experimental data and biological interpretation.

Our team will implement and compare different algorithms of manifold learning, which are suitable to reduce dimensionality and provide a latent space representing a given image dataset. To determine which representation appropriately captures the energy landscape of a given molecule, we will benchmark these methods on a curated set of proteins, presenting distinct heterogeneities in local resolution. In a second approach, we will implement clustering tools to partition the latent space into metastable states, and study the transitions between them. While naive interpolation often yields unrealistic results, we will use optimal transport methods, to approximate the local dynamics and reconstruct continuous transition paths. We will then apply these techniques to the class of pharmacologically very important, but technically very challenging due to their inherent flexibility, membrane proteins. Unraveling their structural dynamics will help for structure-based drug design, and more generally, shows how to extract, beyond the structural content, more valuable information from cryo-EM data.

The extremely high price of commercial lithium-ion batteries (LIBs) is the major barrier to make electric vehicles (EVs) competitive with cars powered by internal-combustion engines, while toxic waste containing transition metal elements generated from the disposal of used LIBs is the main concern on severe environmental pollution. The overarching goal of the proposed research is to realize the economical fabrication of batteries through green synthesis and effective regeneration of LIBs electrode materials.

Towards this goal, the proposed research will focus on: i) the development of novel and fundamental processes for the formation of LIB electrode materials; and ii) the development of new technologies to recycle and reuse LIBs. Towards the goal of green synthesis, green solvents and inexpensive raw chemical reagents will be selected while valuable chemical reagents will be best used to increase the atom economy. Lithium and transition metal materials will be simultaneously recycled using hydrothermal or precipitation processes, which allows for the recapturing of valuable materials while mitigating environmental impact. To achieve effective regeneration, a hydrothermal treatment to pre-dose Li into Li deficient electrode material from used LIBs will be applied and followed by thermal annealing to regenerate various cathode materials with desired microstructure and composition to realize outstanding electrochemical performance.

The novelty of this research lies in that we will target unexplored synthetic routes to obtain high-performance LIBs while focusing on atom economy, energy efficiency, recyclability, and less hazardous chemical syntheses – following principles of green chemistry.  This research not only focuses on fundamental chemical science in terms of materials synthesis and the exploration and understanding of new mechanisms, but also contributes to practical engineering problems. The research is highly challenging, but rewarding as success of this research will reduce the cost and environmental impact of LIBs making EVs more affordable and more appealing for global sustainability.

The majority of the world fisheries are small-scale, family-owned and community-based enterprises. Small-scale fisheries (SSF) contribute significantly to food security, employment for women and men, cultural and stewardship values and economic viability of coastal communities. But SSF are at a critical crossroads, facing multiple challenges including access issues, resource depletion, urban development, habitat degradation and poverty. Climate change and new development agendas, like the Blue Economy, further increase vulnerability and social injustice to SSF, thus requiring them to constantly defend their rights against other ocean users.

Policy interventions, especially those aiming to address climate change, are mostly externally driven, are not gender sensitive and often emphasize adaptation strategies that ignore SSF contexts. Thus, the issues that make SSF communities vulnerable are neglected. SSF communities must be able to communicate the urgency of their concerns for timely, appropriate intervention and responses. Innovation in information sharing is required, along with active participation of actors from different backgrounds and disciplines in co-creating solutions to address governance challenges, especially where resources (data, capacity, financial) are limited.

‘Blue Justice Alert’ is proposed as an interactive, web-based, mobile platform connecting experts, practitioners and SSF. As the first of its kind, the platform will be developed based on the co-production of knowledge between researchers and SSF people, allowing monitoring and evaluation of SSF status. SSF communities can also use it to register crises or threats to rights and livelihoods and seek help from experts and practitioners connected to the platform. The latter will receive the alert, work collaboratively with SSF people in co-designing short and long-term adaptive responses, using the built-in interactive communicative tools available in the platform. Platform development and pilot testing will occur in three sites: Sundarbans, Bangladesh - SSF are highly vulnerable to climate change; Western Cape, South Africa - SSF rights conflict with fisheries law and policies; and Yucatan Peninsula, Mexico - urban and tourism development are displacing SSF and livelihoods. The project will contribute to reducing SSF vulnerability and strengthen their capacity to achieve viability, food security and sustainability – a necessity given the current status of global fisheries.

Anticancer drug discovery and formulation development are time-, labour- and cost-intensive processes that depend on numerous factors. Machine learning (ML) provides promising tools for accurate predictions and improved decision-making to identify the most effective drugs with abundant, high-quality data. The challenges of applying ML for anticancer drugs discovery and development stem primarily from the lack of suitable cancer models that reliably recreate in vivo conditions and the insufficient repeatability of ML- generated results.

Organotypic multicellular tumor spheroids (MCTSs) have emerged as a promising three-dimensional cancer model that replicates many features of cancer tumors and serves as a bridge between two-dimensional cell culture and animal models. This proposal aims to combine ML and a microfluidic (MF) platform for closed-loop MCTS growth and anticancer drug screening. Microfluidics will provide control over MCTS dimensions, oxygen and nutrient supply and metabolite accumulation, drug delivery to MCTSs under close-to-physiological flow, and the capability of multiplexing for drug screening. The MF platform will utilize large arrays of uniformly-sized MCTSs that are grown from different cell lines in a  broad range of biomimetic microenvironments and are treated with multiple drugs and drug combinations supplied in varying doses.

Closed-loop ML methods will employ Bayesan inference to build models of the experimental response system. The team will use algorithms such as the recently-developed Phoenics approach to achieve high anticancer activity of new drugs and drug formulations categorically and in continuous parameter space.

Robotic systems should be equipped with intelligent Guidance, Navigation and Control (GN&C) systems that are capable of goal-based planning, perception, learning, reasoning, and adaptable task execution. These key characteristics overlap in every conscious entity, including human and machine, which are demonstrated essential to enabling flexible adaptation, i.e., rapid and intelligent reaction to changes in mission requirements. The mind (GN&C system) must therefore be equipped with a set of developmental functions, including synthetic emotional investments, that allows robots to become conscious of their body, surrounding environment, and the emerging relationships linking the two.

We propose a research that offers a novel interpretation of the vexed millennial dilemma of the body-mind dichotomy in the trans-disciplinary consciousness science, and we dare to use it as a pragmatic solution, not a problem to be solved. The main objectives of this research are threefold: (1) investigating the brain-body interaction using spiking neural networks, with the focus on topology reconfiguration scenarios (e.g., missing limbs, faulty sensorimotor systems); (2) Developing model-based learning algorithms inspired by the brain functionality and modular self-models, formulated in a coordinate-free geometric fashion, to adapt to considerable changes in robots and their environment; and (3) Developing efficient data mining algorithms through exploiting the geometric structure of the GN&C system to develop high-performance offline or real-time algorithms for handling the large amount of data from robots. Through an interdisciplinary and high-risk approach to study neuropsychological changes in interactive brains, this research not only revolutionizes our vision of adaptable GN&C technologies, but also helps understand some neurological syndromes, such as phantom limb, illusion of disowning a limb (asomatognosias) and other self-awareness syndromes (anosognosias). In addition, this work expands our knowledge of brain plasticity and correlated higher-level functions and contributes to clinical human neuropsychology by providing novel clinical simulative robots. The significance of this research is in defining adaptable developing intelligence for robotic systems with boundless applications in manufacturing, health, automotive, transportation, space, etc. The resulting high-performance computational and learning algorithms will clearly be an area of technological interest.

This proposal aims to develop methods for early detection of neuronal disease, such as Alzheimer’s and Parkinson’s. 

We envision that the lysosome viscosity is a sensitive indicator of lysosome fitness. As a major digestive organelle, functional lysosomes rapidly degrade incoming material and rid of damaged cellular material to provide cell nutrients.  This is of particular importance in post-mitotic cells, such as neurons with long lifespans. Accumulation of undigested material in the lysosomes, common in neurodegenerative diseases, signals catabolic deficiency due to either mutations in lysosomal enzymes or excessive protein aggregation.  Consequently, lysosomes become overly crowded. It is known that lysosome viscosity increases linearly with the degree of lysosome storage regardless the nature of stored material, i.e. proteins, phospholipids or cholesterol. With this, we speculate that lysosome viscosity could be used to detect lysosome fitness. This is critically important, as boosting lysosomal functions has been proposed as therapeutic strategy to delay neurodegeneration and promote neuronal recovery.  Early detection of lysosomal dysfunction is thus essential for effective interventions.

We propose to deliver fluorescent nanoparticles to the lysosomes of neuronal cells.  When excited by optical-fiber-based laser, these nanoparticles emit characteristic fluorescence that reflects the viscosity of their immediate environment and, in this case, the lumen of lysosomes. Similar strategy will be developed in live animal, aiming to create a portable and non-invasive technique to detect lysosome fitness in clinic settings.

We expect to achieve the goal by our multidisciplinary expertise in optical fiber (physicist), disease biology and lysosomal function (cell biologist) and neurological clinical care and needs (neurologist). Together, we expect to develop proof-of-concept methods in cultured cells and in animals with direct involvement of the neurologist. In addition, by fostering collaborations across physical science, biology and clinical research, it will provide a rich and interdisciplinary environment for trainees.

Infectious diseases have exacted high morbidity and mortality on humans throughout history and continue to do so today in a disproportionate manner for those of lower socioeconomic status and with insufficient access to health care and proper sanitation. A better and perhaps more nuanced comprehension of the tightly linked association between infectious disease and the human condition helps us better contextualize the emergence (and re-emergence) of pathogens in the past as well as today.  We have been attempting to chronicle the types of infectious agents in the past to address questions about disease burden, during well-known pandemics (i.e Black Death), but also as a consequence of transitions, such as the adoption of agriculture (the Neolithic transition). Unfortunately, most infectious diseases with acute onset, like plague, don’t leave diagnostic lesions in bones but can, in a few rare cases, leave their DNA. However, it is likely that chronic and enteric (i.e. non-acute) infections –such as dysentery –which leave neither were the predominant causes of morbidity and mortality in the past. Finally, many viruses carry RNA genomes, which precludes preservation in ancient samples. Therefore, we underestimate the relative frequency of disease, leaving many unresolved questions about syndemic processes and disease origins. A possible solution, is to look at the human “memory” response to infection via the antibody repertoire. Bone marrow is an important niche for antibody-producing cells that have been generated by prior infections. B cell antibodies that are good ‘fits’ to a particular antigen are recombined, amplified and hypermutated and thus the sequence of the B-cell VDJ chains can be linked to the antigen from a particular pathogen. By sequencing the repertoire of an individual’s antibodies, we gain access to the history of infection over the course of their life span. Sequences from these repertoires can be used to synthesize the antibody in vitro, which can then be screened against a broad array of pathogen antigens (>100) to link antibody to pathogen. We plan to use ancient DNA from bones and teeth of victims of pandemics (6th-18th C), to enrich for B-cell VDJ combinations, sequence and bioinformatically reconstruct them, guiding the in-vitro synthesis of ‘ancient’ antibodies. By leveraging the immunological “memory” of ancient humans, our novel approach holds the promise of transforming our understanding of infectious disease burdens of the past.

The ability to precisely organize matter on the size scale of tens of nanometers has the potential to revolutionize many areas of medicine and materials technology. The greatest progress made in this area to date exploits the exquisite sequence selectivity of DNA, building on the double cross-over DNA structures designed by Ned Seeman in 1982 and the “DNA origami” technique developed by Paul Rothemund in 2006. Today it is possible create an enormous variety of DNA-based assemblies with different shapes and symmetries possessing advanced positioning, recognition, and response capabilities. Despite these formidable advances, most DNA nanostructured materials are confined to proof-of-principle studies in the laboratory. The chemical stability of DNA is insufficient for most real-world materials applications.

Nature’s molecules of choice for harsh environments are often proteins. It is no accident that the DNA and RNA genetic material of viruses is typically covered in a tough proteinaceous capsid. There have been considerable efforts in using viral capsids in nanomaterials applications, however these assemblies fundamentally lack the site-addressability of DNA which seriously limits their applications. We propose to combine the precision of DNA nanotechnology with the robustness of viral assembly to create “viral origami”. This will be achieved starting from the well-studied tobacco mosaic virus (TMV) scaffold, which generates long protein rods assembled around a single-stranded RNA core. We will engineer strong RNA-sequence preferences into the coat proteins using a combination of rational design, mutagenesis, in-vitro selection, and structural and biophysical characterization. We will then position modified coat proteins at precise positions based on the RNA sequence. Exploiting protein-protein recognition and/or biorthogonal chemistry we will then link the TMV rods together in precise geometries (eg. tetrahedrons, cubes, ladders, sheets, etc.) To test this method, we will position optically-active nanoparticles in various geometric arrangements on the TMV scaffolds to generate novel optical responses.

To our knowledge, no other group is attempting to exploit the natural RNA- and DNA-recognition capabilities of viral coat proteins to achieve site-addressable proteinaceous nanostructures. Viral origami has the potential to move DNA- and RNA-based nanotechnology from the lab into useful and demanding environments.

Opioids are life changing medications for those suffering from injuries and chronic pain.  Unfortunately, opioid addiction is a nascent devastating global public health crisis that impacts Canada – from 2016-18, 11577 Canadians died from opioid overdoses; the number of annual opioid related deaths is increasing.

Synthetic opioids – including fentanyl and carfentanil – are powerful drugs that comprise a significant portion of Canada’s illicit drug market. Exposure to seeming minute amounts can lead to overdoses in drug users and even the general public who are accidentally exposed through dermal contact. This is of particular concern for first responders who may unwittingly come into contact with unidentified powders/residues.

Despite widespread and potentially fatal off-label opioid use, methods to rapidly identify them are limited. An individual’s opioid use can be screened by testing blood, urine or saliva in a lab. This is time-consuming, costly, and requires highly trained personnel. A limited number of “apps” and biosensors appear in the literature, but typically measure indirect opioid use biological indicators (e.g., skin temperature, breathing rate) and can be inconclusive. Also, neither of these options addresses environmental samples that the public and first responders my contact. Clearly, convenient, rapid, accurate, field identification of opioids is a compelling challenge with far reaching societal implications.

We will develop rapid, selective, portable opioid sensors. This unaddressed challenge can only be met via a coordinated interdisciplinary approach. Key sensor elements are the: 1) receptor, which undergoes specific interactions and responds uniquely to targeted molecule(s) 2) transducer, which produces a measurable output when the target is recognized. In developing a sensor that rapidly generates a large signal in response to small quantities of opioids, we will leverage the unique electrical and/or optical properties of non-toxic nanomaterials (NMs). These properties arise because NMs have very high surface area to volume ratios, and are therefore extremely sensitive to local chemical changes which interact with the NM surface. We will design and implement NMs which interact specifically with opioids using the latest tools of Materials Chemistry, and we will integrate these materials into sensors using techniques from Engineering. Collaborations with medical personnel and law officials will be explored to maximize impact.

The quest for greenhouse gas emission reduction and clean energy has been one of the most pressing needs faced by humanity, demanding unprecedented technological innovations. Directly targeting such grand challenge, the proposed research program will conduct multi-dimensional and multi-disciplinary research spanning materials science, artificial intelligence, nanotechnology, photonics and electro-optical engineering, to develop a transformative technology based on a photoelectrochemical (PEC) route towards high-efficiency emission reduction and energy conversion. 

Within the two-year duration of the project, the team aims to design next-generation PEC low-dimensional nanomaterial (LDNM) systems that combine high-performance photovoltaic and electrocatalytic components to enable simultaneous light harvesting, carbon dioxide reduction, and production of value-added chemical feedstocks and fuels, including hydrogen, methane, methanol, and ammonia. Our overarching philosophy to realize this goal is to develop a transformative approach comprising of machine learning (ML) for fast material discovery, data mining of scientific data, and molecular-beam epitaxy (MBE) for precise prototyping. That being said, you get what you design. A state-of-the-art, generalized graph-based neural network (GNN) framework will be established, which encodes both atomic and bonding characteristics to accurately predict structure-property relationships, for quick discovery and screening of material candidates. Natural language processing (NLP) tools will be developed for data mining, to realize automated data extraction from scientific literature and material databases, thus facilitating construction of structured knowledge mapping for the ML model. Meanwhile, adopting the ML-predicted designs, we will directly fabricate and engineer high-quality LDNMs, including nanocrystals, mono-/few-layers, and nanowires, with an atomic precision using MBE. The experimental data obtained will further help refine and improve the ML model. 

The project will establish a paradigm-shifting pathway to achieving accelerated materials innovation and atoms-to-devices realization for emission reduction and energy conversion, a critical step towards the ultimate goal of a carbon-neutral sustainable society and to position Canada as a world-leader in environment protection and sustainability.

In October 2018, Canada became one of two nations with legal commercialization of cannabis for recreational and medical use. To date, there are over 170 facilities with licences to cultivate cannabis. Over 20% of these facilities are located in British Columbia and some of the largest cultivation greenhouses in Canada are located or are being actively developed in the Greater Vancouver region. As the number and size of cannabis cultivation facilities has grown, so have odour-related complaints; a recent report listed 326 complaints in the Metro Vancouver region over a 12-month period.  The odourous emissions from cannabis production facilities are composed of volatile organic compounds (VOCs), which can also affect ground-level ozone and particulate matter concentrations, and so regulators have begun exploring options to curb these emissions.

Due to limited federal legalization, there is an extreme shortage of information on the exact composition of cannabis VOC emissions, and the resulting impacts on ground level ozone and particulate matter formation. Furthermore, the perceived health impacts of exposure to odourous air contaminants and an assessment of the vulnerability of populations exposed to these emissions are also undetermined. The proposed research project aims to characterize these impacts using a novel, multi-faceted approach and a diverse team of experts. The team consists of co-PIs Prof. Naomi Zimmerman (UBC) and Prof. Amanda Giang (UBC), co-applicant Prof. Sarah Henderson (UBC) and collaborators Metro Vancouver and BC Centre for Disease Control (BC CDC). As part of the research program, we will use a newly developed mobile laboratory to measure ozone, particulate matter, and terpenes around cannabis cultivation facilities (Zimmerman), build dispersion models and integrated models of environmental justice (Giang), develop tools for direct interaction with the community such odour-reporting apps and billboards (Henderson), and work with policymakers and regulators to inform new cannabis frameworks for managing emissions (Metro Vancouver, BC CDC).

As more government bodies consider legalization, any new frameworks for enhanced management of emissions developed by Metro Vancouver in this arena are of critical value. In this regard, Canada, and Metro Vancouver specifically, have an opportunity to be world-leaders the management of emissions from cannabis production and processing of various scales, creating a lasting impact for Canadians.

All modern data storage involves the manipulation of material properties to create physical instantiations of information, data represented as extremely fine material iterations.  Ubiquitous examples of this today are magnetic disk and tape.  These are excellent technologies, currently unparalleled in the density at which they can map data into structural patterns (on the order of 10 gigabytes per human thumbnail) and hence by far the market leaders.  But they are also seemingly inadequate to keep up with the rate at which, on a global scale, digital information is being generated; growth rates which are surely on track to increase as machine-to-machine networks (e.g. the "Internet of Things") proliferate.  For example, projections state that by the year 2030, the equivalent of 1 million (conservatively) to 1 billion (liberally) metric tons of silicon (as flash memory) would be needed to store the planet's annual digital information output.  To accommodate these trends surely a denser means of data storage is critical.  Many alternatives exist, have been discussed for decades, and have even passed some proof-of-principles; we propose to pursue one of these - DNA-based molecular data stores - which can theoretically condense data to a volume 10-million times smaller than possible with today's magnetic disks (which, at their current density-improvement-rate would require 300 years to achieve similar scales).  This stunning potential is accompanied by other critical advantages over incumbent methods (+1000-year data retention time, minuscule energy requirements) and is significantly boosted by the emergence of ancillary technologies critical to its realization (e.g. next-generation sequencing, DNA microarrays, etc.).  It is, however, also plagued by substantial difficulties, foremost of which centre on the spatial incoherence of DNA; DNA molecules are awkward to arrange in a solid-state form that allows for writing and finding data in accordance with physical location.  This research proposes to invent a methodology and a technology that solves this problem and creates a practicable DNA-based storage system.  We propose to combine expertise in microfluidics, biochemistry, microelectronics, and bioinformatics to create automated and miniaturized devices that synthesize, localize, and sequence DNA-encoded file systems while providing the opportunity for random data storage and retrieval at densities exceeding current demonstrations by orders of magnitude.

Objectives: We seek to solve a challenging problem in medicine: how to fix a ‘loss-of-function’ (LOF) mutant protein (a product of a mutant gene) that is causing a disease because of the protein’s loss of activity. Our approach brings together a ground-breaking new chemistry concept (Yudin) with deep understanding of the biochemistry and biophysics of a LOF mutant target protein (Arrowsmith), and the clinical knowledge and insight of a pediatric geneticist treating childhood developmental diseases related to the mutant protein (Wexberg).

Approach: We will leverage the new concept of “dark chemistry space.” The hypothesis is that we can decouple agonist/antagonist behavior of chemical probes and therapeutics by installing dominant rotors into peptide structures. This feature is expected to dissect the accessible conformational space of a complex molecule under consideration into two non-interconverting energy wells. Conventional constrained molecules offer access to one conformational ensemble at best, leaving behind unique structures that could otherwise contribute to the discovery of new medicines. By generating and investigating low energy conformers, we will optimize target engagement using peptidomimetics found within “the dark space” of accessible conformations. Peptide-based therapeutics and chemical probes are notoriously challenging to permeate cells because of the presence of highly polar amide bonds in their structures. Fortunately, our approach enables optimization of this property as well because distinct conformations generated using our approach are  differentiated on the basis of polar surface area.

This chemistry approach will be interfaced with cutting-edge structural and chemical biology of the mutant protein (called EED) to guide optimization of potency and activity. The Arrowsmith lab recently demonstrated proof of concept that the activity of this mutant protein can be rescued with a traditional synthetic peptide. However, this peptide was not cell permeable nor drug-like and thus could not be evaluated for its activity against the disease (blood cancer). The Wexberg lab has developed an assay (derived from patient data and samples) capable of evaluating drugs that can revert the disease-causing characteristics of the LOF mutation.

Novelty and Impact: We will develop an entirely new approach to the rational design of cell-permeable drugs, with broad utility in drug discovery and medicine.

The goal of this project is to develop a high throughput micro-scale antibiotic discovery platform that brings together ideas and techniques from Microbiology, Organic and Analytical Chemistry to facilitate coupled growth of microbes, biomolecule extraction, mass spectrometry detection and bioactivity assay to rapidly identify new naturally-occurring antibiotic drug leads.  Environmental bacteria are an excellent source of new antibiotics, however, when cultivated in the laboratory they frequently fail to produce the vast majority of their encoded molecules unless very particular snd specific conditions are used. This project will develop new microfluidic chips coated with slippery liquid infused porous surfaces (SLIPS) and decorated with an array of localized functional polymers to facilitate high-throughput on-chip microliter-scale (~20μL) cultivation of microbes under a large range of mono- and combinatorial co-culture conditions. The high throughput screening of growth conditions will identify organism-specific parameters for antibiotic production that will also be tested on-chip. Molecules responsible for the antibiotic activity will be directly analyzed from cell cultures using mass spectrometry and the platform will also be used to develop microfluidic chemical extraction protocols to access molecules not detectable by direct mass spectrometry analysis of whole cells. In this way our platform will be able to rapidly identify/prioritize new antibiotic drug leads. The rise of antibiotic-resistant bacteria is one of the biggest threats to human health in the 21st century and if left unchecked the mortality rate from such infections is poised to overtake that of cancer by 2050. Bacteria have been warring with each other for millennia and thus have evolved a diverse and potent arsenal of antibiotic "weapons". Through technological advances in the areas of microfluidic chip design and manufacture, bacterial cultivation, molecule extraction and detection this project will allow unprecedented access to naturally occurring antibiotic molecules not feasible using slow and low-throughput traditional approaches. The drug discovery community will feel the impact of this platform immediately, obtaining fast and easy access to the huge reservoir of microbial bioactive molecules. On a far larger scale, we anticipate that drug leads identified by this study will impact all Canadians as a new generation of antibiotics for the fight against resistant bacteria.

Rationale

SARS, H1N1 2009 Pandemic, Ebola or Dengue outbreaks are a reminder to the risk and regular emergence of new threats and epidemics, often affecting the most vulnerable. When new infectious diseases arise, identifying the agent is challenging because reagents such as antibodies are lacking, limiting the ability to isolate the agent and study it. Sequencing can now be performed using relatively low concentration material, but de novo sequencing is laborious and slow. Antibodies can now be derived directly from human survivor B-cells used to make hybridomas, but require advanced laboratory technologies and remains a lengthy and intensive process.

The OVERALL GOAL is to develop a method for rapid isolation and enrichment (< 1 day) of antibody secreting cells against new emerging viral infectious diseases using an agglutination assay. The proposed approach does not require knowledge about the infectious agent. In short, plasmablasts will be collected from a recent survivor and secreted antibodies biochemically attached to the surface of each cell, forming antibody displaying cells (ADCs). Next, ADCs will be incubated with plasma from a patient with viremia, leading to the agglutination of ADCs targeting the virus.

Aim 1: Antibody-displaying cell agglutination using Dengue virus (DENV) and anti-Dengue hybridoma.

We will study and optimize the conditions for sensitive and specific agglutination by producing ADCs from anti-Dengue hybridoma, including mixtures of ADCs and non-ADC cells, different titers of DENV, and different mixing conditions.

Aim 2: Agglutination of ADC generated from patients that underwent Dengue vaccination.

Plasmablasts isolated few days after vaccination will be used to form ADC, and incubated with plasma samples spiked with DENV.

Aim 3: Agglutination of ADC using plasmablasts and DENV collected from infected patients.

The agglutination will be tested using human samples representative of an emerging threat. Single cell sequencing will be used to determine antibody repertoire diversity of vaccinated and infected patients.

Significance

The proposed method could help accelerate the identification of emerging threats and epidemics by rapid and simultaneous enrichment of virus and ADC cells via simple agglutination. Isolated cells could be immortalized for hybridoma formation, or for phage display library generation and selection of antibodies for diagnostics and vaccines.

This project investigates human behaviour and brain function through the lens of indoor air quality. We will integrate cognitive neuroscience and indoor environmental engineering to systematically assess the impact of exposure to indoor pollutants on mental activity and its neurobiological underpinnings. This project will combine cognitive experimentation and sophisticated neuroimaging methods with the precise control and measurement of indoor pollutants.

Objectives

1) We will explore the impact of common indoor pollutants (e.g., CO2) and pollutant sources on complex cognitive behaviours using a battery of tasks that measure attention, memory, learning, and decision making.

2) We will measure brain network activity with fMRI methods across exposure scenarios to link findings to fundamental neurobiological processes.

3) We will integrate a formal theory of cognition that quantitatively relates exposure to human performance and neural function.

Significance

Poor indoor air is Canadians’ largest environmental risk, yet known chronic health consequences accumulate over a lifetime of exposure in different buildings, limiting public interest, investment, and regulatory action. This interdisciplinary project aims to mechanistically link measures of critical cognitive function with indoor pollutant exposures. Findings from the proposed work will motivate the development of neurocognitive models that formalize the links between environment, brain, and behaviour. This proposal will extend indoor air engineering with a new understanding of pollutant concentrations and control approaches in terms of direct impacts on human cognition. This novel research direction will provide unique training for a new breed of interdisciplinary HQP who capitalize on integrating research domains to support a healthier future for Canadians.

Novelty

Simultaneously considering indoor air quality and human cognitive performance will make novel and important theoretical contributions to both psychology and engineering. In psychology, models of cognition focus on the individual and do not consider environmental factors.  In indoor engineering, demonstration and understanding of cognitive impacts from exposure will provide a clear value proposition for investing in improving indoor air quality.  The proposed research will also test a truism in indoor air that pollutant removal is the only goal: the potential that some safe exposures may improve cognition will test this paradigm.

Human civilization has been pushed forward by the discovery of new materials. Over the past centuries, metallic materials have been the major workhorse of our society, thanks to their unique and irreplaceable properties. For example, metallic joint replacement is one of the most successful procedures in all of medicine. However, joint replacement may fail earlier than it is supposed to last – redoing replacements, or revision surgeries, are needed.  The early failure of the joint implant, significantly reducing the function of patients and placing a heavier burden on the health care system (137 million annually in Canada). This failure is most associated with implant materials. The discovery of new metallic implant materials, however, has been a slow and arduous task, even nowadays. The urgent need in the health care system, however, poses a challenge to speed up the rate of screening materials for creating new implant materials with a combination of outstanding properties.

Our collaborative research team includes expertise in materials science, computational science, mechanical engineering, surgery, and biomedical engineering. Underrepresented groups are engaged within the research team. The multidisciplinary and diverse team proposes a high-throughput methodology to accelerate materials discovery and validation by combining materials science, data science, and manufacturing technology. Using machine learning techniques, the team will screen millions of material composition before experimental validation. With the high-throughput mechanical testing method, a huge amount of numbers of samples can be screened and evaluated. Based on this combinatorial method, we aim to achieve material properties that cannot be obtained using conventional techniques. Particularly, the team will focus on the design of novel high-entropy alloys for medical implantation.

The proposed transdisciplinary research would considerably reduce materials waste and shorten research and development cycles from discovering new materials to producing final products. Furthermore, new materials with unique properties provide manufacturers with opportunities to produce new products with exceptional functionalities. New generation implant materials with allows to generate components for best custom fitting, significantly reducing the revision surgery rate for joint replacement.

Our long-term objective is to generate self-assembling materials that mimic the unique properties of biological tissues. Towards this goal, we must develop a quantitative understanding of the physical and chemical processes by which biological organisms assemble tissues and materials. Yet, this is extremely challenging and requires new biophysical tools. In the current proposal, we will overcome this challenge through careful selection of model systems and application of novel, high-resolution methodologies to image and characterize materials. Specifically, we will investigate how mussels produce tough and self-healing adhesive fibers known as byssal threads. Threads form via self-assembly from condensed liquid protein phases stored in secretory vesicles, which when secreted, rapidly transition from fluid-to-fiber. Recently, we have isolated vesicles in high yield, enabling in vitro investigation of assembly. In the current proposal, we exploit this advance to uncover mechanisms that govern the mechanical and structural transition from condensed fluid phase to tough viscoelastic solid.

The project is high risk: New biophysical tools and synthesis methods are required to understand the mechanisms biology uses to self-assemble materials and to reconstitute them in the lab; high reward: Biological materials have properties unmatched by conventional engineered materials. The knowledge gained here will enable the next generation of tissue engineering. Self-assembly, as evolved by biology, provides an efficient and sustainable way to design materials at the nanoscale; and interdisciplinary: Progress in this endeavor requires integrating approaches from chemical synthesis, materials engineering and microfluidics, and single-molecule biophysics. The Harrington lab will investigate the structural and biochemical transitions in the precursor molecules under controlled conditions mimicking assembly, using advanced characterization methods (e.g. FIB-SEM). The Hendricks lab will measure viscoelastic response at each stage of self-assembly and track single proteins within the material with molecular resolution using optical tweezers and superresolution fluorescence microscopy.

By controlling pH, shear forces, ionic strength and redox conditions, we will extract triggers for supramolecular self-assembly and correlate them to changes in anisotropic viscoelastic properties – principles relevant to assembly of new materials for technical and biomedical applications.

Global climate change and poor air quality are two of the main environmental challenges of our time. A warming climate threatens us with a wide range of perils to the health, economy, and the way of life of the upcoming generations. And every year millions of people die worldwide due to exposure to air pollution, resulting in a global average reduction in life expectancy of 20 months (HEI, 2019), and inflicting an economic cost in trillions of dollars (OECD 2016). Emissions of combustion-based CO2, the main contributor to a warming climate, are always accompanied with the release of air pollutants that affect public health. While the drivers of climate change and air pollution overlap significantly, policy options to address each challenge are often examined and developed independently from each other. As the political will to curb carbon emissions gains momentum at various levels of government worldwide, this lack of coordination between climate and air quality policies misses on an exceptional opportunity to achieve significant ancillary public health benefits (termed co-benefits) around the globe while climate change mitigation options are undertaken.

Past work has shown that health co-benefits from improved air quality, when monetized, are significant and larger than the social cost of carbon. These studies have mainly used air quality co-benefits as a means to provide economic justification for climate action, suggesting that the co-benefits can help offset part or all of mitigation costs. While the impact of CO2 is the same everywhere around the world, co-benefits of reducing co-emitted pollutants are strongly dependent on the location. Without accounting for the spatial structure of co-benefits, climate policies will inevitably prioritize options based on mitigation costs, rather than the overall societal impact. We propose to provide a framework to further use quantitative, sectoral, and location-specific co-benefits to guide climate policies towards maximized societal health benefits from air quality improvements. Our proposed work, will develop methods to estimate spatially resolved co-benefits for various emission sectors, and will explore approaches to incorporate co-benefits as a decision metric into regulatory and/or economic instruments for reducing carbon emissions.

Unsettling but true: One in two people develop Alzheimer’s disease (AD) by the age of 85. There is no cure, but effective drugs already exist that can delay the age of onset and disease progression — if taken early enough. The objective of the project is to use and combine our team’s collective knowledge of a cutting-edge small particle analysis technology, machine learning, and expertise from the fields of virology, kidney research and antibody engineering to design a new and highly sensitive way to detect AD earlier than ever before.

Small Particle Flow Cytometry (spFCM) is an emerging and transformative technology that analyzes the composition of cell-derived surface markers expressed on tiny biological particles called extracellular vesicles (EVs). EVs are constantly released by all cells, serving as a natural way for them to communicate, coordinate growth, and differentiate. But EVs also warn other cells of potential dangers such as infection and diseases (e.g., cancer, AD). Markers on EV surfaces reflect those on the surface of their parental cell. If a cell is damaged or in distress, it will express stress markers on its surface and release EVs that also express these distress markers. Amyloid beta plaques are toxic protein aggregates that accumulate over decades in the brain of AD patients. AD is also associated with the dysfunction of tau proteins in neurons, resulting in neurofibrillary tangles believed to form as a result of intense neuronal stress, and well known to trigger the expression of neuroinflammatory and cell-death markers on the surface of neurons of AD patients.

Our goal is to analyze EVs that are released into cerebral spinal fluid (CSF) by stressed and damaged neuronal cells of AD patients. We hypothesize that broad characterization of all possible surface markers on EVs isolated from CSF of AD patients compared to healthy controls will identify a combinatory group of AD biomarkers. We will use machine learning to process all permutations of the 248 surface markers that will be probed in relation to study participant metadata. We will then engineer and produce small single-domain antibodies that target the identified AD biomarkers even more efficiently, increasing the overall sensitivity of the technology and thus allowing for earlier AD diagnoses. A highly multidisciplinary team will carry out this unique project, with its strength relying on its diversity and direct knowledge of each component required for this project.

During brain development, establishment of both neuronal and vascular systems is orchestrated to ensure proper neuronal growth and function. Healthy neurovascular crosstalk relies on the harmonious interdependence between vascular cells and neuronal progenitors. Hence, vascular deficits affecting early developmental stages will alter the normal course of brain maturation.

Autism spectrum disorders (ASD), characterized by developmental delay, intellectual disability and higher rates of metabolic disorders, are associated with neurological deficits. Yet, an important knowledge gap remains concerning the involvement of cerebrovascular deficits in ASD pathogenesis. A recent, provocative discovery from the Lacoste lab demonstrates the contribution of vascular deficits to pathogenesis of the ASD-related 16p11.2 deletion syndrome (16pDS). We reveal the existence of structural (faulty brain angiogenesis) and functional (cerebral blood flow dysregulation) vascular abnormalities that are causally linked to ASD phenotypes related to neuronal deficits in a robust 16pDS mouse model.

It is thus expected that dysfunctional angiogenesis contributes to altered neurogenesis in 16pDS patients. Here, we hypothesize that human endothelial cells harbouring the 16p11.2 deletion will alter the development of healthy patient-derived brain organoids in vitro. To test this, we will first characterize and compare human-induced endothelial cells (hiECs) differentiated from healthy or 16pDS patient-derived pluripotent stem cells (iPSCs) using advanced genomic, proteomic, and metabolomic technologies. Subsequently, organoids will be generated from either healthy or 16pDS iPSCs and co-cultured with either healthy or 16p11.2 deletion hiECs, using different combinations to further asses causality. At various stages of organoid maturation, we will assess neurovascular development, gene expression patterns and metabolite production using structural, transcriptomic and proteomic analyses.

This project, which tackles a novel biological question, aims to provide a new link between neurovascular crosstalk, neuronal maturation, and metabolic regulation in ASD. To do so, we gathered a team of international experts from different and complementary expertise (neurovascular development, cellular metabolism, applied bioinformatics, and artificial intelligence). Outcomes of this study will help decipher the role of neurovascular deficits in ASD pathophysiology, opening new doors for ASD research.

A cancer.org report shows that gastrointestinal (GI) cancers caused 4.5M global deaths per year (data from 2013). Two-third of such cancers are detected in an advanced stage. If diagnosed early, the survival rate goes up from 43% to 83%. Therefore, early detection of malignancies at a curable stage is critical for improving prognosis and reducing mortality.

GI abnormalities are diagnosed with a tool named Wireless Capsule Endoscopy (WCE), where a patient swallows an electronic capsule that travels through the small bowel; it captures and sends colour images that are used offline for diagnosis. Although the current system works well for small bowel abnormalities, it suffers heavily in detecting precancerous cells and malignant GI tumours due to the use of conventional RGB camera, poor visibility of GI features, and low device life.

We propose to overcome the limitations by developing the next generation WCE tool with three advantages:

(1) We will integrate on-chip multispectral sensor arrays and use targeted light waves, instead of conventional white lights, that penetrate deep into the tissue and cause normal and cancerous cells to exhibit distinguishable optical characteristics. As a result, new mucosal features become visible enabling early detection of malignancies.

(2) GI bleeding is currently diagnosed by offline image analysis, which is error-prone, resulting in suboptimal treatment. We will use on-chip colour sensor array to capture spectral details of internal GI features. It will then be used to detect accurately various GI bleeding conditions (active, chronic or clot) in real-time.

(3) Current e-capsules are not trackable, i.e., physicians cannot localize polyps and tumours, which leads to an incomplete diagnosis. We propose to integrate low-cost 18x18 monochrome image sensors on the sidewalls of the e-capsule and use digital image correlation (a technology used in modern optical mice) to track its motion real-time. In addition, we will use on-chip motion sensors and accelerometers, and employ data fusion techniques to assist the location. As a result, physicians will now be able to localize GI lesions from mouth to anus and treat accordingly.

Overall, the proposed program will lead to the development of a new diagnostic tool in human endoscopy. With only four WCE pills in the market and the demand growing (~US$455M in 2014 to increase by 8.7% in 2020), the research is positioned to make a global impact in medical technologies.

Persons with disabilities are dynamic beings who have the right to circulate in urban public spaces in their daily lives as citizens. Nevertheless, public spaces are often not inclusive and accessible to people with reduced mobility. To create truly inclusive environments, new platforms and tools are necessary to understand, account for and provide real solutions for the ways people interact with the world.  Currently, there is no mechanism to comprehensively measure the complex interplay between cognitive, psychosocial, physical, environmental, and financial factors that influence mobility. The vision of the Electronic Mobility Monitoring and Intervention (EMMI) program is to optimize mobility and meaningful participation in society for individuals with disabilities across the lifespan.  The main objectives are to 1) identify the factors limiting or enhancing mobility in community environments (public spaces); 2) to evaluate the complex interplay between determinants of mobility across different spaces for individuals of all ages, and 3) to customize community environment mobility training. We will achieve that by 1) prioritising the features to be included in EMMI; 2) develop a sequence of testing within a novel platform trial, and 3) evaluate short-term outcomes (usability, feasibility of EMMI), and impact of EMMI on intermediate (individuals: e.g. time spent moving, activation to change behaviours, and community: e.g. accessibility, walkability), and long-term outcomes (individuals’ mobility, participation).  Our participatory action research approach will include individuals with a disability and families, consumer advisory groups, as well as health care providers who will inform on EMMI features and implementation, and decision-makers who can influence systems-changes. Our interdisciplinary team of researchers will use a novel adaptive design approach to plan, implement, and evaluate EMMI. Platform trials identify a cohort of individuals with disabilities who participate in a long-term research study with the incentive of possibly - and equally likely - exposed to the latest modern treatment alternatives, ideal for iteratively developing better care and community strategies. Moreover, the methodology that includes reinforcement learning for designing adaptive experiments is fairly new. This project presents the opportunity to further develop the methodology with the ultimate goal of optimizing EMMI to impact individuals’ mobility and participation.

Dental caries remains the most prevalent chronic disease in both children and adults, imposing significant financial and societal burdens on families, governments, and health care systems. Among 5-17 year olds, tooth decay is more common than asthma, hay fever or chronic bronchitis and is responsible for large numbers of days missed from school and work. By age 19, 68% of youth have experienced tooth decay in permanent teeth. Similar trends are observed in adults, where 92% of 20 to 64 year olds have had dental caries in their permanent teeth. The prevalence of caries suggests that the disease is not being effectively managed in the current standard of care in Dentistry due to insensitivity of clinical detection tools and techniques for early caries. The proposed project aims to develop enhanced Truncated-Correlation Photothermal Coherence Tomography (eTC-PCT), a non-invasive 3-D imaging modality recently pioneered at the University of Toronto, for the clinical detection of surface (enamel) and early subsurface caries. eTC-PCT uses a near-infrared laser source and a mid-infrared camera and could reduce or even eliminate the need for radiographs and their associated ionizing radiation.

There are 4 objectives:  1) Adaptation of an existing laboratory tabletop eTC-PCT system to dental imaging and in-vitro testing with demineralized / remineralized tooth matrices; 2) validation of eTC-PCT dental imaging using benchmark non-destructive and destructive conventional dental caries diagnostic methods (transverse microradiography, microcomputer tomography, and optical coherence tomography); 3) test, redesign and translation (hardware and software) of the laboratory system into a pre-clinical eTC-PCT imaging prototype and 4) comparison of the sensitivity and specificity of eTC-PCT with conventional dental radiographic analyses and  confocal laser microscopy for the detection of early caries. The proposed technology is expected to reveal dental demineralization at very early stages when the lesion can still be remineralized or healed, before it requires surgical intervention and restoration, creating a painless, cost-effective and non-invasive treatment for tooth decay instead of the conventional drilling and filling approach. The outcome of this research will be widely useful as an early dental caries diagnostic imaging technology for Canadians and the world, and also to dental researchers for carrying out a broad spectrum of research themes in Dentistry.

Water is life and has a spirit. Beginning from this premise, this project will probe Indigenous knowledge of sacred, cultural and spiritual relationships with water, with the purpose of better understanding the agency and personhood of water. Indigenous peoples have affirmed that the solution to water crises around the world is the reclamation of sacred knowledge and ceremonies relating to water, for the benefit of future generations, a right confirmed in the United Nations Declaration of the Rights of Indigenous Peoples (art. 25). This proposed constructive and Indigenized research paradigm may have implications for many nations, regions and for the global water crisis (all of which often defy quantitative or qualitative measurement or evidentiary conclusiveness).

Facilitated by host organizations (including Indigenous health NGOs, water guardians and grassroots advocacy organizations) and an interdisciplinary group of researchers and technicians (law, anthropology, visual arts) from Colombia, Ontario, and Manitoba (primarily Indigenous researchers), the project transcends the boundaries and disciplinary silos of academic research to ensure space for Indigenous outcomes that are spiritual, ceremonial, cultural, artistic and infused into the memory of human and other than human beings, most notably the water itself.

Building on a legacy of annual water gatherings in Treaty 3 territory, this research project brings together Indigenous knowledge holders from parts of Canada (Manitoba and Northwestern Ontario) and Colombia (Choco, La Guajira and Sierra Nevada regions) to exchange with each other. Land and/or water based gatherings will be held in each region in accordance with local Indigenous protocols and ceremonies and in their respective languages (with translation). Through this dialogue, participating nations will explore their sacred and normative relationships to water (including waterways and water bodies), interruptions through practices of development and commercialization, and their approaches to conflict management.

These spiritual and cultural exchanges will enhance knowledge about Indigenous legal orders, relationality theory and Indigenous governance practices. By marrying these disciplines, the cultural normative values that underlie Indigenous legal orders can be brought to life through ceremony and artistic expression and made more accessible to Indigenous people, as well as local and international communities.

Cancer is the leading cause of death in Canada, and accounts for almost 10 million deaths per year worldwide. Traditional forms of cancer treatment, such as radiation and chemotherapy, target both cancerous and non-cancerous cells in the body, resulting in extremely harsh side effects. As such, increasing research efforts have been focused on developing more targeted therapeutic strategies using small molecule drugs. These drugs, however, often have multiple targets in human cells, resulting in unintended side effects. They are also very susceptible to the development of drug resistance, frequently losing treatment efficacy.

Pathogenic bacteria have evolved unique and diverse strategies to manipulate host biological processes and establish infection. One common strategy is the use of specialized toxin proteins called effectors that are secreted into the host. These small proteins target and modulate host proteins to induce or suppress host biological processes for their benefit. Effector proteins demonstrate exceptional specificity in their host targets, and as proteins, rather than small molecule structures, effector function is less susceptible to host resistance. Bacterial effectors are also well recognized for their ability to modulate signalling pathways that are commonly targeted for anti-cancer therapy.

This research will develop bacterial effectors as new tools for cancer therapeutics, using a triple negative breast cancer model system. Triple negative breast cancer accounts for the majority of breast cancer-related deaths. As this tumor type does not have common targets for existing treatments, new therapeutic strategies are urgently needed. We have generated a panel of bacterial effectors that target well-established signalling pathways that promote cancer growth. We will screen the efficacy of these effectors on killing cultured tumor cells using multiple techniques. The most effective bacterial effectors will be used to generate nanoparticle-based formulations, both individually and in combinations. We will assess their potential using cancer cells and cancer tissues, followed by a mouse model carrying primary patient tumors.

Collectively, this research will use a specialized class of bacterial toxins in combination with cutting edge nanoparticle drug delivery methods and a mouse-patient tumor model to develop a new cancer therapeutic strategy. Successful bacterial effector candidates may also be viable options to treat other cancers.

Quantum biology is an emerging field that explores whether some of the foundational concepts and applications of quantum physics may be at play in biology. Specifically, quantum biology asks whether nature may have found ways to harness quantum effects (QEs) such as coherence and entanglement, critical ingredients for quantum computing, to boost or “design” processes of singular importance for biological systems. In this context, there exists the intriguing possibility that neuronal activity in the brain makes use of QEs, possibly spawned from biochemical processes, which may account for superior abilities of human brain as compared to computers. An experimental demonstration that some QEs may be operating in neuronal networks would constitute a significant breakthrough in life sciences and health research, and inspire new ideas in the areas of quantum computing and quantum technologies. In this New Frontier Exploration, we will search for some of the QEs proposed to be at play in neuroscience.  This high-risk/high-reward project is eminently interdisciplinary and would not naturally attract funding from NSERC or CIHR. Yet, it, brings together researchers in biophysics, cell biology, neuroscience and quantum physics whose combined specific research expertise is a sine qua non for this research to bear fruits. To carry out this research, we have assembled a team of co-applicants and collaborators that will contribute their diverse and complementary experimental and theoretical skills to address three main objectives:

(1) Search for candidates for biological qubit a (i.e. “bio-qubit”).  We hypothesize that one of the candidates, calcium-phosphate Ca9(PO4)6 cluster, a molecular storage mode for entangled phosphorous nuclei, might be found in mitchondria.

(2) Search for the indication of quantum entanglement (non-locality, or “spooky action at a distance”) in neuronal cell networks and neuronal tissues.

(3) Explore the effects of Li and Mg isotopes in biological processes related to brain activity, neurodegeneration and ATP-driven bioenergetics in the brain.

Methodology: we will use theoretical quantum physics, density functional theory (DFT) and molecular dynamics simulations (MD); experimental biophysical methods, including atomic force microscopy, fluorescence microscopy, nuclear magnetic resonance, Raman spectroscopy, electrophysiology [long term potentiation (LTP) and patch clamp] as well as biochemical, cellular and animal biology techniques.

Positron Emission Tomography (PET) is among the most sophisticated in vivo imaging modalities using radioactive isotopes that decay by positron emission. PET is non-invasive, painless, and hence patient friendly; provides full-depth images of the human body featuring dynamic space and time resolution of injected radio-labeled diagnostics (e.g. for cancer and neuro-imaging); and offers unprecedented detection sensitivity. PET radionuclides attached to bio-molecules or nano-materials (e.g., nanogels) follow the biodistribution of these compounds for disease staging, therapy, and/or biodistribution mapping. The latter feature is important to follow the in vivo dispersal of radio-labeled nanogels intended to deliver a therapeutic payload encapsulated within the nanogel structure to a tumor location. If loaded nanogels are injected into a cancer patient without the ability to understand their biodistribution (and accumulation near tumor sites), then an adequate assessment of their time-dependent therapeutic delivery cannot be obtained, thus hampering drug development. Only when the accumulation is high enough should the therapeutic payload be released by external stimulation/manipulation (e.g. radiation induced heating).

Our multidisciplinary team aims to develop radiolabeling protocols to chemically introduce fluorine-18 to chemotherapeutic-loaded nanogels by a simple one-step labeling procedure based on three non-canonical labeling methodologies: 1) the SiFA strategy which was developed by the Schirrmacher group and has now found its first human clinical application for in vivo tumor imaging (First-in-human 18F-SiFAlin-TATE PET/CT for NET imaging and theranostics, IMAGE OF THE MONTH, lhan, H. et al Eur J Nucl Med Mol Imaging (2019); 2) the BF3 isotopic exchange labeling strategy (Perrin et al); and 3) the Al[18F]F chelation chemistry (Goldenberg et al). These labeling strategies will be applied to introduce the isotope 18F into the nanogel structure to follow their bio-distribution in vivo in a cancer animal model using small animal micro PET imaging. Nanogels will be used to “hold” the therapeutic payload, as they have a large free volume that can be used as a reservoir. The kinetics of the loaded/un-loaded nanogels’ bio-distribution within tumor bearing animals will be accurately assessed by acquiring temporal dynamic PET images to prove that 18F-labeled nanogels can serve as delivery shuttles for tumor therapy.

‘Apophis’ will pass within 40,000 km of Earth in 2029. The 370-meter asteroid does not pose an impact risk, though it will momentarily be closer than satellites in geosynchronous orbit. Next year, NASA will send a spacecraft to another asteroid to test if it can be deflected. But who should be responsible for vetting the science, assessing the risks, and making decisions in an actual Earth-impact scenario?

Two other spacecraft are currently extracting samples from asteroids to test the viability of asteroid mining. But mining, by removing mass, could change an asteroid’s trajectory and steer it toward an Earth impact. Mining could also create debris that endangers satellites in Earth’s orbit. Should nations be allowed to regulate asteroid mining companies on their own? What if such a company incorporated in a ‘flag of convenience’ state?

Satellites are already threatened by their own increasing numbers as well as an accumulation of debris, including from in-orbit collisions. These risks will only increase. SpaceX has begun launching 11,000 communications satellites into low Earth orbit. Anti-satellite weapons, such as the one tested by India this year, could add further debris and thus destroy unintended targets. Yet there are no international rules governing access to low Earth orbit.

This project will research and analyze five high-risk challenges:

(1) Decision-making should an asteroid on an Earth-impact trajectory be found;

(2) Production of Earth-impact trajectories through asteroid mining;

(3) Mining debris threatening satellites or future lunar operations;

(4) Millions of pieces of human-made debris already in Earth orbit;

(5) Anti-satellite weapons.

None of these challenges are adequately addressed by the existing governance regime based on the 1967 Outer Space Treaty. This project will produce clear guidelines for governments and companies.

All of these challenges extend across the natural, social, and legal sciences and demand an interdisciplinary approach. Unlike other groups working on Space governance, this project centrally involves astrophysicists. It also involves considerable gender and ethnic diversity.

Knowledge dissemination will occur at all stages of the project so as to provide decision-makers with time-sensitive information and recommendations. The risk of ‘getting it wrong’ must be balanced against the risk of informing decision-makers too late.

“It’s the song, not the singer” (ITSNTS) theory was developed to legitimize and supplant claims that we and our microbiomes (“holobionts”) – or complex communities more generally (maximally, the biosphere) – are units of selection (“Darwinian individuals”). ITSNTS holds that it is the processes implemented, not the implementing taxa (individually or collectively) that are the relevant units, evolving through differential persistence and recruitment of implementing taxa, not differential reproduction (Proc Natl Acad Sci USA 115: 4006-14). ITSNTS engages and challenges traditional philosophical concerns about individuality, function, causation, emergence and hierarchy, is increasingly relevant biomedically (as in the new discipline of “microbiomics”), and should provide a much-needed and novel theoretical underpinning for evolutionary biology and ecology. Applicants are (1) a feminist philosopher concerned with robust theorizing about biological objects and complex interacting causal processes without essences (Letitia Meynell, Philosophy, Faculty of Arts and Social Sciences, Dalhousie), (2) a microbial genomicist focused on evolutionary mechanisms (W. Ford Doolittle, Biochemistry and Molecular Biology, Faculty of Medicine) and (3) a statistical modeler addressing evidence for selection (Joseph Bielawski, Biology, Mathematics/Statistics, Faculty of Science.

ITSNTS theory needs further theoretical development (as philosophy), further grounding in evidence from genomic and metagenomic databases, and establishment of relevant parameters through carefully constructed computer models. In particular we will (1) develop the theory of ITSNTS around complex causation in interacting hierarchies and how these might be represented and explored philosophically and through simulation, (2) determine the importance of lateral gene transfer in microbial community adaptation, asking whether (sometimes) genes are better thought of as belonging to processes, not organisms, and (3) deploy a novel combination of Markov processes within-species and agent-based simulation between-species to model a complex network of causal interactions with feedback between levels of organization (genes, species, community and ecosystem). We will then explore what kinds of systems can cause genes (lowest level) to adapt to persistent top-level structures (e.g., emergent community individuality) thereby decoupling (to some extent) top-level from species-level dynamics. 

Professor Keryn Lian and her students in Flexible Energy and Electronics Lab (F.E.E.Lab) have developed several high performance and low-cost bio-mass carbon electrodes from various bio and agricultural wastes stocks. They have also demonstrated world-class proton-conducting and hydroxide ion-conducting polymer electrolytes, which have enabled the highest charge/discharge reported to date for supercapacitor devices, liquid or solid. These building blocks will enable them to move to the next phase: assembling and integration into solid flexible and wearable Solid Electrochemical Energy Storage (SEES) devices.

Professor Timothy Bender is equally focused on sustainable energy. He has developed Organic Solar Cells (OSCs) with high ambient environment stability and prototypes have been active for more than 4 years. He has developed the active organic materials of OSCs - boron subphthalocyanines (BsubPcs). BsubPcs are a subset of materials used extensively in the dye and pigment industry - phthalocyanines (Pcs). Prof Bender considers a broad life cycle for materials and has developed chemical processes to minimize the embedded energy into the chemical production of BsubPcs, enabling OSCs to have a short energy payback period. Recently, Prof Bender has identified a bio-source for all carbon atoms present in a BsubPc. This enables a version of OSCs to now be based on materials that themselves have harvested CO2 from the environment and are sustainable.

Prof Bender’s students have also shown high electrochemical stability of BsubPcs on both oxidation and reduction - stability showing the ability to store electrical power. Their potentials ranging from (+/-) 0.6 - 1.4 V (vs Ag/AgCl) enabled by structural variations.

The goal of this project is for Profs Lian and Bender’s lab and students to collaborator on merging the bio-sourced electrodes and bio-sourced electroactive BsubPcs into SEES and other electrical energy storage devices. Prof Bender’s students will continue to develop bio-sourced BsubPcs and will expand to Pcs, their bio-source being similar with modification of the chemical process. Prof Lian’s students will continue to develop the bio-sourced electrode materials and will engineer the collaborative supercapacitors and other electrical energy storage devices. The ultimate goal of this collaboration, within a 2-year period, is to develop the intellectual property and consider how to move the bio-sourced energy storage devices to the Canadian market.

Background: Impaired barrier function at the intestinal epithelium can lead to the translocation of microbial-derived products from the lumen of the intestine into the systemic circulation. This can result in a low-grade inflammatory state, which is associated with a number of chronic diseases in humans, including inflammatory bowel disease (IBD), metabolic syndrome and type 2 diabetes. New strategies to counteract the detrimental consequences of altered gut barrier function are urgently needed.

Hypothesis:  We will leverage existing expertise in engineering, synthetic biology, and conventional and germ-free mouse models of intestinal and metabolic disease to develop engineered probiotics to target and fortify the gut barrier. Our hypothesis is that engineered probiotics that can sense inflammation and deliver microbial-derived, anti-inflammatory molecules to the gut mucosa will fortify the gut barrier and limit systemic inflammation.

Approach: The probiotic bacterial strain, Escherichia coli Nissle (EcN), will be genetically engineered as a novel biosensor of inflammation that couples inflammatory sensing to the delivery of therapeutic molecules, including microbial anti-inflammatory molecule (MAM) from Faecalibacterium prausnitzii and Aeromonas immune modulator (AimA) from Aeromonas veronii, to the gut mucosa in order to bolster gut barrier function.

Aim 1 - Creation of an engineered probiotic as a novel inflammatory biosensor: Transcriptomic profiling of EcN within the inflamed murine gut has identified transcripts induced in the inflammatory environment. Using riboswitches, we will convert these transcriptional markers into gene expression outputs, creating a suite of new biosensors.

Aim 2 - Coupling inflammatory sensing to payload delivery: The biosensors will be integrated into negative feedback control circuits in EcN, limiting therapeutic production to required situations, and regulating the output to safe levels.

Aim 3 – Testing of engineered probiotic in mouse models: Engineered EcN will be tested for the ability to secrete anti-inflammatory therapeutic molecules and improve barrier function in mouse models of IBD and high-fat induced metabolic disease.

Overall Significance: Our approach will demonstrate proof of concept that the creation of a living therapeutic to improve intestinal barrier function will help to promote both gut- and system-level health.

Rationale and Objectives: Recent progress in stem cell technology and regenerative medicine have underscored the need for effective banking of stem cells. Currently used cryprotective chemicals for cell banking, such as dimethyl sulfoxide, can be cytotoxic, can induce metabolic damage or unwanted differentiation of the stem cells, and must be thoroughly washed away before clinical application. Trehalose, a nontoxic sugar molecule synthesized by microorganism to survive freezing, has recently been investigated as an alternate to provide cryoprotection. This natural disaccharide does not pose any risk of cytotoxicity to the stem cells. However, trehalose has very limited cell membrane permeability that significantly limits its potential for cryopreservation purposes. The long term objective of this NFRF exploratory project is to address this critical issue by introducing a novel exploratory strategy that can enhance intracellular delivery of cell membrane impermeable molecules, such as trehalose, into the cell cytosol, to improve the process of banking stem cells.

Research approach: Towards that goal, the research team proposes to design and develop a high-throughput microfluidic system that can create transient pores in the cell membrane by mechanical deformation and rapidly transport extracellular cargos into the cells before the pores reseal and membrane recovers. Specifically, the following two key objectives are proposed here: (1) Develop a high-throughput microfluidic device to efficiently deliver trehalose molecules intracellularly into the stem cells and (2) Confirm the integrity of cell membrane surface protein and inherent functionalities of the trehalose-internalized stem cells post cryopreservation.

Expected outcome: It is expected that the stem cells cryopreserved through this new method will demonstrate high delivery efficiency of trehalose molecules into cell cytosol, and hence will dramatically improve cell cryopreservation and cell banking ability. Importantly, the project integrates complimentary and unique expertise of the participating investigators from diverse research backgrounds including microscale technology, stem cell biology, analytical biochemistry and medicine to address this research gap and unmet need in cell banking. To conclude, this highly interdisciplinary NFRF project is expected to result in new paradigm shift in methodology of cell banking with wide-ranging implications in the field of regenerative medicine.

Our application to the New Frontiers Exploration Program will posit the idea of a ‘digital twin’ for Canada and explore the implications. Bringing together a multidisciplinary team of academic, public and private partners, we will develop a roadmap for Canada that considers technological, social, and cultural imperatives. Rather than simply play a game of catch-up with other international players, we will create a strategic framework to support Canada’s AEC industry in becoming a world leader in digital construction research and innovation.

Built and digital environments are becoming inextricably intertwined—with building information modelling (BIM) and Smart City technologies emerging as some of the first manifestations of this relationship. From mitigating environmental impact to increased efficiencies in building construction and operation, early adopters have demonstrated a broad range of social and economic benefits. However, despite the promises of digital integration for the architecture, engineering, and construction (AEC) industry, Statistics Canada reported a 4.6% sector decline in productivity in the final quarter of 2018. There is a clear and pressing need to re-assess the digital transformation of Canada’s AEC sector for the next wave of disruptive technologies.

To address similar AEC productivity indicators, the United Kingdom took a leadership role in policy development for digital integration in 2011. In 2018, it launched “Digital Built Britain”, an initiative centred at Cambridge University that is mandated to develop a ‘digital twin’ of the UK. The digital twin “...includes the whole built environment, existing and new...” and “...interfaces with the natural environment and the services delivered—social, economic and environmental.” (The Gemini Principles 8) The UK initiative has defined a digital twin as “...a realistic digital representation of assets, processes or systems in the built or natural environment…that adds social and economic value by augmenting the decision-making process.” ((The Gemini Principles 10) What distinguishes the digital twin from the models produced through BIM, is its capacity to exchange real time information with its physical twin and to use that information to learn and predict (or enact) a possible response. While advocates for the economics of digitization are optimistic, this scale of connectivity also brings with it concerns about cybersecurity, data privacy, and governance.

High stress levels, delirium, and sleep deprivation are common among critically-ill patients and may compromise recovery and survival as well as increase length and costs of hospital stays. Pharmacologic approaches are the usual mode of treatment for these conditions, but with non-negligible expense, limited effectiveness, and potentially harmful side effects.  Music and sound therapies are low-cost and non-invasive, without dangerous side effects. Research has shown them to be highly effective if customized to the patient. Yet critically-ill patients cannot be expected to cooperate fully with music therapists, who are also scarce and expensive. We thus propose to design, prototype, and test an autonomous system for generating therapeutic soundscapes adapted to the critically-ill patient, aiming to induce relaxation, improve sleep, and reduce anxiety and delirium. Design of the soundscape space of possibilities will require close collaboration between project researchers in music and medicine and will be shaped by experimental results obtained from a large, diverse group of healthy subjects. A binaural sound generator will create an immersive audio experience auditioned through headphones or speakers. A reinforcement-learning approach will guide the search of the soundscape space based on biosignals: observations of the patient’s current state, including response to the current soundscape. Thus the patient will not need to actively engage with the system but rather will passively provide biofeedback. The explore-exploit tradeoff in the search algorithm must be carefully tailored for critically-ill patients so that the search itself does not cause additional stress. Doing so will require close collaboration between the project’s researchers in computer science, medicine, and music as well as extensive experimentation with healthy subjects. Our innovative synthesis of medical ethnomusicology, music therapy, critical-care medicine, and machine learning aims to produce a cost-effective, adaptive, patient-centered approach to stress reduction in critically-ill patients, one that is non-invasive, non-pharmacologic, and free of harmful side effects, resulting in better quality of life for patients and their families, and more efficient use of hospital resources. Our project also offers learning opportunities for students, and promises to spur future synergistic collaborations between medicine, the arts, and computer science, for the public good.

The aim of this project is to better understand how new approaches in personalized neuromedicine and psychiatry can influence the trajectories of individuals suffering from, or at risk of developing, major brain disorders.

The main focus will be the development of models of risk trajectories that integrate factors related to economic vulnerability with genetic risk factors for youths who have at least one parent affected by major brain disorders (schizophrenia, bipolar disorder and recurrent major depression). We will seek to determine how the socioeconomic environment (especially families’ absolute and relative levels of income and wealth) interact with genetic vulnerabilities, measured by genotype-based risk scores, to influence the use of health care services and risk trajectories. We will also investigate the mechanisms involved (increased stress, changes in health behaviour, access to and utilization of preventive care, etc.). Our empirical approach to meet these objectives will rely on econometric and statistical genetic analysis, which will help identify the heterogeneity in the impacts of increased socioeconomic vulnerabilities on children’s risk trajectories, across varying degrees of genetic predispositions to developing major brain disorders. We will also test the extent to which integrating our constructed indicators of socioeconomic status to algorithms of risk classification can improve their predictive power.

Recent progress in the literature suggests that focusing on a population of children born to a parent affected by brain illnesses is a promising avenue for understanding the opportunities offered by personalized neuromedicine and precision psychiatry (as proposed by Maziade in the New England Journal of Medicine; 2017). Taking this into account, our analysis will partly rely on data provided by the scientific and clinical program Horizon Parent-Enfant (HoPE), an ongoing family-centered personalized prevention and treatment approach involving affected parents and their children. It contains longitudinal information on the clinical and socioeconomic situation of hundreds of participating families, in addition to genetic data.

The benefits from the proposed project are non-trivial, as brain disorders and mental health have become a leading cause of growth in the burden of disease worldwide. The knowledge generated could help design protocols and policies to help some of the most vulnerable subgroups within the population.

Arriving at a pathological diagnosis is a complex intellectual process that involves integration of multiple sources of data into a single diagnostic report. The central component of this process is the morphological assessment of tissue specimens by a pathologist using light microscopy. Machine learning (ML) is an area of artificial intelligence (AI) that uses computer algorithms to extract meaningful patterns from data, with little or no human intervention. ML algorithms such as deep convolutional neural networks (CNN) have been successfully applied to image analysis, in some cases exceeding human ability to categorize images correctly. Given the critical role of morphology in pathological diagnosis, there is recent interest in applying ML to image analysis in pathology. However, similar to any other laboratory test, integration of ML into a pathology diagnostic workflow will require a clear demonstration that adoption of this technology would fulfil an unmet clinical need.

Hematopathology is a subspecialty area of pathology that focuses on diagnosis in the hematopoietic (blood and bone marrow) tissue. A requisite component of the morphological review of a bone marrow specimen is the manual differential count (MDC), wherein individual bone marrow cells are manually enumerated and classified into specific categories by an experienced operator. This is a time-consuming and subjective process that requires a high degree of technical skill and shows significant interobserver variation.  The ability to automate bone marrow differential counts using ML would enhance laboratory workflow and render the MDC a relatively objective process, potentially impacting both pathological diagnosis and patient outcomes. Therefore, developing a novel ML approach that could perform a bone marrow MDC would fulfill a currently unmet clinical need and change practice in the field. To this end, our cross-disciplinary team brings together diverse expertise in hematopathology, artificial intelligence and hematology, with the following specific objectives:

1) Develop ML algorithms that can perform a bone marrow MDC by comparison to human operator – performed MDC.

2) Examine how bone marrow cell classification by ML algorithms would potentially impact pathological diagnosis and clinical outcome.

3) Assess the feasibility of a ML-performed bone marrow MDC as a clinically relevant alternative to a human operator-performed MDC within a hematopathology diagnostic workflow.

The emergence of synthetic plastics as versatile industrial and consumer polymers has led to an unprecedented accumulation of recalcitrant macroscopic and microscopic waste in terrestrial and aquatic ecosystems. Today, an average of 8 million metric tonnes of plastic waste is estimated to flow into the ocean every year which is equivalent to a full truck load of plastic garbage dumped every 60 seconds. Dispersed by winds and ocean currents, plastics in one form or another can be recovered in even the most remote oceanic locales. The accumulation of plastic particles in marine food webs poses a number of unconstrained ecological concerns with visible impacts on the health of more than 300 animal species. This accumulation shows no signs of natural attenuation and recent studies have linked microplastics to microbial biofilm production, increased horizontal gene exchange and altered metabolic states relevant to nutrient cycling. Despite emerging concern, significant challenges remain to understanding the role and fate of microplastics in the environment. Here we aim to develop novel methods for microplastic analysis using microbial indicators and metabolic networks to determine the fate and impacts of microplastics in the environment, including their role in the transfer and storage of genes related to polymer transformation, antimicrobial resistance and carbon utilization. Our interdisciplinary team of scientists and engineers working closely with the Ocean Wise microplastics facility and Metro Vancouver will conduct time series monitoring of wastewater outfalls associated with microplastic discharge into north Pacific coastal waters. We will profile these particles and their associated microbiomes using shotgun sequencing and high throughput functional screening approaches. These in situ studies will be accompanied by intensive mesocosm experiments in the laboratory based on enrichments from the same discharge locations on defined plastic compositions provided by leading textile companies. Our work will solidify Canada’s policy leadership on microplastic research at the G7 and globally, contribute to innovation in the private sector, and provide solution-oriented opportunities in household, municipal and storm water liquid wastewater streams and treatment facilities including but not limited to the development of novel diagnostic tests and bioremediation systems.

Antibiotic resistance poses an increasingly dire global health threat, where once-treatable bacterial infections now cause life-threatening illness. Gram-negative bacteria like Neisseria gonorrhoeae, Neisseria meningitidis, Vibrio cholerae and Pseudomonas aeruginosa are particularly difficult to kill as their outer membranes make them inherently resistant to structurally large antibiotics like vancomycin. And even when antibiotics are effective in treating infections, they can cause severe damage to the afflicted patient by simultaneously eliminating beneficial bacterial of the microbiota. There is an urgent need for new and creative ways to identify, develop, and deliver novel antibiotics with greater specificity and efficiency, and also to repurpose existing ones. Here we propose to exploit the bacterial Type IV pilus (T4P) as a novel antibiotic delivery system. T4P are long thin retractile filaments on the surfaces of many bacterial pathogens. These filaments are polymers of thousands of copies of the major pilin protein, with a cluster of minor pilins located at the pilus tip. T4P are dynamic organelles that rapidly assemble, adhere to surfaces or substrates like DNA or bacteriophage, and retract to pull the bacteria along surfaces or to pull substrates into the periplasm. The minor pilins have recently been shown to mediate many of these interactions. We plan to identify “recognition” molecules – antibody fragments as well as DNA aptamers – that bind with high specificity to the tip-associated minor pilins, to be used as carriers for antibiotics. Such carriers could thus function as Trojan horses, being delivered into the periplasm upon pilus retraction, thus circumventing the outer membrane and killing with high precision and specificity. Dr. Craig is a microbiologist and leader in the Type IV pilus field, elucidating their atomic structures, functions and assembly and retraction mechanism. Dr. Sen is a world class chemist who has used aptamer libraries to develop nucleic acids for biocatalysis and biosensing. Together they will identify potential carrier molecules and conjugate these to vancomycin and other large antibiotics and test their antimicrobial activity. This exploratory multidisciplinary collaborative project is expected to repurpose existing antibiotics like vancomycin for use against Gram-negative bacteria, thereby broadening our arsenal of treatment options, and may lead to new treatments for multi-drug-resistant bacterial pathogens. 

Alleviation of suffering at the end of life is critical during withdrawal of life support measures (WLSM) in intensive care units. It is achieved through patient observation and reactive administration of pain and anxiety relieving medications in response to signs of distress. The intent is to alleviate suffering without hastening death and involves subjective interpretation of distress by those present at the bedside. As a result, WLSM practices vary between cases and providers, with the risk that some patients may experience suffering at the end of life.

Given that some patients undergoing WLSM are also organ donors, determining the time of brain function cessation following WLSM is critical to ensure donor protection from suffering. Furthermore, an objective understanding of the brain function at the end of life may help increase the number of organs and improve their function in recipients by shortening the time from brain and heart function cessation to organ removal, thereby limiting organ injury due to low oxygen levels. However, a comprehensive study of brain function during WLSM has so far been elusive, due to the private and emotionally charged nature of WLSM for patients, families and healthcare providers.

In this study, we will partner patient-families and health care providers experiencing WLSM in critical care with cognitive neuroscientists, organ donation and palliative care experts to develop a patient-centered assessment of brain function during WLSM. We will record cognitive, cortical and brainstem function in a cohort of critically ill patients undergoing WLSM. Finally, we will interpret our results from the ethical, legal, and social dimensions, and translate this unique knowledge to inform and standardize WLSM and deceased organ donation laws and practices in Canada.

Our unprecedented interdisciplinary and patient-centered approach seeks to clarify physiological processes, rights and obligations to promote dignity, comfort and wellbeing at the end of life. Objective data regarding cognitive and therefore possible conscious experience in the brain will help to address fears regarding the potential for suffering at the end of life. In the context of deceased organ donation, our data will ensure that organs are removed as soon as possible after brain and heart function cease, which may increase the number of organs from the existing donor pool, as well as improve organ function in recipients following transplantation.

If we had medicine to treat abnormal biomechanics, we could save the Canadian health care system >$27B per year in osteoarthritis (OA)-related costs. In this proposal, we will discover targets for a new class of “anti-mechanical medicines” that target mechanically-induced inflammation in knee OA to prevent disease progression.

Background: OA symptoms and progression are mechanically-driven, but synovial inflammation (synovitis) is prevalent in >70% of knees with OA. Knee inflammation is associated with worse symptoms and much higher risk of future joint damage (progression). This strong epidemiologic data suggests that mechanically-driven inflammation is a key driver of worse outcomes for patients with knee OA. To leverage this into a treatment opportunity, we must explore and discover the mechanisms linking abnormal joint loading mechanics to knee inflammation. Further, since joint repair mechanisms are also active in knee OA, segregating which mechanisms are helpful (friend) or harmful (foe) is critical to identifying effective anti-mechanical medicines. None of this has been possible until now.

Rationale: By changing mechanical loading of the knee in patients with knee OA, we can explore the biological response to correction of knee mechanics. Valgus-producing, medial opening wedge high tibial osteotomy (HTO) is an excellent model for inducing stable changes in medial knee joint loading in patients with knee OA. We can apply this model to study mechanically-induced knee inflammation and compare "active" vs. "inactive/healing" disease states within the same individual.

Approach: Using knee synovium samples collected before and after load-altering surgery, we will use advanced molecular biology technology to identify damaging mechanisms driven by abnormal joint loading ("active" disease pre-HTO) and simultaneously identify and exclude restorative mechanisms driven by normal joint loading ("inactive/healing" disease post-HTO). We will use advanced biomechanical engineering to discover the patterns of mechanical loading associated with active and resolving inflammation.

Significance: This approach will allow us to achieve our overall objective to identify new targets for a new class of disease-modifying “anti-mechanical medicines” for knee OA. Our discoveries will bring a huge increase in development activity in musculoskeletal medicine in Canada and set the stage for long overdue benefit for the millions of Canadians suffering with this disease.

Indigenous peoples are less likely to engage in research with the collection of biospecimens, a result of numerous factors that have led to mistrust in genetic and other biological health research led by academics. Our team of interdisciplinary researchers and First Nations community leaders has identified a need to create ethical space for community-led research on biological factors that integrates Mi’kmaq knowledge. Elder Albert Marshall’s concept of Two-Eyed Seeing emphasizes the need to take the best of what we know from Indigenous and Western knowledges, and with the leadership of The Union of Nova Scotia Mi’kmaq we will bring together Knowledge Holders, health leaders, and community members to:

1) Learn about biological research (genetics, epigenetics, the microbiome, and other topics relevant to health of Mi’kmaq peoples)

2) Assess views of Knowledge Holders, health leaders, and community members on genetic, epigenetic, and other biological health research regarding perceived risks/benefits, and interest in leading/participating in projects

3) Develop ethical guidelines for health research involving biological samples at the regional, provincial, and/or community level as determined by communities

4) Discuss Mi’kmaq knowledge relating to human development and biology and promote the use of this knowledge in future research projects and policy-making

5) Create capacity and opportunities for Mi’kmaq communities to lead biological health research that meet their priorities

A scoping review will be conducted on existing guidelines for the use of biological specimens in research with Indigenous peoples. This will be shared in gatherings where community members will learn about genetics, epigenetics and other biological health research, and will join in talking circles to share their views on risks/benefits of research, ethical guidelines for the collection of biospecimens, and what supports their communities need to carry out their own biological health research projects. To assess other community members, a survey will ask about views of biological research, interest/willingness to participate, and resources necessary to do so. Talking circles and interviews with Knowledge Holders will explore traditional knowledge and cultural protocols to consider. Based on the knowledge gathered, a meeting will be held to refine the draft guidelines and discuss how to support interested communities in leading biological research that address their priorities.

Amino acids, or the building blocks of proteins, are related to most life processes, and are particularly attributed to the origin of life. Various types of molecular species have been identified in interstellar medium whose chemical nature is closely related to amino acids. Nevertheless, amino acids have been detected in meteorites but not in interstellar medium. As such, it might be the interstellar chemistry which is in charge of the formation of amino acids identified in planetary surfaces. In 1953, Miller and Urey pioneered the experiments of the chemical synthesis of amino acids from methane, amine, hydrogen, and water, while applying an electrical discharge. At the border between chemistry and physics, the interdisciplinary surface science studies benefits from the clean environment of ultra-high vacuum (UHV) condition, i.e. in the absence of water and air with a pressure better than 10-10 mbar. UHV chambers offer a distinctive environment to make and characterize nanomaterials. As such, the synthesis of biological nanomaterials can be controlled not only by the chemical nature of the molecules and the reaction parameters, but also by the catalytic activity and crystallinity of the employed surfaces. However, the direct formation of peptide bonds from non-amino acids reactants in solution chemistry is not well-understood, and has not been reported under UHV condition. If under controlled UHV conditions, peptide bonds are formed from a non-amino acid pathway, can amino acids be still assigned as the unique evolutionary path of the origin of life? The present proposal aims at addressing this question by investigating the formation of peptide bond from non-amino acid reactants under UHV. The proposed multidisciplinary approach is based on the physical, chemical, and biological sciences to take steps in the pathways of the origin of life studies. The objectives are to (1) adapt Miller’s experiment to UHV condition; (2) form peptide bond from the reaction of amines and carboxylic acids, led by surface catalytic activity; and (3) compare with peptide bond formation from amino acids. In all cases, single crystal surfaces of metals, semiconductors, or insulators will be employed as a platform on which the reactions occur under UHV. In summary, the overall goal of this proposal is to unveil the step-by-step mechanistic understanding of the peptide bond formation at nanoscale, which will be addressed using high resolution scanning probe microscopy techniques.

There is a growing awareness that addressing the climate emergency will require understanding and harnessing social forces.  However, current Intergovernmental Panel on Climate Change (IPCC) targets rely upon ad hoc projections of emissions generated by humans. This project will incorporate social dynamics into existing climate models to refine climate change predictions and chart new achievable pathways towards IPCC targets.  The project will build on recent modelling research by the co-PIs showing that realistic social processes can dramatically alter climate change predictions, and thus models need to include the two-way coupling between social and climate dynamics (socio-climate dynamics).  However, there are still many unknowns, both theoretical and practical. We assemble here, for the first time in Canada, a group that includes experts in climate modelling, environmental psychology, and human-environment models. We also include both established and new collaborations with policy-makers (federal, provincial, municipal) and stakeholders who will inform policy and implementation aspects of the project. Compared to existing models, our socio-climate model will contain significantly more structure and realism, allowing it to inform climate change projections and suggest policy interventions. This new model will allow us to answer outstanding questions such as:  how do echo chambers within social networks slow down social learning (e.g., adopting mitigation behaviours) and how can they be broken down? What are the differences in how individuals and governments use social forces to guide change? How can we characterize socio-climate tipping points and help prepare societies for non-incremental change?  Some of the social model parameters will be based on country-level time series data on emissions, GDP per capita and population size. This will be supplemented with collection of new data and a systematic review of the social/environmental psychology literature. We will also use a large existing database of tweets on climate change to analyze social network structure and dynamics. Finally, we will use current momentum to link with international consortia who have reached out to us to generate ensemble forecasts (combining diverse model predictions) using socio-climate models currently in development by other groups in Norway, France and the US, all of whom are becoming interested in socio-climate modelling.

Development of new effective, environmentally benign, low-cost antimicrobial materials is an emerging area of research drastically important for modern biomedical applications. Common antimicrobial protecting coatings like bacteria-killing paints are based on the creation of thick layers that slowly release biocidal compounds into the media and therefore are not environmentally benign and suffer from short shelf-life. For all technologies of antimicrobial coatings existing so far, long term effectiveness is a major drawback preventing their effective applications. We propose to create a new class of hybrid materials based on covalently attached organometallic monolayers with quaternary ammonium centers on various conductive supports that decrease initial adhesion, growth, and proliferation of a variety of bacteria, viruses, and fungi. In addition, the unprecedented chromogenic nature of these antimicrobial coatings will allow easy naked-eye colorimetric assessment of the level of the bacterial contamination. We plan to utilize a unique feature of electrochemical self-cleaning for easy elimination of initiators of bacterial contaminations and effective removal of dead cells from the surface to fully prevent the growth of biofilms at the very initial stage that is believed to be the critical event in the mechanism of the infection. The monolayer nature and strong covalent attachment of well-defined antimicrobial metal complexes will allow us to create a wide range of effective, ultra-durable materials with universal antimicrobial characteristics. Antibacterial performance, long-term effectiveness, self-cleaning properties, and the ability for effective sensing of bacterial contamination will be examined to get an in-depth understanding of the anti-biofouling mechanisms of new materials. Utilization of smart self-cleaning, self-sterilizing and self-indicating materials will lead to a significant decrease in hospital infections. Comprehensive use of these smart materials together with the cutback of antibiotic treatment will help to overcome the antibiotic resistance crisis, the problem of the rapid emergence of antibiotic-resistant bacteria, which is occurring worldwide. In addition, this research will be heavily applied in biosensing, food processing, marine industries, and many other strategically important manufacturing sectors in Canada.

Despite being one of the most prosperous country in the world, Canada has unsatisfied performance in measuring children’s health and safety, as well as child poverty. One critical aspect related to children’s wellness is their living conditions. It has been recognized that children’s living conditions have life-long implications for their risk of developing chronic diseases and mental health. For example, using the Early Development Instrument (EDI), a widely used measure of the state of child development, children from low-income neighbourhoods in Canada have higher rates of vulnerability (35%) than children from high-income neighbourhoods (20%)

The objective of our inter-disciplinary research project is to exam how social and environmental factors lead to child disease status. Based on these measurements, we will develop a statistical model to predict the potential disease risks for children given the data of living conditions and provide suggestions to improve the living conditions in order to reduce child’s disease risks. We will begin our project with biological assays using hair and saliva samples. These two types of biological samples are non-invasive, easy-to-collect matrix that have exceptional ability to store both endogenous metabolites and exposure chemicals. This first specific aim is to assay the metabolome, epigenome, and exposome for 100 children that have already recruited in the ongoing UBC Preschool Family Study. Comprehensive statistical analysis and modeling will be performed to interpret the large-scale dataset to discover potential exposure molecules that are highly correlated with child development. The second specific aim is to find out the sources of these exposure molecules. For example, whether these molecules are produced by specific industrial activities or environmental perturbations. Once we recognize where these exposure molecules are from, the third specific aim is to develop an “exposure source to child disease status” model and test this model in several other survey-based large scale child development projects. This proposed project involves fields of study from all 3 tri-council agencies and will provide comprehensive insight into how, when, and under what circumstances early life environmental factors become biologically embedded to affect child health and development. It will also lead to policy interventions and/or treatment to improve living conditions for better children’s wellness.

Program Objectives:  We address the clinical problem of infection near orthopaedic implants, which has become a leading cause of joint-replacement revision surgery, costing over $500 million each year in Canada. The current approach to treat an infected component is by removal of the implant, implantation of a temporary plastic antibiotic-eluting spacer, and then finally implanting a new component. We propose to investigate novel, cost-effective approaches to treat infections near orthopaedic implants, obviating the need for two-stage surgery.

Research Approach:  Our approach combines expertise from multiple disciplines to investigate two new approaches for enhanced therapy:

Obj. 1: Improved antibiotic elution

One limitation to the current surgical approach is that the acrylic plastic spacer elutes only about 10% of the antibiotic, and typically within the first week; this is clearly sub-optimal for treating infection. We propose a new approach to this problem, combining a 3D-printed porous metal scaffold loaded with optimized antibiotic carriers, which could serve as a permanent implant.  The approach involves the fabrication of titanium-alloy scaffolds, in vitro testing with antibiotics to characterize elution kinetics, and mechanical modeling and testing of the hybrid components.

Obj. 2: RF-induced hyperthermia

Any therapy that allows retention of the original component would transform clinical care; we are investigating the use of RF-induced hyperthermia of the in situ implant. We propose to use optimized RF fields to raise the surface temperature of the metal (to about 60°C) to disrupt the biofilm and kill the bacteria. This approach will be investigated with in vitro tests, using 3D-printed orthopaedic components that have been inoculated with appropriate bacteria (such as Staphylococcus aureus).

Novelty and Significance:  This program combines new technologies from different disciplines to address a significant unmet clinical need. The combination of 3D-printed metal scaffolds and advanced antibiotic carriers has tremendous potential.  The idea of using the physics of inductive heating to treat bacterial infection near implants is technically challenging, but could offer a new way to treat infections without removing the implant.  Both of our research approaches could ultimately reduce or eliminate the need for “two-stage” revisions, which would significantly reduce cost and morbidity, and result in better patient outcomes.

The oceans play a fundamental role in the global carbon cycle and store ~ 60 times more carbon than the atmosphere. Over 662 gigatonnes of marine carbon is comprised of small dissolved organic carbon molecules (DOC) – the second largest reservoir of organic carbon on the planet. The cycling of DOC in the oceans is driven by complex and diverse microbial communities that are thought to produce and consume a diverse array of organic compounds. The fate of DOC – either degradation by microbes to CO2 or storage in the deep ocean – remains a crucial and long-standing question in both oceanography and climate science. Mapping the fundamental role of DOC in the global carbon cycle is ever more critical: climate change is rapidly altering the temperature, pH and oxygen content of our oceans which will modulate the growth and activity of oceanic microbe populations. 

Marine microbes break down DOC through their enzymatic activity and release carbon dioxide (CO2) as a byproduct of their metabolism.  Consequently, changes in the rate and extent of microbial activity has the potential to substantially alter how carbon is processed in the ocean.  Our proposed research uses a new approach, both conceptual and analytical, to address the fundamental question of how DOC is degraded and consumed by ocean microbes. By combining innovative analytical tools and experimental approaches from three distinct disciplines – microbial ecology, isotope geochemistry and enzymology – we will examine the long-standing paradox of deep ocean carbon and quantify the vulnerability of DOC to microbial degradation.  We will carry out well-constrained laboratory experiments to resolve why certain DOC compounds are readily consumed by microbes whereas others appear to be more resistant to degradation, persisting in the deep ocean where they are sequestered for thousands of years. In addition, experimental models accompanied by high-precision analytical methods will be used to assess how changing oceanic conditions will influence the activity of key degradative enzymes.

This work will be the first to resolve how microbial activity will change with warmer and more acidic waters and ultimately impact deep ocean carbon storage. This carries significant implications for Earth system scientists, oceanographers and climate modellers and is critical knowledge for making informed decisions about adapting to and mitigating climate change.

This project seeks to develop a strategy for commemorating the few remaining residential schools in the Province of Alberta. Surviving Indian Residential Schools (IRS) are the material representations of an education system, in name only, that caused great pain and suffering among Canada’s Indigenous peoples for over one hundred years. They have been called “witnesses to history” and “sites of conscience”, yet of the 114 schools that operated during the peak of the residential school era in the 1940’s, only 17 remain standing today. Many of these surviving schools have been preserved only because new uses have been found for them. The remaining schools have fallen into varying states of disrepair and are often prone to vandalism. Many Indigenous communities are divided over the question of whether these existing buildings should be preserved or demolished. Regardless, establishing a national strategy for their commemoration is among the recent calls to action issued by the Truth and Reconciliation Commission. However, should these schools be "commemorated" in the colonial sense of the word? Or is there a uniquely Indigenous way of perpetuating the memories and meanings of these places? When physical preservation is not possible, are there ways to ensure that remaining residential schools are preserved for future generations, regardless of their present condition or purpose?

This project will explore these and other issues relating to the preservation and remembrance of residential schools through a community-guided digital heritage preservation project. Two former residential schools in Alberta will be digitally captured by Blackfoot and Cree students working with University of Calgary researchers in Archaeology, Computer Science, and Geomatics Engineering. Terrestrial laser scanning will be used to capture the interiors and exteriors of each building. With the assistance of knowledge keepers who attended these schools and can recall various details of their appearance, a metadata tagging system for archiving the resulting digital data sets at the National Center for Truth and Reconciliation will be developed which will incorporate Indigenous descriptive elements that are meaningful to survivors and community members. Working with our Indigenous partners, we will also explore how the resulting digital data can be used to create physical (3D printed) and virtual visualizations of these schools that will help ensure their history is not forgotten.  

Children today are growing up in an immersive digital media culture, with nearly continuous interaction with mobile applications (apps), including via parents’ online behaviours. Child digital engagement has extended to the realm of health, where apps target a range of health promotion and disease management foci. The perceived value of health apps has resulted in their endorsement by child health organizations and prescription by clinicians, often without a complete understanding of data privacy and security. It is known that app developers routinely transmit user data to third parties to enhance user experiences or monetize the app. Although the data sharing practices of these third parties are largely unexplored, adult health app research indicates that commercial entities may be the recipients of personal and health data. In the case of children, serious safety and privacy issues can arise if health information is used for data-driven health product and service advertising without clinician consultation. Further, data aggregators may identify child users and create digital health dossiers that eventually impact on education or employment in adulthood. It is therefore critical to characterize the data sharing practices of child health apps and examine the advertising impact of transmitted data. Using a phased-approach that combines the disciplines of pediatric nursing, health policy, and computer science, we will meet this need. In Phase 1, we will use a rapid scoping review to identify apps endorsed by influential child health institutions and oversight bodies. In Phase 2, focusing on review-identified apps and those most downloaded from commercial stores, we will use novel software methods to electronically intercept and analyze data transmitted to external servers. In Phase 3, we will conduct a systematic content analysis of targeted advertising presented to children within apps, using dummy profiles. Our analyses will enable the characterization of data being transmitted by child health apps, the entities receiving the data and their data sharing practices, and the resultant advertising (and potential health) impacts on children. This research will provide a crucially needed picture of the privacy risks to children associated with health app use. Results will be disseminated to app developers, child health organizations and policy makers to guide recommendations and education to children and families, and inform digital privacy regulations.

The complex, nonlinear and multi-scale dynamics and organization of the nervous system creates immense challenges in phenotyping and understanding neurological disease and cognitive impairments.  While it is known that excitatory-inhibitory (E-I) imbalances underlie these pathologies, the details of E-I disruptions are difficult to determine due to cellular specifics.  Oscillatory dynamic activities are a ubiquitous feature of brain recordings and accumulating evidence indicates that rhythms are part of the cognitive code.  Moreover, rhythmic activities show specific changes with disease states as captured in data analysis metrics, thus indicating that they can be ‘targets’ for biomarker, mechanistic and therapeutic investigations.  Examining microcircuits allows mathematical models of them to be able to have analytical and computational ‘tractability’ and thus able to garner dynamical insights that include cell-specific pathways.

Our objective is to develop a cognitive readout platform to identify altered cell-specific pathways in brain injury disease states.  We will employ a juvenile rodent model of traumatic brain injury (TBI) known to lead to changes in hippocampal oscillations correlating with impairments in spatial memory and cognition.

Our approach will involve: (i) electrophysiological recordings of rhythmic activities in the hippocampus in control and TBI animals in vivo and in vitro, (ii) sophisticated data analyses that leverage machine learning, signal processing and statistical inference methods to obtain ‘mappings’ between in vitro and in vivo data, (iii) cellular-based microcircuit mathematical models of in vitro rhythmic activities.  We will identify cell-specific pathways in vitro by optimizing model parameters for control and TBI datasets and use in vitro-in vivo mappings to identify cell-specific pathways in vivo.

Our work is novel in linking in vitro, in vivo and computational modeling studies that can gauge underlying cellular mechanisms in cognitive impairments.  This would be a panacea and would additionally lead to accelerations in drug development, testing and screening.  Billions of dollars in yearly direct and indirect costs are due to the high prevalence of TBI in the Canadian population including TBI in children with potential life-long consequences.  A better understanding of how alterations in network circuitry are associated with cognitive impairments in TBI would have a huge impact on Canadian healthcare. 

Une lésion de la moelle épinière bouleverse profondément la vie des personnes atteintes et des aidants, avec des défis personnels et sociaux majeurs. L’atteinte des fonctions motrice, sensorielle, cardiovasculaire et respiratoire affecte grandement la qualité de vie et la participation sociale. Les plaies de pression (40% des blessés médullaires) sont particulièrement redoutées car elles engendrent des conséquences biopsychosociales néfastes et une mortalité accrue. Pour prévenir et traiter les plaies de pression, le consensus actuel implique des changements de position aux 2 heures et ce, à vie. Comme les tétraplégiques (paralysie des 4 membres) sont incapables de se mobiliser de façon autonome, ils requièrent l’assistance des aidants pour chaque repositionnement. Ce problème est particulièrement marquant la nuit, car le repositionnement va troubler le sommeil, accentuer l’épuisement des aidants, et affecter l’adaptation des personnes atteintes et des aidants.

L’originalité du projet relève du regroupement d’expertises variées pour proposer un système inédit de repositionnement autonome pour tétraplégiques dont les objectifs sont de 1) minimiser les plaies de pression, 2) améliorer le sommeil de la personne tétraplégique et des aidants, 3) alléger le rôle des aidants et 4) favoriser l’adaptation et la résilience face à la lésion médullaire. Ce projet s’appuie sur une équipe interdisciplinaire combinant des compétences médicales (orthopédie, physiatrie, réadaptation), des sciences humaines (psychologie, sommeil, soutien à la qualité de vie, partenariat de soins), et en ingénierie (conception, optoélectronique, mécanique et asservissement, traitement de signal numérique).

Tout au long de ce projet, les patients- et les aidants-partenaires travailleront de concert avec les chercheurs et les cliniciens pour développer un système de repositionnement dont les tétraplégiques profiteront toute leur vie. Suivant une approche bio-techno-psycho-sociale innovante intégrant des spécifications cliniques, techniques et psychosociales pour la conception et l’évaluation du système, le prototype combinera 1) un système de positionnement, 2) le suivi de paramètres physiologiques et 3) des fonctions de rétroaction et de commande. Le concept sera validé dans l’environnement naturel des blessés médullaires autant à l’hôpital qu’à domicile. L’adaptation des aidants, ainsi que les barrières et facilitateurs à l’intégration du système seront aussi évalués.

Rationale: Bacteria can be engineered as sensors of the environment, reporting on inflammation and other environmental/metabolic changes. Chronic inflammation has long been recognized as a significant contributor to Alzheimer's Disease (AD) etiology and progression. Importantly, the inflammatory and metabolic status of the gut is increasingly becoming appreciated as a readout of neurodegeneration, and there is evidence that the gut microbiome may contribute to AD development. To date, bacteria have been developed that can read various inflammatory molecules and metabolites (e.g. nitric oxide, iron, tetrathionate). We hypothesize that a personalized panel of microbial biosensors could be used for AD staging and stratification.

As proof-of-concept, we will begin by detecting tetrathionate, a labile byproduct of an inflammatory response. Diagnostic E. coli have been engineered to recognize tetrathionate using a bidirectional bacteriophage promoter element that acts as a memory switch (doi. 10.1038/nbt.3879). A colorimetric assay can detect whether bacteria have come in contact with tetrathionate, and the number of bacteria that respond and turn the switch on can provide a readout of the degree of inflammatory molecules in the gut. This sensor has been developed and patented for use in the mouse gut (PMID: 28373240), and the Rice University has filed for a patent to use the thiosulfate sensor (ThsSR) to diagnose or treat gut inflammation. However, this sensor has not been applied to neurodegenerative disease models. The advantage of this approach is that several other sensors have already been made, and new ones can be designed to respond to different metabolites/biomarkers that may be AD-specific.

Experimental Plan:

• Test the tetrathionate biosensor in AD mice. We will acquire the ThsSR sensor and test its ability to stage AD using our well-characterized AD mouse model across disease trajectory. 

• Establish models of comorbid diseases in our humanized AD model (mid-life hypertension, covert stroke, and unhealthy lifestyles) to develop biosensors that report on the common targets of these interactions. 

• Engineer additional novel biosensors to other metabolites implicated in disease pathogenesis, such as short-chain free fatty acids, and hormones such as serotonin.

Deliverable: Development of novel microbial biosensors to probe gut status to stratify the diverse AD patient pool and assess therapeutic response.

Even in the healthy brain, memory is notoriously fickle; with no apparent cause, you may recall an acquaintance’s name one moment, but forget it the next. This fickleness is exaggerated in memory disorders where, for instance, patients with Alzheimer’s Disease cycle between ‘good’ moments of clarity and the all too frequent ‘bad’ moments of confusion. But what drives the very same brain to alternate between memory successes and failures, and how can we harness these mechanisms to foster success? Theories inspired by the physiology of rodent brains offer a surprising insight: neural mechanisms supporting the formation of a memory may be at odds with those supporting its retrieval. These phases of a memory, thus, would be best achieved at separate times, relegated to different phases of a prominent brain wave called theta oscillations. This provocative theory has not been causally tested in humans, however, because we have lacked the tools to manipulate the brain during these precise phases – until now.

Bridging across psychology, neurosurgery, physiology, and engineering, we innovated on conventional deep brain stimulation (DBS), in which surgically implanted electrodes are used to stimulate patients’ brains. Rather than applying DBS at random times, we engineered a system to stimulate a critical brain region for memory – the hippocampus – as it enters into different phases of theta. Across two experiments, we will now use this system as patients with epilepsy either form or retrieve memories. Using customized cognitive assessments, we will determine (1) if the theta phase at which DBS is applied determines how it modulates memory and (2) if memory formation and retrieval depend on different theta phases. Using electrophysiological recordings, we will also uncover the neural mechanisms underlying theta and memory phase specificity.

The results of this work could incite a paradigmatic shift in thinking about memory, the human brain, and the treatment of memory disorders. Causal evidence that human memory formation and retrieval depend on opposing neural states would shift the field from seeking interventions to influence memory as a whole towards more dynamic approaches targeting the coordination of brain states and specific memory processes. Further, by engineering precisely timed DBS systems, our work will also lay the foundation for next-generation devices capable of delivering the right brain stimulation at the right time to improve memory.

Optogenetics is a method for controlled stimulation of brain cells. It involves activation and silencing of light-gated channels of genetically-modified neurons using optical means. Over the past decade, due to its cell-type specificity and high spatio-temporal resolution, it has been widely and increasingly used for studying fundamental biological mechanisms underlying brain functions.

In recent years, there have been many attempts to confine stimulation of the light-gated channels to a single-cell or subcellular regions. This is particularly advantageous for mapping how neurons connect within a functional network, which leads to a better understanding of cell interactions during neuronal activities.

While techniques such as two-photon excitation or focused laser beams have been shown to be effective in single-neuron stimulation, their physical size and tethering (needed for power and/or light delivery) pose substantial limitations for their use in behavioural studies, as they restrict the animal movement, hence, bias the results. On the other hand, tether-less μLED-based stimulators are reported with a significantly-smaller form factor, at the cost of losing proper control over optical stimulus characteristics as well as low spatial resolution due to lack of light directivity.

To date, there is no implantable (i.e., wireless and miniaturized) tool available to drive individual neurons or sets of neurons, with neuron-specific activity patterns exhibiting the temporal precision that is required to mimic natural neural codes.

To address this technical gap, we propose to design, develop, and experimentally validate a mm-scale wireless and battery-less 16-channel digitally-programmable optical stimulation and electrochemical recording system-on-a-chip (SoC). Each stimulation channel will host a dual-wavelength custom-designed μLED structure that can trigger largely-overlapping excitatory and inhibitory effects on step-function opsins, resulting in a subcellular optically-stimulated region. Additionally, a dome-shaped transparent μlens will be inkjet-printed on each channel's μLED, enhancing the light directivity and consequently, reducing the heat generation by more than an order of magnitude. Acquired data and configuration commands are communicated from/to the SoC wirelessly, and power is provided using a magnetic inductive link. The SoC will be tested in vitro for simultaneous single-cell optical stimulation and electrochemical recording.

Exosomes, a sub-type of extra-cellular vesicles that detach from cells and circulate in bodily fluids, are associated with biological processes such as immune response, tumorigenesis, and metastasis. Tumor-associated exosomes are an emerging class of cancer biomarkers, with promise for enabling the much desired “liquid biopsy” approach to non-invasive cancer diagnosis and management.  Early-stage detection of such exosomes is extremely challenging due to their low concentration in bodily fluids. Microfluidic-based biosensors have been developed for exosome analysis; however, they do not offer the required combination of sensitivity, speed, and multiplexing for clinical integration. The goal of this project is to develop a disruptive technology for real-time exosome analysis by combining the unique knowledge of our team in biosensing, creating anti biofouling surfaces, and discovering and evaluating cancer biomarkers.

We propose to develop a truly innovative technology for exosome analysis, Exosome Lab In a Tube (ExLIT). Conventional microfluidic biosensors operate by integrating sensing interfaces on their channel walls. ExLIT is composed of bio-inspired anti-fouling wrinkled electrodes that cover the walls of a standard medical tubing and are immersed into the channel volume to create a porous capture network, improving the poor capture efficiency, and the resultant speed/sensitivity metrics of conventional microfluidic systems. Upon exosome capture using specific antibodies immobilized onto the multiplexed porous electrodes, a measureable change in electrical impedance is detected. The unique anti biofouling properties of the ExLIT electrodes allow them to be used in unprocessed biological samples for real-time analysis.

During this project, ExLIT will be engineered and characterized in-vitro with exosomes extracted from ovarian cancer cell lines (suspended in buffer or spiked in plasma) using antibodies selective for epithelial cell adhesion molecule (EpCAM), CD24, and folate receptor alpha (FRalpha), and its performance will be evaluated against standard techniques. Subsequently, this system will be clinically validated using patient samples (post grant). We expect to extend ExLIT to ex-vivo (as a flow-through blood analysis system) and in-vivo (as an implantable catheter) real-time analysis (post grant). In addition to cancer diagnosis, ExLIT will enable clinicians to monitor response to treatment and assess disease progression and relapse.

Research in machine learning has the power to transform healthcare by providing more accurate models of a patient’s current state and trajectory. Medical records are of course sensitive by definition and call for privacy-preserving data analysis techniques; undertaking such research involves de-identifying personal health information (PHI) to protect individual privacy. Commonly used methods may lead machine learning models to report different performance than would be true if such models were applied in practice. The increasing presence of technology coupled with high profile data breaches are pushing the society towards tighter data protection, which increases the need to understand what impact each data transformation has. To advance responsible machine learning in medicine, this project will investigate privacy at three stages of the data analysis pipeline: input, analysis, and output.

Here, we focus on noising the analysis itself to preserve privacy. Using differential privacy mechanism will alleviate the need for any form of data anonymization and will enable us to perform ML on data that was previously unaccessible due to privacy concerns. Why is the healthcare domain specifically challenging for privacy-preserving data analysis through machine learning: unbalanced data per institution and potential distribution shifts across institutions, few actors have data, difficult to centralize data. Regulations and privacy concerns make it difficult to share data across institutions, so centralized privacy-preserving machine learning is difficult. This is unfortunately the easiest setting to learn with privacy, for instance with differentially private SGD~\cite{abadi}.

Here, we need to operate in a decentralized collaborative setting. We therefore plan to investigate the impact of each de-identification method using the GEMINI dataset. GEMINI is a unique clinically granular dataset from 7 Toronto-area hospitals, including administrative data, laboratory data, pharmacy and cardiology data on over 240,000 admissions, with growth to include 30 hospitals in Ontario in the next 3 years. We plan to investigate the impact of dataset creation variations in state-of-the-art machine learning models. We believe the potential reward is high because this is the first time that a dataset of such size and diversity has been available to understand the nuance of machine learning model development in a clinical setting with the constraints of protecting patient data.

The proper function of human organs depends upon specialised cell types that are organised in an optimal way.  Morphogenesis, or the organisation and shaping of embryonic tissues, has long been recognised as an inherently physical process that is poorly understood.  Critically, the tools required to unravel how physical rules shape biological structures have not previously been available.

The collaborative team consisting of the Hopyan (developmental biology) and Sun (mechanical engineering) labs is engaged in the production of tools to measure physical properties and forces within mammalian embryos, and in establishing how physical laws drive morphogenesis.  Two important processes that we identified are rigidity transition, in which tissues flow like melting glass before solidifying into mature structures, and durotaxis, in which cells move toward stiffer areas in developing tissues.

We believe that rigidity transition and durotaxis together explain the physical basis by which all organs are initially organised.  Our primary goal is to combine physical data using new tools that we will generate with a computational model we created to define how these processes are interrelated.  The biophysical tools we generate will be freely available to researchers worldwide, and the conceptual advance arising from our work will open doors for explaining the structural basis of birth defects and for mechanically enhancing efforts at organ regeneration.  These advances will draw scientific recognition and collaborative opportunities for scientists in Canada.

This project unites researchers in architectural design and technology, human computer interaction (HCI), cultural anthropology and material culture studies, and constructed textiles to investigate the integration of of Augmented Reality (AR) in handcraft and educational design. The study adopts a two-pronged approach: first, developing and evaluating novel AR techniques to capture, encode, and represent gesture in handcraft; second, exploring new forms of communication through AR and how these enable, foreclose, or disrupt disciplinary roles, intergenerational communication, and forms of collaboration.

Explorations occur in two distinct sites linked by a modality of using coordinated gestures with textiles to build physical structures. The first site is an academic and non-profit collaboration with South Sudanese refugees documenting and sharing material heritage in the form of beaded accessories and the skills required for their fabrication. The second is an educational architectural design studio where novice architects use chord, rope, and fibers to make free-standing structures informed by beadwork stitches.

In each context participants use AR headsets to encode and guide sequential, step-by-step actions, creating a finished bead-work piece or building element. In the South Sudanese refugee community the AR application expands existing forms of heritage documentation, recording gestures to initiate a process of encoding hand, tool, and thread positions and their sequencing. In the architectural studio researchers learn from this embodied practice and explore communicating through sequentially stepped three-dimensional instructions for building.

The investigation’s risk is attempting to bridge these two contexts, and see how they speak to one another. Attached to this is the possibility that the existing state of AR technology will limit the nuance of what is captured and transmitted, and disrupt organic person-to-person interactions. In return, the investigation contributes a sociotechnical method of AR mobilization. It supports marginalized or at-risk craft knowledge practices and innovative design training; it is disseminated in forums of digital humanities, computational design and construction, smart textiles, and tangible, embedded and embodied interactions; and it is mobilized in professional and non-profit communities of mixed reality application developers, cultural preservation, architecture and textile design, and technology education.

The structure of many biological tissues relies on a network of complex molecules that are polar, meaning their two ends have opposite electrostatic charge. This polarity is intimately connected to their function – as discussed in almost any biology text – from the highly organized proteins in muscle, to mitotic spindles that guide DNA during cell division, to the microtubules that regulate transport in neurons. However, many open questions remain, such as, what role does the loss of polarity of microtubules play in neuronal dysfunctions, such as Alzheimer disease?

Such molecules possess another peculiar property: they are twisted, like the twist in the threads of a screw. Thus when exposed to laser light, they will in turn emit light at a different colour – the second harmonic of the laser light – meaning they may be directly imaged by microscopes without adding dyes.

The ability to image molecule orientation in real time would allow one to infer polarity, with tremendous potential impact not only in fundamental science, but also in the early diagnosis of neuronal diseases, and drug discoveries for such diseases. Existing approaches are slow, relying on either very complex preparation or transgenic mice containing light-emitting dye molecules.

We will develop a second harmonic generation (SHG) microscope to image molecular orientation in cells and tissues in real time, with a resolution 1000x smaller than the width of a human hair. With this, we will investigate a yet unanswered question in neuroscience: what is the precise role of microtubule polarity in neurons, where uniform and non-uniform polarity is detected in different cell areas?

Ramunno will develop and numerically validate the concepts of SHG orientation imaging, whereby orientation is retrieved from SHG images via an iterative numerical algorithm. For experimental validation, she and Dolgaleva will design an artificial material consisting of tiny twisted metallic rods, where the location and orientation of each is precisely known; this will be fabricated by Dolgaleva via state-of-the-art nanofabrication. Légaré will build the SHG orientation microscope, and will apply it first to the artificial material. Leclerc will then perform neuroimaging with the validated microscope. Due to its interdisciplinary nature, crossing from theoretical physics to nano-engineering to microscopy to neuroscience, this project is very high risk, but promises major impact beyond basic research.

Aquatic environments globally face human-caused threats including pollution, invasive species, overharvesting, diversion, drainage, and climate change. The 2018 World Wildlife Fund Living Planet Index suggests that freshwater species have declined by 83% on average since 1970, a rate faster than either terrestrial or marine species. Indeed degradation and loss of freshwater environments and inaccessibility of drinkable water is predicted to be among the greatest challenges of the 21st Century, particularly for indigenous communities. Management of freshwater resources often focuses on water potability and supply rather than ecosystem integrity, yet human water security, aquatic biodiversity, and ecosystem functioning are inextricably linked – data on aquatic biodiversity provide key insights on ecosystem function and water quality. Water resource management requires high-quality, repeatable monitoring data in real time and with high geographic intensity. Working with ecologists, geneticists, indigenous communities, and engineers, we will develop a new platform for monitoring aquatic environments that combines eDNA approaches with community capacity building. Focusing on Lake Ontario and the St. Lawrence River as a test case, we will: 1. Develop a multi-marker, ‘tree of life,’ DNA metabarcoding toolbox to survey all aquatic diversity (bacteria & algae through plants & vertebrates) with a focus on fish and invertebrates; and to build on The River Institute’s (https://www.riverinstitute.ca) fish survey program to test how well eDNA profiling captures aquatic diversity; 2. Develop new technologies to automate sampling of inaccessible water bodies using unmanned aerial vehicles; 3. With Tyendinaga and Akwesasne First Nations and other communities, develop capacity in traditional and eDNA monitoring, empowering them to assess local freshwater ecosystem health. Multiple risks must be mitigated for this to be successful: 1. Protocols must reliably capture the totality of aquatic biodiversity without taxonomic biases. 2. eDNA sampling must be of sufficient temporal and spatial resolution to reliably reflect anthropogenic impacts and address limitations in duration of the DNA signal. 3. Bioinformatics pipelines must capture all species and their abundances. If successful, the payoff would be local capacity and a protocol for continued eDNA monitoring. Our program could serve as a model for aquatic ecosystem monitoring across Canada and around the world.

Nuclear receptors (NRs) are a highly druggable family of transcription factors that coordinate metabolism with timed processes such as circadian rhythm, puberty and reproduction. To date, the majority of scientific research on NRs has focused on their functions in metabolically active tissues such as the liver and adipose tissues. However, recent efforts, including our own, are pointing to widespread NR activities in the brain that coordinate these processes systemically through as yet, unidentified neuroendocrine pathways. Even more recent studies suggest that many NRs are also expressed in the gut epithelia where they can respond to ingested and microbiome-secreted metabolites. We hypothesize that the brain and gut communicate directly via NRs and their ligands, similar to their control the HPA, HPG and HPT signaling axes, but in this case, coordinating metabolism with behavioral responses such as hunger, satiety, circadian rhythm and mood. We plan to unravel these distant connections by identifying novel, NR-specific ligands in the brain and gut. We will start by using our newly established mass spectrometry (MS)-based NR profiling method to identify all NR proteins expressed in these tissues. We will sample dissected brain and intestine subregions over 24hrs to identify NRs expressed in a circadian and diet-specific fashion. We will then use a second newly perfected technique to affinity-purify tagged NRs mixed together with total metabolites from corresponding tissues. Co-purified small molecules are then extracted from the purified proteins and identified by our new analytical platform that incorporates cutting edge MS with in-house computational algorithms for spectral denoising and database matching. The Identification of new NR ligands is ideally suited to this high-risk/high-reward interdisciplinary call, as it requires a full range of expertise from Analytical Chemistry to Systems Physiology, to understand the impact of the discoveries. In terms of risk, although our techniques have been fully validated, we have no idea if the ligands we seek will be sufficiently abundant, stable or accessible in our metabolite libraries. On the other hand, the identification of new NR functions is almost always predicated on the identification of endogenous ligands, which will provide powerful new tools to elucidate the mechanisms underlying gut-brain communication – pathways that figure highly in metabolic, behavioral and neurodegenerative diseases.

Sponsors of scientific research can strongly influence research questions, study design, and publication practices, leading researchers to selectively publish positive findings and suppress negative findings, publish results favorable to their sponsors’ products or viewpoints, and advocate positions unsupported by evidence. Many high-impact scientific journals thus require authors to voluntarily disclose conflicts of interest (COI) and relationships with entities that might influence their work. However, while disclosure has produced a wealth of information about relationships between researchers and sponsors, this information is fragmented, noisy, unstandardized, incomplete, and difficult to interpret. It is thus a promising but imperfect tool for assessing sponsors' influence on individual studies and scientific research as a whole.

Our project will address these problems through the creation of a comprehensive, centralized, standardized, open-access database of information about relationships between authors of scientific publications and the entities that support them. Since this information is dispersed across hundreds of thousands of publications, we will develop and/or scale-up automated methods for the following three tasks: (1) We will develop and refine python scripts to extract metadata (article title, author name, document object identifier) and disclosure text from scientific publications. (2) Using training data from a pilot project that we have already completed, we will develop natural language processing algorithms to extract and verify information about relationships between authors and sponsors, and to match sponsoring entities across publications. (3) We will develop a database that makes this information easily accessible in a clear and standardized format.

Current understanding of sponsors' influence on scientific research is based on manual, small-scale, labor-intensive studies. Our project - the first of its kind - will consolidate and standardize a huge amount of information, and thus facilitate answering a broad range of important questions, including: What is the extent and pattern of sponsorship and COI across the scientific literature? Where is it most and least prevalent? Who are the most influential funders of scientific research, and how much do they influence the content of scientific articles? How consistently do researchers disclose relevant funding or COI information? 

Increasingly, cognitive neuroscience is recognizing the importance of using real-life contexts in functional magnetic resonance imaging (fMRI). Indeed, naturalistic stimuli like movies have been suggested to reveal human neural processes more powerfully than more typical reductionist stimuli and tasks. Even movies, however, do not engage the entire human brain, particularly neglecting neural regions involved in actions and executive processes. Therefore, we will develop an immersive, engaging 3D virtual gaming environment for fMRI in which the participant is an active agent, enabling the study of human cognition in fluid, dynamic, and naturalistic scenarios.

We will create, test, and optimize gaming scenarios to assess key sensory, cognitive, and motor functions. The participant will either actively control a first-person avatar or passively view a replay of comparable events. In parallel, we will develop cutting-edge computational tools to analyze data in which the flow of events is entirely under the participant’s control. To do so, we will pioneer analytic methods to combine data across participants performing the same actions but at different times. We hypothesize that active play will yield more robust activation than passive replay.  Moreover, we expect that the active video game approach will outperform existing paradigms by engaging the natural sensory, cognitive, and motor processes of everyday life.

If successful, this novel virtual gaming approach could be a “game changer” for cognitive neuroscience. It combines the ease of some current paradigms (resting state; movie viewing) with the fluid unfolding of neural processes in natural, immersive tasks (vs. unnatural, dull, isolated task-based fMRI). Thus, it examines a wide variety of brain systems within a restricted time, an important consideration for future clinical applications. Though the approach will be initially developed for fMRI in typical adult humans, it can be expanded to other methods, ages, populations, and species. The project is high reward and the risk is mitigated by the longstanding, complementary advanced expertise of the team: advancing realism in neuroscience research for sensory and cognitive systems (Culham, Johnsrude), actions (Culham, Diedrichsen), and executive functions (Owen); game development (Katchabaw); and creation of cutting-edge computational neuroscience analysis tools (Diedrichsen). 

Machine learning, and deep learning in particular, has made incredible leaps in the past decade.  Deep learning systems are built from artificial neurons connected together in a structure inspired by the human brain.  But these advanced systems are still trained using the typical labeled data that we have been using since the advent of artificial intelligence.  Labeled data tells machine learning algorithms what classes exist in a training set, but not how to differentiate them. We propose to push the boundaries of machine learning by developing new kinds of supervision (labels) for deep learning models.  Specifically, we will further constrain convolutional neural nets (CNNs) so that their internal hidden representations respect the patterns of neural activation recorded while humans perform a similar task (e.g. object categorization).

Our aims are to 1) Use brain imaging data to provide more detailed "how to" information to constrain the internal representations of convolutional neural nets trained to perform general object categorization; 2) Improve fine-grained object categorization (e.g. dog breed identification) using brain imaging data collected while subject experts view domain-specific images; 3) Expand the notion of expertise by including medical diagnosticians (e.g. radiologists) applying their extremely specialized categorization skills to medical images while we record their brain activation patterns.

This proposed work cuts across multiple research fields (neuroscience, machine learning, computer vision, medicine) in order to improve machine learning, and expand upon our existing methods for training machines to perform automated diagnostics. Though this work is proposed for computer vision models, the main ideas could be expanded to any model that creates hidden representations as a byproduct of learning (e.g. recurrent neural networks, encoder/decoder networks).  This research program will provide proof of concept that models improve when we supply machine learning not just the final labels of prediction, but also a signature of how humans solve complex problems.

Cities and their residents are at the front line of responding to complex challenges like ongoing colonization, growing inequity, and catastrophic climate change. Cities have never seen these kinds of challenges before, and are not set up to tackle them effectively. Evidence from cities like Vancouver, that have set ambitious goals and targets on reconciliation and climate action and are not yet achieving the types of results needed, tells us there is a limit to what can be achieved while working within the existing governance paradigm. 

An interdisciplinary team of researchers working in public policy, Indigenous community planning, sustainability, and adult education at UBC will join forces alongside some of Canada’s major cities to develop and test how we might move beyond incremental improvements and into more disruptive and discontinuous change on these complex challenges. We will use a prototyping approach to our work. It is experimental, involves skillful risk taking, co-creation with users, and requires iteration in response to learning as we go. Our approach will use the research teams’ well-established networks and existing regional and national gatherings to identify innovative leaders from cities, network serving organizations, universities, and research organizations. Through grounded theory building and participatory action research, and a decolonizing approach to research methods, we will learn how research participants approach their ambitious goals, the resistance of trying to meet them, and co-create and test alternative approaches.

We hypothesize that realizing the transformative ambitions of cities on these issues will require a re-examination of the foundational ways that city governments work. The prototype that we will develop and test through this project aims to create a different set of foundational systems, structures, competencies, and mindsets that might lead to transformative change for decolonization efforts, inequity, climate change, and other complex challenges like them. If successful, we hope to scale this approach to other interdisciplinary academic teams, working co-creatively with local governments, at an international scale. Our team of researchers and practitioners has uncovered an active global practitioner community of public sector innovators, operating in a highly undertheorized environment that is only supported by a handful of researchers, and thus provides a great opportunity.

Chronic Wasting Disease (CWD) is a contagious prion disease of elk, deer, moose and reindeer. This fatal brain disease occurs in wild and farmed cervids. The geographic range of CWD continues to expand with the disease currently reported in 3 Canadian provinces, 26 American states, South Korea, Norway, Finland, and Sweden. CWD prions are shed by the infected host via saliva, feces, urine and blood where they can persist, as infectious agents, for years to decades.

CWD contaminated soils present a long-lasting risk with vast ecological and economic consequences. The only effective CWD decontamination method is restricted to game farms and involves the spraying of caustic sodium hydroxide on the landscape followed by stripping upper soil layers - an expensive and destructive methodology. An effective environmentally friendly method for prion decontamination is needed to remediate CWD-infected lands.

Our studies have examined the ability of soils and soil components to impact CWD infectivity.  We have, for example, demonstrated that certain soil minerals can strongly bind to and can even enhance CWD infectivity. We have recently shown that humic acids can degrade prions, reducing infectivity. We hypothesize that humic acids and related compounds can be adapted to be an environmentally friendly method of prion degradation.  We propose 3 aims:

Aim 1: Delineate the biochemical properties of humic acids responsible for prion degradation.

Aim 2: Identification of additives that enhance humic acid degradation of prions.

Aim 3: Validate these formulations to degrade prions in soils.

Initial experiments will involve spiking experiments in the lab to determine the most efficient means of degrading the prions. Long-term applications will involve testing these compounds in contaminated soils.

This research is high risk as prions are difficult to inactivate and soil-bound prions provide an additional challenge.  The research is high reward as large regions of North America now have soil contaminated with prions. We anticipate that this research program will produce potential prion decontamination protocols for game farms and natural environments as well as provide guidance to wildlife management programs and public health agencies. This body of research will also involve First Nations and Metis peoples as CWD affects cervids, species with cultural and subsistence relationships to indigenous people.

High-throughput scientific measurement technologies offer the prospect of observing biological processes at unprecedented resolution. Datasets are growing rapidly as the cost of sequencing decreases, but the questions biologists want to answer cannot typically be addressed with off-the-shelf methods. Some of the most exciting questions are related to temporal processes, including differentiation and development. If we could track developmental trajectories, and examine which genes turn on and off over time, we will shed light on the genetic forces that create and stabilize different cell types. However, it is not currently possible to observe a specific cell over time because the measurement process is destructive.

Members of our interdisciplinary team have recently developed a method to analyze this type of time-course data based on a novel application of a classical mathematical tool called Optimal Transport, originally invented in the 18th century to redistribute piles of earth and build fortifications for Napoleon’s army. Today, Optimal Transport is widely used in statistics and machine learning to provide an elegant way to define a distance between probability distributions. The distance between distributions is measured by the cost of redistributing mass from one distribution to the other. Our innovation was to apply Optimal Transport to estimate the temporal couplings of a stochastic process, and successfully apply this to study induced pluripotent stem cell reprogramming.

Through a diverse team with expertise spanning the spectrum from theoretical mathematics, statistical methodology, through to biomedical applications with clinical impacts and of fundamental biological interest, we will create new mathematical tools to enable new types of scientific analyses and guide experimental design. Objectives are to develop:

a) Methods to compare parallel developmental processes, where for example one population develops normally and another develops under some perturbed conditions.

b) Methods to guide cells towards or away from specific cell states with a control theory perspective in an Optimal Transport setting.

Ultimately, this proposal will provide a deeper understanding of normal and pathologic developmental processes (i.e. spermatogenesis). Furthermore, this proposal will provide a novel methodologic platform for translational applications such as cellular reprogramming, stem cell engineering and novel therapeutic target discovery.

The ability to predict material properties based on its chemical structure has played a tremendous role in fine optimization of materials and has provided life-altering breakthroughs in materials science and technology. The reverse design problem -  whereas the new material structure needs to be predicted that meets the requirements for particular properties of interest, as well as satisfies any imposed constraints - is however orders of magnitude harder. But this is exactly the problem current materials science faces. One particular example is when an application cannot tolerate toxic ingredients, for example, materials for solar cells, or consumer goods, or medicine. This means that the current best materials with useful functionalities will never be deployed, but there are no non-toxic alternatives developed yet.

The objective of our proposal is to teach a machine the principles of materials science (e.g., stability, synthesizability, etc.), and then use these principles to synthesize new materials with desired properties.

To collect the data needed to train our machine learning (ML) algorithm, we will employ a high-throughput robot to execute thousands of experiments rapidly. Microfluidic and micropipetting platforms will mix ingredients to cover a large compositional and procedural space. The specimens will then be prepared using crystallization methods and will be characterized by various physicochemical methods. The ML algorithm will recognize similarities and differences to develop the ability to predict compositions based on given properties. We will then use the algorithm to synthesize new materials with desired properties.

The algorithm will not just predict hypothetical useful compounds but will actually synthesize them. It will have an immediate practical impact, for instance, to address a key concern in emerging photovoltaic technologies such as perovskite or quantum dot solar cells containing toxic heavy metals. To collect the training dataset in this case, the solution will be blade coated and crystallized through annealing or anti-solvent dropping. Then the film will be characterized by in-situ absorption, photoluminescence, and an optical microscope to extract three key semiconducting properties – bandgap, trap density and morphology.

Industrial activities associated with extraction of oil and gas that inject fluids into the subsurface can create earthquakes. These earthquakes, referred to as induced seismicity, have increased in number in recent years in Canada and around the world, yet their occurrence is currently unpredictable. The time, location, and magnitude of potentially hazardous induced earthquakes therefore cannot be anticipated. Current efforts to mitigate the hazard from induced earthquakes typically restrict water injection rates at some empirically determined level to attempt to modulate seismic activity during the period of operation, which is only partially successful as felt induced earthquakes still occur. Accurately forecasting whether a fluid-injection operation will induce any earthquakes and how large they will be requires a better understanding of the physics controlling earthquake occurrence.   

This project aims to clearly articulate the conditions necessary and sufficient for inducing earthquakes. To do this, we will focus on a case study area in northeast British Columbia where felt earthquakes linked to fluid injection have occurred, but the conditions required to cause them are unknown. As a first step toward a large-scale observatory at an injection site to study the earthquake source in detail, this project will measure the critical physical characteristics of a site that may impact the occurrence of induced events. We will use drill core samples already collected from the subsurface to measure and infer structural, frictional and hydrogeological properties of the faults at depth and how they change under stress perturbation from injection. These parameters will be used to build numerical models to create earthquake rupture scenarios with input from new and existing earthquake and groundwater contamination monitoring efforts and fluid injection parameters. Integrating these datasets will allow us to predict injection rates and volumes that may trigger seismicity in faults and elucidate which fault conditions are most valuable to know before beginning a new operation. In tandem, we will investigate how the perceived environmental, human and social consequences of induced earthquakes can be integrated into a regulatory framework built on quantitative assessment of the seismic susceptibility of a specific fluid-injection operation. The results will inform the mechanics of inducing earthquakes generally, and therefore be applicable worldwide.

Cultural identity is usually preserved across generations through social practices such as grandparents telling stories to their grandchildren. These practices are disrupted during crisis or economic migration and resettlement. This creates significant barriers for older generations (grandparents) in building cultural resilience and imparting cultural knowledge and a sense of identity to younger immigrants, while at the same time facing challenges themselves in adapting to a new culture.

The techno-political solutions enabled by government organizations, NGOs, or tech industry to address these issues, are often promoted as neutral cultural arbiters. However, even simple support tools such as to record digital stories suffer from techno-determinism, power, and colonial values being embedded in the processes used to create these tools. Other, more participatory approaches, often lead to solutions that are rarely materialized.

We thus propose to A) address the broad lack of meaningful support for cross-generational cultural resilience during and after migration, and B) decolonize the techno-political processes for designing current solutions. We follow a transdisciplinary approach drawing from three areas: critical theory, sociology of technology, and human-computer interaction (HCI). We expect this to bring three high impact scholarly and social contributions:

1. Methodology: A novel interdisciplinary approach to understanding migrants’ resilience building through storytelling, grounded in ethnographic methods applied through the lenses of critical feminist theory. This is needed due to the age and gender dynamics of storytelling as a vehicle for cultural preservation.

2. Design: A new design framework to incorporate multiple interpretations and meaning-making of the material realities surrounding immigrants through storytelling. This framework will connect postcolonial theories to HCI methods, aiming to help migrants develop and situate their cultural identity.

3. Technical: A novel digital platform for storytelling, designed through the proposed new approaches. This will be inclusive of all digital and language literacy of the beneficiary communities, by using advances in HCI and Artificial Intelligence (e.g. natural language processing). This will be evaluated through field studies, which will also validate our proposed methods for a postcolonial feminist understanding of how migrant communities build cultural resilience through storytelling.

Tumour cells are organized into functionally distinct subpopulations that have widely different characteristics in terms of self-renewal ability, differentiation, stem-like properties, and the ability to metastasize – these characteristics are largely determined by the gene expression landscape of the cell. However, the gene regulatory networks that drive the cell-to-cell variability in tumours are mostly uncharacterized. Our previous research has shown that both transcriptional and post-transcriptional programs play a major role in determining the cell function and behaviour in different cancers, warranting the need for approaches that can probe these two layers of gene regulation at the single-cell resolution in tumours.

We have pioneered new computational approaches that, in combination with transcriptomics data, can be used to characterize the determinants of transcription rate (e.g. transcription factors) and RNA stability (e.g. microRNAs and RNA-binding proteins). Application of these methods to measurements that are obtained from single cells, however, is extremely challenging, primarily due to the noise, sparsity, and high-dimensionality of single-cell data.  The objective of this project is to develop a first-in-class framework that integrates statistical inference, machine learning, and single-cell RNA-sequencing to reveal the regulatory networks that drive programmed induction in cancer cell heterogeneity, using kidney cancer as a model:

Aim 1: We will develop a computational approach that simultaneously models the transcription rates of genes, their mRNA stability, gene networks, and the cellular heterogeneity in order to obtain a single-cell-resolution picture of the regulatory landscape in tumors.

Aim 2: We will examine the intra-tumour heterogeneity in kidney cancer as a model, using single cell RNA-seq of tumors as well as patient-derived xenografts. We will use these data to identify the sub-populations of cells that are involved in tumor growth or metastasis, and to characterize the regulatory factors that drive these characteristics.

This project will create the computational tools necessary to disentangle transcription rate from mRNA stability at the single-cell resolution, and provides the first glance at cellular heterogeneity in kidney cancer as well as the transcriptional and post-transcriptional factors that mediate this heterogeneity. Identification of these factors can potentially lead to new therapeutic strategies.

Transcription profiling by RNA-seq or microarray promises to detect gene markers for diseases at their early stage to facilitate intervention. However, the gene markers for the same disease are often poorly reproducible from one dataset to another. We hypothesize that the driver genes in the cell of origin may give rise to a tree of derived cells of diverse types by activating or deactivating certain cell-type-specific genes. These derived cells further give rise to more derived cells. As a result, when we look at the bulk gene expression in cases versus control samples, we are essentially looking at the differential genes due to differential cell abundance rather than the driver gene in cell of origin.

On the other hand, the increased practicality of single-cell RNA sequencing (scRNA-seq) have unlocked the cell transcriptome with at cellular resolutions. scRNA-seq does not, however, scale well across many tissue samples, is very costly, and can be challenging to perform on large-scale patient cohort of complex diseases. To address the low cellular resolution of bulk transcriptome profiles, attempts have been made to devise probabilistic models to “deconvolve” bulk sample transcriptomes into the substituent sub-population transcriptomes.

However, given a large public repository of bulk gene expression on various diseases, there is a lack of efficient computational approach to leverage scRNA-seq data in small samples to deconvolve the bulk gene expression in a way that will aid discovery of disease-specific gene drivers. We propose a novel approach is to robustly detect driver genes in complex traits. We will jointly refine gene drivers by using deconvolved differential expression and deconvolving only the genes within the expression module of the gene drivers. We will evaluate our approach on autoimmune traits for which we have deep expertise using UK Biobank data and existing scRNA-seq reference panels.

In Canada, 230,000 individuals are admitted annually to an Intensive Care Unit (ICU) due to critical illness and up to 50% will develop a condition known as ICU Acquired Weakness (ICUAW). Muscle inactivity and unloading as a result of continual bedrest, sedation and at times paralysis required for treatment of the unstable patient result in inadvertent muscle injury. ICUAW increases ICU mortality and weakness can be permanent, resulting in life-long physical disability, thereby increasing health resource utilization and health care costs (up to $3.5 million/person 1- year post-ICU discharge).  We have no effective therapy to prevent, or treat, ICUAW.

Neuromuscular electrical stimulation (NMES) is successfully used following limb trauma to build and maintain muscle when loading, and exercise is restricted. In the ICU NMES use and efficacy is compromised by the fact that current devices require manual probe placement on one muscle group at a time, with continual monitoring and protocol adjustment by a therapist, making delivery of regular treatment of adequate duration and frequency operationally and financially impossible.

Our objective is to create novel smart textile garments, (leg stockings and arm sleeves), enabling automated, sustained NMES therapy to prevent ICUAW. The garments are a novel combination of components including: i) flexible conductive fabrics to deliver coordinated electrical stimulus to motor points of multiple muscles concurrently, ii) embedded sensors to provide continuous monitoring of muscle response, ensuring patient comfort, enabled by machine learning techniques to dynamically control input (stimuli site, frequency and intensity), iii) custom hardware, iv) a mobile app for protocol management, coordinating multiple devices (i.e. 2 leg, 2 arm) and v) a software system for coordination and monitoring of multiple patients by a single therapist for sustainable administration of therapy in an ICU setting.

If solved, this challenge, requiring coordination of expertise from engineering, industrial design, physical therapy, and medicine will enable an ICU therapist to easily and quickly apply, co-ordinate, and optimize individualized NMES therapy to all patients in the ICU. Full or partial prevention of ICUAW will decrease ICU mortality, mitigate subsequent physical disability enabling return to work and continued independent living, and decrease health resource utilization and health care costs post ICU discharge.

Despite the tremendous improvements in the outcome of cancer patients in recent years, there remains an urgent need for effective and less toxic therapies to improve the outcome and quality of life of treatment-refractory cancer patients and their families.

Oncolytic viruses (OVs) are an emerging class of bio-therapeutics with the capacity to selectively kill cancer. Despite their promise, OVs remain at an early stage of development. Two of the main limitations are that: (1) Not all cancers are sensitive to OVs and (2) the systemic delivery of OVs is not very efficient as most of the viruses are neutralized and do not reach the tumor.

Our solution: The labs of Drs. Bourgeois-Daigneault, Alain and others have recently shown that several anti-cancer drugs can pre-condition tumors to OVs and dramatically improve outcome. However, the systemic delivery of these drugs is often associated with severe side effects, and when combined with systemic OV-therapy, can also compromise the tumor specificity of the virus. Interestingly, microbubbles (MB) have been shown to allow targeted delivery of therapeutic agents. Indeed, drug-carrying MB can be burst by ultrasound (US) at the tumor site to release their content, thus increasing the local concentration of the drug and minimizing systemic toxicities. Dr. Yu is an expert in such technology. Here, we propose to combine MB and OVs in 2 different approaches. Our aims are to: (1) Deliver OV-enhancing drugs to tumors by using MB and US and (2) locally release OV-loaded MB into the tumor microenvironment. Ultimately, both approaches could be combined.

Methods/approach: Drug-carrying MB will be developed and fully characterized in Dr. Yu’s lab as done before. Drug loading will be quantified by HPLC and mass spectrometry. In vivo testing will be performed using models of murine and patient-derived xenografts models of cancer that are already established in our labs. The first series of experiments will be performed with the Vesicular stomatitis virus (VSV). Viral replication will be measured using our in house in vivo bioluminescence imaging system, plaque assays and immunohistochemistry and the therapeutic efficacy of our treatments will be determined by tumor growth and survival analysis.

By the end of the two years of this funding opportunity, we are expecting to have successfully completed the work described here. We are expecting the knowledge gained here to initiate several projects.

The goal of surgical oncology is to remove the malignant tissue along with a rim of normal (healthy) tissue around it, called the negative surgical margin. This ensures that all resectable disease has been taken out, and no malignant tissue is left behind. The consequences of not achieving adequate surgical margins include poorer patient outcomes, follow up operations and re-excisions, and the need for potentially unnecessary additional treatments such as adjuvant chemotherapy and/or radiotherapy.

The ability to accurately distinguish between cancerous and healthy tissue is currently impossible in intraoperative conditions (during surgery). For decades, histology has been the gold standard for post-operative margin analysis, taking several days or weeks depending on the case and specimen. To examine surgical margins intraoperatively, contemporary surgical oncologists have relied heavily on clinical judgment and frozen section analysis. Although intraoperative frozen pathology has proven to be a powerful tool that decreases margin positive rates and reoperation rates, the accuracy of the frozen tissue section analysis compared to final pathologic analysis can be variable. Furthermore, it takes about one hour to perform one frozen pathologic assessment, which significantly prolongs operating time and cost, not to mention increased anesthesia risks for the patient. In certain oncologic surgeries where multiple frozen pathology analyses are required, this increases the complication rate for patients and adds a significant burden to the healthcare system.

Therefore, there is a desperate need for a new technique to provide repeatable, real-time, non-contact microscopy level imaging for intraoperative pathologic analysis. The proposed research brings together Engineering and Medical experts to advance Photoacoustic Remote Sensing (PARS) Microscopy, a non-contact, high-resolution technology that can image the margins of a surgical cavity in real-time. Unlike conventional histopathological tools, PARS may provide imaging feedback while tissues are still in situ, and pathologic analysis can be done in a matter of seconds. The outcome would be dramatically shortened operation times, increased throughput of surgeries per day per operating room, improved patient prognosis, and decreased anesthetic complications for patients. New techniques to skew the battle against one of the world’s most deadly diseases will benefit patients, clinicians, and the healthcare system.

The proposed research brings together expertise in Atmospheric Science (Preston, McGill), Organic and Supramolecular Chemistry (Friščić, McGill) and Planetary Geology (Neish, Western), to understand the unique chemistry of Saturn’s largest moon, Titan. The team, who have previously never collaborated, will develop models to aid in the interpretation of data from the recently announced NASA Dragonfly mission to Titan, currently scheduled for launch in 2026. Titan is one of the most unique worlds in the solar system, as its dense, hydrocarbon-rich atmosphere and surface geology are considered to be an analogue to the prebiotic conditions on the early Earth. Unravelling the chemical processes that take place on Titan could provide insights into the origins of life on our own planet. The Dragonfly mission, with Neish as the only Canadian Co-Investigator, will send a rotorcraft-lander to Titan to explore its organic-rich surface and lower atmosphere. The mission design and interpretation of results depend critically on models based on accurate physicochemical measurements that must be generated from laboratory experiments. Little is known about Titan’s surface composition, but photochemistry is initiated in its upper atmosphere, leading to haze formation followed by deposition on the surface and subsequent geological processing. Due to the mainly organic composition of its surface, a large component of the chemical processing on Titan is thought to be based on soft, supramolecular chemistry and self-assembly. Such unusual geology calls for non-conventional expertise, combining organic and supramolecular chemistry with geology and exploration of other planetary systems – areas that rarely overlap. Our team is ideal for addressing this challenge, with the expertise of Neish in geology of planetary surfaces, Friščić in organic solids and photoreactivity, and Preston in atmospheric science. Our focus will be a laboratory-based study of the molecular solids, cocrystals, solvates and hydrates formed by solid-solid and solid-gas chemical reactions mimicking abrasion and weathering during different stages of mineral creation under the alien environment of Titan. Using a combination of laboratory mechanochemistry, weathering, irradiation, and high-precision single particle experiments designed around X-ray diffraction and vibrational spectroscopy, we will be able to directly investigate the formation and lifecycle of carbon- and nitrogen-based compounds on Titan.

Communities have been expressing their relationships to their land using art since time immemorial. Artistic representations of culture, story-telling, and tradition demonstrate nuanced relationships between the landscapes that surround people and their perceptions and values. Art can catalyze shared cultural motivations necessary to inspire commitments to enhanced wellbeing, but there is a gap. For many Indigenous communities, their development aspirations remain far out of sight.

Our hypothesis is that art can organize knowledge and break communities free from institutional constraints in ways that are locally appropriate and culturally contextual. Art will be used as a boundary tool, to dissect dialogues and preferences for economic and environmental outcomes, inclusively among local and external stakeholders. We will explore innovative technologies, such as newly available wood processing and design and new media to bridge culture with economic aspirations. Involving communities and artists, we will use art in a participatory way to make connections among otherwise disconnected people. We will use art to inclusively elicit a deep understanding of complex cultural-ecological systems that lead to a future of well-being, culture, and connection to the land. We aspire to reconcile tradeoffs between economic and cultural objectives by using art to diversify and add to cumulative ways of knowing.

We will trial the use of visual methods to enable Indigenous communities to target economic and environmentally sustainable landscapes. We will work with communities in biodiverse rural areas in Indonesia, Malaysia, Canada, and New Zealand. We will use locally appropriate visual arts (drawings, paintings, woodcarvings, weavings, metalsmithing, photos, videos, etc.). We seek to better understand how art can provide opportunities to build capacity in a culturally and environmentally sustainable manner in places where communities are marginalized, where they face institutional barriers to achieving their development aspirations.

This study will combine the knowledge and skills of art, visual and cultural anthropology, economics, technology, and human geography, and from perspectives of Indigenous researchers from Indonesia and Canada. The principle investigators and collaborators have decades of experience of working from within rural Indigenous communities. Our ultimate goal is to bridge ways of knowing for more vibrant future for rural Indigenous communities.

Approach: Dysregulated mRNA translation can lead to several physiological disorders including cancer. Several studies show a limited correlation between the transcriptome and the corresponding proteome, suggesting that when it comes to translation not all transcripts are treated equally and the non-canonical translation prevails under certain disease conditions. We have demonstrated that eukaryotic initiation factors (eIFs) play a critical role in non-canonical translation initiation and cancer cell survival. Our recent findings have clearly implicated eIF5B in the survival of glioblastoma (GBM) cells. We have shown that eIF5B collaborates with eIF1A and eIF5 to modulate non-canonical translation initiation via regulating delivery of initiator tRNA. The overarching goal of this proposal is to establish modulators of non-canonical translation (eIF5B, eIF1A, & eIF5 together) as therapeutic targets for the treatment of glioblastoma patients.

Aim 1: To assess the role of eIF5B, eIF5, & eIF1A in non-canonical translation and GBM survival using patient-derived brain tumor-initiating cells (BTICs) and orthotopic xenograft mouse models. Aim 2: To define the mechanistic role of eIF5B, eIF1A, & eIF5 in non-canonical translation initiation using in silico modeling. Aim 3: To identify lead compounds targeting eIF5B, eIF1A, & eIF5 in silico and validation of their interactions using computer modeling. Aim 4: Synthesis of lead compounds and validation of their interactions and bioactivity using BTICs. Aim 5: To test the lead compounds using orthotopic xenograft mouse models. Aim 6: To assess the effect of eIF5B, eIF5, & eIF1A depletion and small molecule compounds treatment at the molecular level using multi-omics approach (transcriptome, translatome, and metabolome).

Impact: Glioblastoma is a ‘hard to treat’ and ‘high fatality’ cancer with the median survival rate of 15 months, which indicates the urgent, unmet clinical need to develop innovative therapeutic approaches. This multipronged project will employ expertise in several fields of research, including cell and molecular biology, bioinformatics, computational biology, and organic chemistry, to uncover novel mechanisms of non-canonical translation initiation that lead to GBM survival, and proliferation. This research project will provide new and significant insight into the unifying context of eIF5B, eIF5, & eIF1A biology in GBM and will provide an opportunity to target these eIFs to improve patient outcome.

Objectives and context: Our overarching objective is to develop a novel quantitative methodology based on polarized light (polarimetry) for studying tumor microenvironment (TM), specifically for prediction of tumor behavior and patient outcomes. This is driven by a clinical need to develop new prognostication tools and better personalize cancer treatment. Peri-tumoral stromal changes are shown to correlate with patient outcomes. Polarimetric imaging exhibits excellent tissue contrast that reports on the underlying tissue micro-organization. We propose a polarimetric methodology to image peri-tumoral stroma in unstained histology slides, analyzed with artificial intelligence (AI) algorithms to decode complex architectural patterns of stroma, to derive quantitative TM prognostication biomarkers.

Expertise and approaches: Drawing upon the expertise of our interdisciplinary team in (1) biophotonics/polarimetry, (2) pathology (3) surgical oncology and (4) machine learning (ML)/AI, we propose a rigorous research plan comprised of four Specific Aims (SAs). SA1: optimization of our biophotonic polarimetry methodology for imaging and extraction of morphological features of peri-tumoral stroma; SA2: applying ML/AI approaches to the polarimetic images to develop and validate quantitative polarimetry signatures of stromal architecture patterns (e.g. myxoid vs. sclerotic); SA3: development of prognostic/predictive polarimetry scores (e.g., risk score for lymph node metastasis, tumor recurrence) by using AI to classify stromal architecture signatures that correlate with the outcome of interest. Archived human breast and colorectal cancer histology slides will be studied retrospectively to achieve the above three SAs. SA4: The developed polarimetry prognostic scores will be validated in a case-control study, where end points and analysis designs are defined prospectively.

Significance and outcomes: Quantitative nature of the proposed methodology will yield a non-binary continuous prognostic score range indicative of the spectrum of the heterogeneous tumor biology; this will significantly improve the ability of clinicians to identify the risk groups and personalize management plans. This methodology can extend beyond breast or colorectal cancer, and in future can be developed for other solid tumors. In addition, the unique ability to quantify stromal micro-organization patterns can furnish a useful scientific tool for the detailed study of the complex TM milieu.

Antimicrobial resistance (AMR) has become a serious threat to global public health, defined by the UN as a “global health emergency”. Projections show that AMR deaths could surpass annual cancer fatalities. Common medical procedures are now frequently at risk of life-threatening infections, particularly for the immunocompromised, and hospital-acquired infections add an estimated $20B in healthcare costs per year in the US.

A persistent site for pathogens within hospitals is within sinks, drains and entire building-wide plumbing networks. Pathogen transmission occurs by aerosolization from contaminated sinks, and there is a growing realization that AMR infections (such as P. aeruginosa) within ICU and patient rooms often originate from biofilms within hospital drains and plumbing systems. Unfortunately, such drain-based biofilms have proven impossible to eliminate, despite extensive efforts (disinfectants, pressurized steam, etc). Whole microbial networks seem to extend throughout the plumbing systems of entire buildings, and can migrate, re-populate newly-cleaned drains. We understand very little about these biofilms (strains, metabolism, structure), their relationship to commercial drain surfaces, or the rate/mechanisms of microbial migration. And there is an urgent need for technologies to monitor microbial growth within whole building networks.

Recently we have engineered silicone compositions with robust, highly non-adhesive surfaces that significantly limit long term biofilm growth (log 4). We hypothesize this greatly reduced surface adhesion may actually prevent long distance migration of biofilms within plumbing networks. Our aims are:

(1) Clinical microbial microbiome sequencing/identification within hospital drain environments.

(2) Optimize non-adhesive silicone coatings for large plumbing networks, to minimize biofilm surface adhesion (under flow) and long term growth.

(3) Test biofilm migration rates through connected drain networks in a multi-sink setup, and hospital floor.

(4) Develop low cost, in situ optical sensors for planktonic bacteria within drain traps, for real time, building-wide monitoring of microbial growth, through wireless data.

We expect the important outcomes to be; (1) reduced long term biofilm growth due to rapid detachment during flow/disinfection routines, (2) prevent migration of microbes through plumbing networks, and (3) an ability to track microbial growth in real time throughout whole hospitals.

Canada is fifth largest producer and fourth largest exporter of natural gas in the world, and much of this natural gas is used as a source of energy. Although Canada’s natural gas sector generates over $50 billion in revenues each year, transitioning away from combustion and moving towards valorization could provide substantially greater economic returns and even reduce our nation’s carbon footprint. We propose to convert methane, the dominant fraction of natural gas, to methanol, a critical feedstock for chemical manufacturing, using biohybrid catalysts. Biohybrid systems retain the programmability and chemical versatility of biological systems such as enzymes and cells but overcome critical limitations such as sensitivity to processing conditions by combining them with abiotic materials such as nanoparticles or polymers. Our team has previously constructed biohybrid electrodes for photovoltaic and battery applications. We now seek to fabricate novel biohybrid catalysts using chromatophores synthesized by engineered strains of the bacterium Rhodobacter sphaeroides. Chromatophores are photosynthetic organelles whose surfaces are punctuated with three unique enzymes, a light harvesting complex, the cytochrome bc1 complex and ATP synthase. These enzymes function in concert to generate protons and ATP, which then drives fixation of carbon dioxide by the cell into additional biomass. Consequently, we will modify the chromatophores of the native strain using genomic engineering to co-localize an additional enzyme, the particulate form of a methane monooxygenase. This enzyme utilizes protons and reducing equivalents in the cell to convert methane to methanol. We will extract the modified chromatophores and stabilize them using inorganic nanoparticles to produce the biohybrid catalyst. Previous studies have demonstrated that chromatophores and their constituent enzymes can function normally outside the cellular environment. Our use of biohybrid system circumvents manufacturing challenges such as poor solubility of methane and toxicity of methanol to bacterial cells. The overall reaction scheme that we are proposing involves capturing and generating methanologenic chromatophores using CO2, followed by synthesis of methanol using stabilized chromatophores. Our team involves experts in biophysics, synthetic biology and process engineering, and our proposal to co-capture and co-convert CO2 and CH4 will deliver unprecedented environmental and economic benefits.

Objectives: To interrupt the devastating opioid cycle there is an imperative need to develop new non-opioid analgesics for chronic pain indications. Gabapentinoids (GBPs) are non-opioid, non-addictive first-in-line treatments for long-term pain. Whilst effective, GBPs exhibit numerous side effects; e.g., ataxia, blurred vision, dizziness, drowsiness, fatigue, headache, peripheral edema, tremor, weight gain and visual field loss. Our objectives are to employ a novel green chemistry catalytic process to generate a comprehensive series of β-disubstituted GBP derivatives in order to identify novel preclinical agents targeting pain signaling.

Approach: GBPs are β-substituted γ-aminobutyric acid (GABA) derivatives prepared using multistep synthetic sequences. Pregabalin is prepared using an enzymatic process not generally applicable across the GBP class. Gabapentin, has a β-disubstituted GABA derivative with a quaternary carbon incorporated into the backbone.  Derivatives are synthesized via laborious multi-step approaches and thus few β-disubstituted GABA derivatives have been investigated. Advances in Green Chemistry from the Schafer lab have resulted in a one-step, atom-economic catalytic transformation (hydroaminoalkylation) that uses commercially available amines and gem-disubstituted alkenes to access β-disubstituted amines. IP has been filed for a class of N,O-chelated catalysts that can rapidly assemble selectively substituted amino acid precursors by direct C-H alkylation. This route avoids by-product formation, thereby facilitating product purification and reducing waste generation all while streamlining the synthesis of a library of new β-disubstituted GABA derivatives. The Snutch lab has identified and characterized multiple classes of calcium channels implicated in disease pathophysiology including pain. The lab has developed screening assays for testing calcium channel blockade underlying pain processing to be utilized for screening/identification of lead GBPs derivatives suitable for preclinical development.

Significance: Our approach will dramatically expand the GBP class of drugs, using an environmentally friendly and cost-efficient synthesis. The collaboration leverages the world-leading expertise to tackle the challenge of non-opioid pain therapies to impact the health of Canadians and address the opioid crisis in the Canadian healthcare system. Economic opportunity arises from IP to be spun-off into a company for new pain therapeutics.

This New Frontiers proposal is motivated by one of the grand challenges in materials science: How do remarkable properties of matter emerge from complex correlations of the atomic or electronic constituents and how can we control these properties? Specifically, this proposal is concerned with understanding, predicting, and ultimately controlling subtle material properties using a combination of ab-initio first principles methods with novel aspects of machine learning and optimization to design materials à la carte.

Materials play an important role in many aspects of our lives. From structural materials to transportation and drug delivery, many materials properties are given by the complex interactions between atoms and electrons, that ultimately define the intrinsic properties of materials. Discovery of new materials can revolutionize and transform many fields, such as medicine, transportation, electronics, etc. However, the current approach to discover new materials is based on expensive trial and error procedures that are time consuming and expensive. This proposal seeks to accelerate materials discovery by using a revolutionary approach that will combine state-of-the-art ab-initio simulations with novel aspects of machine learning and optimization to develop materials à la carte. During the course of the project, we will develop a computational framework that can integrate multiple aspects of materials, including atomic interactions, thermodynamics, free-energies and entropies to explore a large portion of the configuration space of possible materials. These properties will be then integrated in a machine learning framework, to obtain multiple recipes to develop new materials with à la carte properties. The proposal will focus on two main challenges: i) the design of new lightweight metallic alloys needed in transportation vehicles to reduce green-house gas emission; and ii) the design of new radioisotope/binding ligand combinations to design for the detection and treatment of cancer. These goals will be achieved through multidisciplinary collaboration in our team. The outcome of the project will be the discovery of new materials that can be architected from the atomic scale to achieve otherwise mutually exclusive properties such as strength and toughness, extraordinary resistance to irradiation, etc.

The Arctic Ocean is warming four times faster than lower latitude seas, leading to earlier melting and later freezing of the sea ice cover. The open water season will continue to expand in the future, opening opportunities for resource extraction and use of shipping lanes, along with an increased likelihood for spills of petroleum products including crude and fuel oil. Natural biological degradation (bioremediation) of oil spills has been shown to be an important cleanup pathway in warmer waters, but the efficiency of this microbe-driven process in low temperature Canadian waters remains uncertain. The Port of Churchill receives a large (and increasing) amount of ship traffic traveling through Hudson Bay, so we will base our field sampling out of the newly-constructed Churchill Marine Observatory (CMO) in Churchill, Manitoba.

This will be the first-ever multi-year time series of marine microbial community composition in the Canadian Arctic, and will be used to test the hypothesis that the structure of marine microbial communities affects the efficiency of oil bioremediation. Results from these experiments may challenge the current paradigm - imported from warmer seas - that bacterial biodegradation is a significant pathway for the cleanup of spilled oil in low temperature marine waters.

Objective 1 seeks to quantify the annual cycle of microbial diversity using real-time long-read DNA sequencing. Sampling for this Objective will be conducted weekly at CMO by indigenous community members trained and employed to conduct sample collection, preparation, and real-time DNA sequencing using an Oxford Nanopore MinION device to determine taxonomic composition of microbial community members. Objective 2 builds upon Objective 1 by adding weekly experimental incubations of natural microbial communities with petroleum products. Using petroleomics techniques we will measure the detailed molecular structure of oil after exposure to natural microbial communities to determine the efficiency of oil bioremediation by these communities. Using metagenomic sequencing of incubation endpoints on the Illumina NovaSeq platform we will reconstruct the complete genome sequences of bacteria responsible for oil bioremediation. Objective 3 links the first two Objectives by using machine learning computational techniques to enable the prediction of oil bioremediation efficiencies given new real-time DNA sequencing data collected by local stakeholders.

The world is facing one of the biggest environmental challenges threatened by the unbalanced release of carbon dioxide (CO2) from burning fossil fuels and deforestation. Increase in the atmospheric greenhouse gases has driven climate changes. Reducing the reliance on non-renewable resources has been the focus of global efforts to mitigate climate change. However, recent 2015 Paris agreement urged that the reversal of the current climate change requires direct efforts of converting CO2 into resources. The goal of this research is to provide a proof-of-concept that can potentially overcome the primary barriers to implement biological CO2 conversion solutions by introducing photosynthetic living organisms into a nano-scale fabric.

Microalgae refer to microscopic photosynthetic organisms free-living in ocean and soil, and responsible for approximately half of the atmospheric oxygen and up to 50% of the total CO2 fixation on earth. Microalgae are considered as a sustainable solution to mitigate climate change for their efficient photosynthesis and wide-range of application. Microalgae have been utilized to treat waster water or exhaust gas while producing feedstock for biofuels and high-value compounds used for food supplements, pharmaceutical, and cosmetics. Despite such promises, the application of microalgae for CO2 capture has been limited by existing methods relying on large-scale cultures such as open ponds and liquid-holding containers. Global utilization of microalgae requires innovative technology to mobilize them to harsh conditions and remote places.

Our project aims to generate green nanomaterial capturing live photosynthetic cells. This green nanomaterial can be readily tailored in various forms and a wide range of scales. Recent advances of nanotechnology offer solutions and ideas for synthesizing hybrid polymers combining nanoparticles and living cells, whose exploration is so far limited. Taking advantage of the great flexibility and adaptation of microalgae to grow in diverse environments, we propose a pioneering project that produces a prototype of microalgae-nanofiber. This prototype will be capable of natural CO2 capture and conversion to biomass with oxygen production, whereby it is readily deployable. If successful, its manufacturing will offer indoor/outdoor CO2-conversion systems for waste gas or water treatment and for medical application such as wound-healing patches that supply oxygen and antibiotics.

Objectives of the proposed research: The main objective of the research will be to generate entangled photons from single molecules. The research will require a combination of expertise and know-how that encompasses the fields of surface chemistry, nanotechnology, photonics, quantum computing, and quantum optics.

Novelty and expected significance of the work: Conventional computational and communication technologies are reaching their limit. Quantum approaches are being sought to replace the current state-of-the-art. Devices that exploit the quantum behaviour of light use a few photons to achieve communication with 100% secure cryptography; they also enable the design of universal quantum computers that can solve problems that are intractable today. The key resource for quantum communication and computation with photons is the generation of entangled photon pairs. The standard method for the creation of entangled photon pairs requires high-powered laser systems and yet produces a very low yield of entangled photons. In this research, we propose a “molecular approach” for the generation of entangled photons using low cost and low power light sources. If realized, this research has the potential to greatly accelerate the development of quantum technology and to completely change communication and computation as we know it today.

Summary of the research approach: In this program, we will first explore the generation of surface-enhanced Raman signal from single molecules adsorbed on individual nanoparticles. Then we will monitor the evolution of intensities from the two Raman channels: Stokes and anti-Stokes. The Stokes - anti-Stokes (SaS) ratio will be controlled by engineering the optical characteristics of the nanoparticle resonances. The next step will be to demonstrate the generation of single photons Raman scattering from single molecules. Finally, we will explore nonlinear Raman effects by creating the conditions for coherent generation of SaS entangled photon pairs, using measurements of the second order quantum coherence function to establish their entanglement. In parallel to the experimental steps, a new theoretical framework involving the effects of surface plasmon resonance in SaS photon pair generation will be developed. The molecular avenue for entangled photon generation described here is both unique and high-risk. However, our research team is well-poised to tackle these challenges and realize the significant goals described above.

OBJECTIVES: It is critical to ensure that manufactured drugs or devices are free from microbial contaminants. Current methods for detecting Gram-negative bacterial endotoxins, such as lipopolysaccharide (LPS) structures, are problematic and not accurate due to variability between different bacteria; furthermore, this strategy does not apply to Gram-positive bacteria as they completely lack LPS. Thus, there is a need to develop a method to accurately measure bacteria in specific environments, and to do it quickly and cost-effectively.

PROPOSAL: Our innate immune system has an uncanny ability to recognize patterns in microbial structures such as LPS and even bacterial DNA using proteins called Toll-like receptors (TLRs). We propose designing a portable spectro-electrochemical device using TLRs to detect bacteria. TLRs are useful for bacterial detection as they have a specific dimerization and conformational change, due to binding of bacterial components. Transduction into an electrochemical signal involves binding TLRs to an electrode surface and measuring the change in the access of a redox species to the electrode surface due to the conformational changes of the TLRs. These electrochemical signals can be easily measured on a portable device, analogous to a blood glucose monitor. In practice, environmental samples may contain interfering compounds that could result in false positives or negatives. We address these issues by using an orthogonal detection strategy that relies on two largely uncorrelated positive signals to ensure a true positive, eliminating false positives or negatives. The other signal is a spectroscopic measurement using fluorescence and Förster resonance energy transfer (FRET). We will attach a fluorophore to TLRs. When a bacterial component bind to TLRs, they are brought closer together (so are the fluorophores) resulting in an increase in FRET signal, which accompanied by a change in the electrochemical signal, reveal an actual positive result.

NOVELTY AND EXPECTED SIGNIFICANCE: This novel orthogonally coupled approach is uniquely an aspect of our sensor, forming a platform technology that is not realized in any biosensor methodologies currently under study and has widespread applications - the TLR family recognizes conserved signatures from multiple microbes. Our multi-disciplinary team, with experts in surface chemistry, electrochemistry, synthetic biology, and innate immunology, is naturally suited to address this proposal

Communities and ecosystems face huge challenges due to climate and environmental changes caused by human activities that result in land degradation, ocean and air pollution, and biodiversity loss. These ongoing radical changes are significantly reducing ecosystem resilience with consequent threats to human and nonhuman wellbeing and survival. To respond to these challenges, international agreements and conventions have been developed and countries have adopted the UN 2030 Agenda and the Sustainable Development Goals. However, there is growing suspicion that these will never be effective because of the current global socio-politico-economic system that still holds to notions of infinite economic development and growth and ignores that we live on a finite planet with limited resources. There is an urgent need to conceptualize a new path forward that goes beyond ineffective so-called “green” planning and reconnects humans, nonhumans, and nature. This can only be done by acknowledging planetary boundaries which will lead to successful ecosystem governance. We are proposing is a radical transformation of how we conceive of ourselves and the world we live in. Our objective is bold and twofold: 1 to define the path for the radical transformation of the current social-ecological system and its underlying defective worldview toward a system thinking model that reconnects humans and nature and 2 to develop a planetary plan for all beings and the Earth system as a whole to survive and thrive within the planetary boundaries. To achieve this, we have gathered a team that combines expertise from disciplines that do not traditionally engage with one another. Only a truly transdisciplinary team, such as ours with expertise in environmental science, philosophy, economics, performing arts, literature, and political science, can allow to reconceptualize ourselves appropriately and embrace a worldview that genuinely reflects our entanglement in nature. Following the development of our conceptual framework, our team will invite experts from different spheres of work and disciplines and engage with them in a series of proactive camps of 2-3 days to develop the radical transformation we seek. We will challenge participants to go beyond defining the current issues, think outside the box, and put on the table ideas that can lead to the system transformation we are aiming for. The ultimate goal is to develop large scale projects in the future where such a novel path can be tested.

Objectives of Research Program: We aim to reveal how Indigenous community-driven research has incorporated traditional Indigenous knowledge, across the social science, humanities, health, and natural science disciplines. We will examine how traditional Indigenous knowledge is included in research and benefits Indigenous peoples in Canada. We will: 1) identify how and what kinds of traditional Indigenous knowledge sharing (IKS) is incorporated into research, across disciplines; 2) identify concerns, lessons learned, and successes that can be shared across disciplines to better understand how IKS is valued, preserved, and protected in research contexts; and 3) showcase diverse and effective processes, approaches, and methods of IKS.

Summary of Research Approach: An Advisory Team (Indigenous elders, knowledge keepers and senior scholars) will provide guidance throughout the project. A Research Team (mostly Indigenous and several non-Indigenous scholars) will be directly involved in research activities. Research Methods: 1) a realist review of studies conducted with Indigenous communities to identify how traditional IKS is included in research, the contexts in which the knowledge was shared, the ways in which the knowledge was shared, and with whom it was shared; and 2) in-depth case studies of past Indigenous projects funded by each of the Tri-Council funding agencies to unpack the realities, processes, challenges, successes, and considerations of traditional IKS experienced by researchers, community leaders, and other key rightsholders alike.

Novelty: We will 1) focus on traditional Indigenous knowledge as a valid and scientific form of knowledge; 2) have Indigenous elders, knowledge keepers, and senior scholars guiding this study; 3) bring together researchers across disciplines to advance IKS in research to benefit Indigenous people; 4) facilitate cross-disciplinary learning.

Expected Significance: We will 1) reveal strengths and shortcomings of how different disciplines include traditional IKS for the benefit and wellbeing of Indigenous people; 2) illustrate and suggest how and when traditional IKS must, can, and has been incorporated into research that respects, preserves, and serves Indigenous communities across Canada; 3) produce a wise practice interdisciplinary framework to guide researchers conducting Indigenous research in the areas of IKS, building culturally appropriate projects and ensuring that projects benefit participating communities.

The confluence of robotics and machine learning has enabled us to rethink our notions of modern transportation, agriculture and logistics. The role of automation in chemistry labs, however, has remained largely unchallenged for decades, with only a few recent exceptions. We re-imagine the interplay between chemists, informed exploration of chemical space, and the execution of chemical synthesis experiments. Drawing inspiration from recent advances in computer vision and robotics, we propose two research directions that aim to distill chemists' collective expertise into representations that are useful for robotic planning/control and material discovery, respectively:

(D1) Program induction from video demonstrations: Distinct experimental protocols are often used across labs and informally shared among chemists, which results in inadequate reproducibility, standardization, and public dissemination. We propose to automatically analyze large datasets of videos of chemistry experiments and probabilistically map each video to a program defined based on a formal grammar for experimental protocol description.

(D2) Refine and safely execute the learned programs in the lab: These standardized programs will then be grounded in and mapped to the physical space of the lab, and will enable off-the-shelf mobile robots with arms to plan their motion and autonomously perform the desired experiments. A key consideration in our approach is the safety and explicit modelling of the uncertainty of the program, which will enable human chemists to precisely intervene to reduce it.

Recent work in these research directions has shown promise in very constrained manipulation environments. They will be explored here for the first time in modern chemical synthesis in a real lab environment, sharing the environment with chemists who also work there on a daily basis. These techniques will pave the way for end-to-end automation, reaction monitoring, and accelerated materials discovery in chemical laboratories across the world. They will also push the limits of modern human-robot collaboration and interaction, significantly beyond what is currently typically being examined in robotics research circles.

The objective of this research program is to evaluate the detrimental impacts of Solar Geomagnetic Storm, also known as Geomagnetic Disturbance (GMD), on power system and terrestrial infrastructures and develop an optimal disaster risk and emergency management approach for power utilities. GMD is a natural event that if occurs with high intensity, it can result in widespread impacts on electrical power systems, metallic pipelines, oil-field-activities, railway signalling, etc. The published research works have identified the solar geomagnetic storm as a threat to human life. A severe GMD can cause continental-size impacts with $1-$2 trillion damage which is the highest among all known natural disasters to date. A few working groups from academia and industries have been formed worldwide to address the associated concerns. Canada is one of the most vulnerable areas to GMD in the world and the most significant GMD incident to power system happened in Canada (1989 Hydro-Quebec blackout, 9 million people affected, $300M damage). Thus, an interdisciplinary collaboration among various research groups is required to analyze and mitigate the solar geomagnetic storm threats.

The complete solution of power system when subjected to the solar storm is possible with research contributions from the following areas:

1) Physical science: A massive coronal mass ejection from the Sun’s surface interacts with the Earth ionosphere and creates a multi-million amperes of electrojet current in the ionosphere. The electrojet is subsequently inject the Geomagnetically Induced Current (GIC) in power system and the other terrestrial infrastructures.

2) Earth science: The next important step is to determine the reaction of the multi-layer ground to the ionosphere electrojet current and the magnitude of the induced voltage and GIC affecting all grounded metallic infrastructures. The GIC is obtained from the multi-layer earth model within the scope of geophysicists.

3) Electrical engineering: The adverse consequences of the solar storm is due to the flow of GIC in power system and the other metallic objects. With the results of (1) and (2), the comprehensive analysis and solutions can be achieved.

4) Disaster Risk & Emergency Management: When the affected areas and storm severity are identified from the above steps, an efficient disaster risk and emergency management plan will be designed to reduce the possible impacts on the electricity supply and customers.

L'accident vasculaire cérébral (AVC) est l'une des principales causes d'incapacité́ physique dans le monde. Malgré l’accès à des soins spécialisés, le manque de ressources humaines et financières ne permet pas d’atteindre les cibles minimales en termes de fréquence et intensité de réadaptation. Ainsi, les membres atteints ne sont pas suffisamment mobilisés au cours de premiers jours et semaines post-AVC; période cruciale où le cerveau est le plus apte à s’adapter pour récupérer le contrôle des mouvements.

L’objectif de ce projet vise à développer un dispositif innovant, sûr et facile à utiliser, favorisant la réadaptation des fonctions motrices. L’approche de réadaptation de ce dispositif repose sur la stimulation sensorielle par vibration des tendons du poignet du bras affecté. En effet, cette vibration active les fuseaux musculaires et induit une illusion de mouvement spécifique. Cette approche, qui demande encore du personnel spécialisé pour être appliquée, s’est montrée efficace pour protéger les zones du cerveau liées au membre dysfonctionnel et pour augmenter sa récupération. Alors un bracelet électronique facile à installer, composé de plusieurs vibrateurs indépendants contrôlés en fréquence, sera développé pour donner l’illusion de mouvements de tous les degrés de liberté du poignet affecté. Ce bracelet sera commandé en temps-réel par les mouvements du poignet du bras sain, détectés par des méthodes de reconnaissance de mouvements (machine-learning) à partir des signaux électromyographiques (EMG) de cet avant-bras. Ainsi, le patient pourra lui-même induire la sensation de mouvements dans son bras affecté en suivant un plan de réadaptation quotidien et soutenu. Cela constituera un bénéfice considérable en temps, ressources et surtout en efficacité de soin. De plus, l’illusion de mouvement étant une sensation très subjective, le projet vise également à quantifier de manière précise les mouvements complexes induits par le bracelet vibrants. Pour ce faire, les signaux EMG du bras affecté et les signaux EEG seront appliqués à d’autres systèmes avancés de reconnaissance développés pour détecter les mouvements induits au niveau du bras affecté et du cerveau.

Un tel projet possède de nombreux challenges technologiques à solutionner aussi bien aux niveaux du développement de systèmes électroniques embarqués que celui d’algorithmes avancés. Et son succès nécessite une collaboration étroite entre les secteurs de l’ingénierie et de la santé.

Cell/organ replacement therapy remains the only treatment option for many life-threatening diseases and is severely limited by availability of donor organs. While cryopreservation is an attractive option for the long-term storage that would alleviate this limitation, the successful cryopreservation of voluminous and complex tissue constructs is not currently possible.  The reason for this is that significant cellular damage occurs to cells and tissues during freezing and thawing.  Conventional cryoprotectants fail to mitigate this form of cellular damage resulting in tissues that are unsuitable for transplant. Having a means to successfully store and transport organs for long periods of time is the single largest unmet need for health care in the twenty-first century.

Pluripotent stem cells harbor the potential to provide an inexhaustible supply of donor cells/tissues/organs for transplantation. We propose to use human induced pluripotent stem cells (iPSCs) and human skin keratinocytes with a unique bioprinting technology to develop 3D organ constructs such as skin and other essential tissues. Once constructed, these constructs will be cryopreserved and available for transplant immediately after thawing.  We will biofabricate these constructs with a microfluidic bioprinting technology that can recapitulate the human tissue microenvironment by enabling the spatiotemporal bioprinting of up to 5 different cell types thus ensuring cells self-organize into higher-order tissue architectures of physiological relevance.  Successful cryopreservation of these complex tissue architectures will be accomplished using cell and tissue permeating ice recrystallization inhibitors (IRIs) to prevent cryoinjury from the uncontrolled growth of ice during freezing and thawing thus enabling the successful long-term storage and transport of these constructs prior to transplant.

Tissue and organ transplantation is the most significant advancement in medicine in the past 100 years.  However, it is estimated that only 20% of all tissue and organ transplant needs are currently met. Consequently, advances in the construction and successful storage of tissues are urgently required.  This proposal will address the unmet global need and potentially benefit millions of patients worldwide.  The team is highly interdisciplinary with proven track records and expertise in tissue engineering, biomedical engineering, bioprinting, cell and tissue culture and cryobiology. 

Antimicrobial (drug) resistance is a global health crisis, predicted to kill 10 million people per year by 2050 if unmitigated. It is well known that drug resistance can develop genetically (through mutations that cause a change in DNA sequence). More recently, it has been discovered that drug resistance can also develop through a nongenetic component (arising from factors other than DNA mutation). A major knowledge gap exists: how do nongenetic and genetic mechanisms interact in the development of drug resistance? The main objectives of my proposed research program are: 1) Close this knowledge gap by developing quantitative models based in physics and validate them by performing experiments on cells carrying synthetic gene networks conferring drug resistance, and 2) Use these new model systems to discover novel treatment regimens for patients infected with drug-resistant pathogens.

The proposed research program will develop multiscale biophysical models to predict the effects of acute nongenetic drug resistance on the development of permanent genetic drug resistance. The models will be developed based on statistical mechanics to describe gene network dynamics and cellular evolution. These models will guide laboratory experiments on budding yeast (Saccharomyces cerevisiae) cells carrying synthetic gene networks and on yeast pathogens that cause disease in humans (Candida albicans, Candida glabrata, and the emerging multi-drug resistant Candida auris). Synthetic gene networks will be constructed using genetic engineering to mimic natural drug-resistance gene networks. Nongenetic drug resistance will be measured using standard microbiological techniques, and the evolution of genetic drug resistance tracked via DNA sequencing.

The novelty of the proposed research is that multiple scientific fields will be combined to develop new model systems for investigating drug resistance. This will allow the gene networks underlying drug resistance to be studied in a quantitative and controlled manner. Namely, gene expression in synthetic gene networks (unlike natural gene networks) can be precisely controlled using chemical inducers and consist of small well-characterized components that typically lack direct interactions with the host genome, which permits quantitative modeling and data analysis. The expected significance of this research is a more complete understanding of drug resistance and the discovery of novel treatment regimens against human pathogens.

The potential for non-scientists to engage innovations in drug checking technology as a high impact response to the illicit drug overdose crisis.

Canada is currently experiencing crisis levels of illicit drug-related overdoses and deaths, with BC in its fourth year of the public health emergency. Despite all efforts to date, rates of overdose and fatalities remain tragically high. Increased interest has been paid to innovative applications of drug checking technologies as a potential new tool to prevent overdose. Drug checking is a harm reduction approach which identifies the contents of a substance, often using highly technical instruments for chemical analysis.

An unconventional partnership between Social Work and Chemistry has combined science with harm reduction to launch an innovative drug checking pilot project on Vancouver Island as a response to the overdose emergency. An immediate, obvious limitation was the technical expertise required to operate the portable spectrometers and interpret the chemical test results, which restricts the broad scale, high-reward application of this response. The objectives of the proposed research are to:

1. Determine the feasibility for drug checking technologies to be operated by non-scientists, including people impacted by and responding to overdose.

2. Measure the potential for scale-up and comprehensive reach of drug checking as an overdose response by non-scientists by type of technology, population and context, considering criteria of acceptability, appropriateness, accessibility, safety, effectiveness, efficiency, and equity.

3. Use this evidence to develop prototype drug checking models for broad public health application responses by people impacted by and responding to overdose.

This project defies current research paradigms by placing equal weight on science, social innovation, and community engagement as we employ a community-based research (CBR) design with principles of citizen science. Within CBR, we will be guided by implementation science (the Consolidated Framework for Implementation Research, or CFIR) to evaluate trials of the unconventional interventions. The CFIR provides a pragmatic framework for research that explores the influences of five domains on the implementation process: intervention characteristics, outer setting, inner setting, characteristics of the individuals involved, and the process of implementation.

Abdominal Aortic Aneurysm (AAA) screening and an aging population have increased the prevalence of AAA diagnoses. Small AAAs (<5.5cm) are monitored with ultrasound. Large AAAs may rupture and this is usually fatal. Surgery is considered at a crude size threshold of 5.5cm when the annual rupture risk reaches 5%. AAA size is the only predictor of growth and rupture available but growth is non-linear and some small AAAs rupture. Thus, only 1 in 20 patients treated at 5.5cm will have benefited from rupture prevention in the year following surgery, and others may miss out on life-saving surgery. This study will develop an imaging tool with high clinical utility, to improve prediction of aneurysm growth and risk.

Macrophage mediated inflammation leads to weakening of the aortic wall. Our own laboratory work indicates macrophages correlate with AAA severity in mice. In humans, activated macrophages express SomatoSTatin Receptor 2 (SSTR2). For the first time ever, using a radiotracer probe specific for SSTR2 (gallium-dotatate), we will detect activated macrophages in AAAs using Positron Emission Tomography-Magnetic Resonance Imaging (PET-MRI). Patients attending the University Health Network (UHN) Vascular clinic undergoing ultrasound surveillance of small AAAs of differing sizes will be imaged with Ga-Dotatate PET-MRI. UHN is one of the few institutions worldwide that has this novel technology that combines anatomical and structural imaging using MRI with in-vivo biological activity detection with targeted PET probes in the same scanner. We will correlate aneurysm size and anatomical information with in-vivo imaging of aortic macrophages detected with Ga-Dotatate, to determine the risk of aneurysm growth.

A team including a world renowned PET imaging specialist (Dr. Patrick Veit-Heibach) and vascular surgeon-scientist (Dr. John Byrne, second Canadian ever to win the Society of Vascular Surgery Wylie Scholar Award), with engineering, immunology (world renowned macrophage biologist Dr. Clint Robbins) and radiology collaborators are combining techniques of immunology, radiology, mechanical engineering and vascular biology to investigate what could be the first reproducible technique to image aneurysm biology in humans, and refine the prediction of aneurysm growth and rupture. The clinical utility of being able to stratify patient growth risk will bring 21st century precision to decision-making that has not changed since the advent of aneurysm surgery.

While many mammals can hibernate, humans have lost this ability during evolution, as they developed skills to control their environment and food supply, potentially by  epigenetically silencing the relevant genes. We hypothesized that reversal of such an epigenetic signature may allow hibernation. Whole body hibernation (studied by space travel companies) is very challenging, given the high dependency on nutrients/O2 for organs like the brain or heart. However, the lungs have much lower energy/O2 needs (they are “distributors”, not “consumers” of O2) making them ideal for hibernation studies.

We found a robust increase in histone acetylation in human lung fibroblasts exposed to hemolymph from hibernating, but not control Helix Aspersa snails (an easier model to use than hibernating mammals, but we speculate similar triggers maybe operational across diverse species). This suggests a “hibernating factor(s)” can be transferred (from snails) to modify epigenetics in human cells, potentially triggering hibernation.

We assembled a diverse team of 2 basic (molecular biologist, snail biologist) and 2 clinician scientists (cardiologist, lung transplant surgeon) to study hibernating factors from snails on human lungs. We will deliver hemolymph from hibernating vs control snails to cultured lung cells (fibroblasts, epithelial, smooth muscle and endothelial cells) and assess epigenetic and metabolic functions. We predict a decrease in mitochondrial respiration with the ability to resist cell death in severe O2/nutrient deprived cells exposed to hibernating snail hemolymph. If we can achieve such a hibernation-like state in vitro, we will identify these factor(s) via NMR and mass spectrometry, and then bioengineer sufficient quantities to perfuse rodent and human lungs (taken from unused transplant donors) ex-vivo. Perfusing lungs with these factor(s) before refrigerating them, may allow us to perfuse and ventilate them again weeks later, to prove they are still functional.

This is a provocative, high risk - high reward proposal. We have expertise in the molecular biology and organ physiology required to complete this work, yet our chance of success is limited. But if we succeed the reward would be tremendous, as it would revolutionize lung (and other organ) transplantation. Physicians may be able to remove an organ, induce hibernation and keep it in prolonged refrigeration (currently lungs only survive a few hours ex vivo) until an ideal recipient is found.

Background:  Radiation therapy (RT) is offered to about 50% of cancer patients. RT is a highly effective but carries significant morbidity from unavoidable damage to critical organs. Photodynamic Therapy (PDT) is used to treat many surface cancers using light with a photosensitizer (PS) to generate reactive oxygen species. It can kill cancer cells with minimal toxicity, but due to limited penetrance of light it cannot effectively treat deep-seated tumors.

Our group has developed a novel PDT approach using nanoparticles (NP) to address these concerns. X-rays can travel deep into tissues and induce luminescence of a nanoscintillator (NSC) to activate the PS to effect PDT. This process is known as radiation-induced PDT (radioPDT). In vitro and in vivo tumor mice models show encouraging therapeutic effect using this technique, with impressively low toxicity.

Aim: Further refining radioPDT in preclinical studies to determine optimal NP pharmacokinetics, dose, fractionation, and therapeutic yield. These studies are expected to contribute to future human phase I studies.

Objectives:

1. Determine pharmacokinetics of distribution in vivo using tumor bearing mice

2. Find optimal NP dose and RT dose/fractionation to yield highest therapeutic index in vitro and in vivo

3. Study diagnostic capabilities under CT imaging to augment Image-guided RT (IGRT)

Approach: Our novel radioPDT NP is synthesized using Ce:LaF3 NSC and protoporphyrin PS loaded PEG-PLGA nanosphere. Pharmacokinetics will be determined in tumor-bearing mice models by serial injections and blood serum measurements. NP concentration in mice organs will be assessed at serial time points to determine uptake and clearance.

Dose-escalation studies in vitro and in vivo with NP and RT dose and delivery schedule will be used to determine optimal efficacy in treating cancerous tissue, while minimizing toxicity to normal tissue.

IGRT will be carried out using the NP as a liquid fiducial marker of the tumor. Concordance rate of automated planning to treatment position scan registrations will assess IGRT capabilities.

Significance: This research can greatly expand the scope of radiation oncology. By combining the therapeutic efficacy and specificity of PDT with the deep-penetrating capabilities of RT, radioPDT can introduce a biochemically and spatially specific and low toxicity approach to superior cancer cell-kill.

My research aims to revolutionise how the pharmaceutical industry develops new drugs to treat Alzheimer’s disease by building a bespoke blood-brain barrier on a chip using artificial cells. Cells are the basic biological unit of all lifeforms, and the ‘skin’ of the cell, the cell membrane, plays a crucial role in controlling interactions between a cell and the outside environment, for example by allowing or blocking the access of different drug molecules from outside to inside the cell.

Of all the organs in the human body, the brain is not only the most complex, but it is also the most highly protected. Access to the brain is controlled through the blood-brain barrier, which is composed of specialised cells called brain endothelial cells. This barrier is so discriminating that drugs to treat Alzheimer’s disease have to conform to a stringent set of characteristics in order to enter the brain. Furthermore, this barrier degrades in diseases such as Alzheimer’s disease.

I propose to design lab-on-a-chip devices to create artificial cells and tissues to be able to study how the blood-brain barrier regulates access to the brain, and how it stops working properly in patients with Alzheimer's disease. Specifically, we will build these models from the bottom up, starting with the cell membrane, adding cellular components individually, and then building tissues. This will allow us to determine the effect that each component has on drug transport into the brain.

The cost of developing a new drug is around US $2.6 billion and a significant proportion of drug candidates fail because we cannot predict how they interact with cells. Additionally, drugs to treat Alzheimer’s disease fail at even higher rates than drugs to treat other diseases. Drug development is heavily reliant of data from animal studies, and yet the correlation between these data and drug behaviour in humans is so poor that 30% of drugs fail in the stage between animal and human studies.

My research aims to change this paradigm by providing alternative testing methods that will allow us to predict the behaviour of a drug in the human body early on in the drug discovery process, and reduce our reliance on inadequate animal models. We will help make drugs that can interact with cells more effectively, and our bespoke model will help us understand what goes wrong with the blood-brain barrier in patients affected by Alzheimer's disease.

The extracorporeal circulation of blood through microfibers in a dialyzer is the main principle for hemodialysis. It enables to filter waste products from the blood directly. During this procedure, blood is pumped through a dialyzer, which consists of a bundle of microfibers with a diameter of approximately 250 µm. Although heparin is given to prevent blood from clotting in the fibers, occasionally it is necessary to flush the dialyzer with a fluid bolus to restore and ensure its patency.

Since these fibers are usually densely packed in a semi-transparent polyethylene housing, it is challenging to evaluate fiber patency during hemodialysis treatment visually. A reduction in fiber patency not only reduces the efficacy of the dialyzer; it also changes its fluid dynamic characteristics. A reduced number of microfibers will inevitably increase fluid dynamic resistance of the dialyzer and increase shear forces on the blood cells in the remaining patent fibers, ultimately resulting in the release of bioactive components due to induced cell activation and cell damage. Eventually, these bioactive constituents could result in a range of undesirable vascular complications following their return into the patient's bloodstream.

We recently developed an animal model that allows to successfully dialyze small laboratory rats (approx. 250 grams) and simultaneously perform intravital microscopic observation in surgically exposed muscle tissue. As such, it is possible to investigate how microvascular tissue perfusion is affected by hemodialysis. Moreover, by using a photo-acoustic approach, it is possible for a simultaneous real-time and non-invasive examination of the dialyzer's hemodynamic performance.

The ability to relate dialyzer patency with hemodialysis efficacy as well as the occurrence of any associated pathophysiological side-effects is of great importance. Not only does a real-time and detailed analysis of microfiber patency allow to investigate how this relates to the effectiveness of the hemodialysis procedure, but it also allows the investigation of the direct effect of any procedures aimed to improve microfiber patency, e.g., a short flushing procedure. Moreover, the ability for the photo-acoustic examination of the dialyzer's patency may also distinguish the different effects of various microfiber materials, as well as allows to evaluate how the dialyzer's hemodynamic design may affect its physiological performance.

Cancer is the leading cause of death in Canada, responsible for 25% of all deaths annually. In the majority of cases, patients only receive (often inadequate) ‘standard of care’ treatment for their cancer type, independent of their tumours’ unique molecular profile. Even when a patient is originally responsive to a drug, they may develop drug resistance and thus face a relapse of cancer. Moving towards individualized medicine that considers patient and tumour specific factors will decrease cancer mortality. Predicting the patients’ clinical drug response to different treatments (Aim 1) and identifying biomarkers of drug sensitivity that can be targeted to overcome drug resistance (Aim 2) are two major challenges with the potential for significant impact in this area. To address these challenges, it is necessary to use an interdisciplinary approach, in which we first employ advanced machine learning techniques to draw insights from large noisy and otherwise computationally challenging data sets, and then we validate the results experimentally to ensure their biological and clinical relevance. This interdisciplinary approach is supported by the expertise of the NPI in machine learning, bioinformatics and computational cancer genomics as well as the Co-Applicant's expertise in functional pharmacogenomics and cancer biology.

We first develop a computational model trained on preclinical samples (e.g. cancer cell lines or CCLs) to accurately predict the clinical drug response of cancer patients based on their clinical and molecular ‘omics’ profiles (Aim 1). This model integrates different data types including genomic, transcriptomic, epigenomic and proteomic data, incorporates known gene interactions as well as drug similarities, and takes into account a tumour’s heterogeneous cellular nature. We utilize this computational model to predict the clinical response to drugs with unknown true responses and use them to identify potential druggable targets (Aim 2). We validate these findings experimentally by comparing the drug response of CCLs (and other cancer models such as organoids cultures) upon gene knockdown, gene overexpression, and site directed mutagenesis with a control to discover novel druggable targets. The computational model and the novel targets discovered in this project will facilitate individualized medicine, the development of novel targeted therapies, and drug repositioning.

We are at a historic crossroads, where the number of connected objects has massively exceeded the number of connected human users, creating a vast Internet of Things (IoT), expected to reach 80 billion objects by 2025. Artificial intelligence (AI) is the only plausible means of composing all these objects into useful, reliable, and secure systems and federations, with neural networks representing the state-of-the-art AI. However, the realization of artificial neural networks (ANNs) using classical computing is prohibitively complex and energy inefficient at the scale required for IoT, with current energy consumption already exceeding 416 TW. Quantum computing is a plausible alternative that promises “high reward” in terms of an exponential improvement in processing capability and energy efficiency. Our long-term research objective is thus to explore the design of quantum neural networks (QNNs) as a viable solution to the efficient realization of large-scale ANNs.

Despite significant progress in quantum information theory and device-level nanotechnology, the realization and exploitation of a QNN remains a formidable “high risk” task. At the device level, new techniques involving exotic materials and electronic properties such as “spin” must be probed and leveraged to realize “qubits” (quantum bits) and universal quantum logic operations.  At a circuits level, ways to successfully network such quantum entities to realize “qurons” (quantum neurons), and ways to allow them to reliably exchange information with the macroscopic world, must be found.  And finally, at a computer-science level, these qurons must be composed into networks and learning algorithms designed. This “high-risk” but “high-reward” challenge is akin to that faced in the early days of classical computing, where ultimately, the world was taken from single-transistor radios, to logic gates, to the multi-core processor.

This project assembles an interdisciplinary team to begin a similar journey with quantum computing: at a device-physics level, the team will experimentally realize carbon-nanotube (CNT)-based "chirality-protected" spin qubits and demonstrate universal quantum logic operations; at a circuits level, the electrical interfacing of macroscopic measurement tools to the spin qubit system will be realized, and the groundwork will be laid to network such qubits to create a quron; and finally, at the algorithmic level, a training algorithm for spin quron networks will be designed.

A mechanistic linking of mind, brain, and behavior is the primary challenge of neuroscience. Breaching this frontier carries immense potential to resolve fundamental questions about our mental abilities. Do common, shared neural circuits endow us with our abilities? Or do we each have individualized circuitry? Do illnesses arise from global changes across circuits or changes to a susceptible few circuits? The answers have been beyond our grasp because we lack the tools to extract a precise description of a neural circuit—the neural types involved (parts list), their connectivity (wiring diagram), and their behavioral relevance (function).

Here we propose to develop the interdisciplinary tools needed to describe neural circuits and to then apply them to define the circuits involved in perception. Our model is the mouse lateral geniculate nucleus (LGN), a brain structure that helps to impose a salience upon visual inputs from the retina. It is unclear how LGN circuits use states of mind such as hunger, attention, and fear to isolate the most salient visual features.

We will: 1) Calcium image from LGN while mice perform complex perceptual tasks, to identify neurons that apply salience to the visual input; 2) Deploy new single cell sequencing methods to define salience neurons, according to cell type; 3) Rapidly map their wiring diagram using genetic tools and connectomics; 4) Develop new holographic optogenetic stimulation methods to "write" salience signals into LGN circuits to test causality; and 5) Develop artificial intelligence that integrates these datasets to explain salience computation in terms of circuitry.

Creating a circuit-level description of a complex mental function has never been achieved. Our team is ideally suited for this challenge: Krishnaswamy is an expert in the visual circuits of the mouse; Macosko pioneered single cell sequencing; Morgan has expertise in connectomics; Packer has developed holographic optical approaches; Cook has expertise in visual behavior; and Masse has pioneered the development of brain-inspired artificial intelligence.

Together, we will develop novel technology needed to define, dissect, and decipher the neural circuits that underlie our mental abilities. Developing this approach in LGN will reveal how its circuits make features in the visual world salient. Our success will yield a tangible approach for identifying circuit abnormalities that lead to mental illness.

Nociceptors are sensory neurons that have central roles in pain perception. They send electrical impulses to the brain and spinal cord in response to potentially damaging external stimuli, e.g. chemical, mechanical or thermal threats. Nociceptor function is controlled by membrane ion channels. Pharmacological targeting of ion channels can block pain and has been also shown to resolve autoimmune disorders in animal models. Nevertheless, their therapeutic potential remains largely unexploited due to the lack of efficient drug delivery approaches. Current therapies use local administration of non-specific anesthetics. By acting non-specifically on different nerves, these treatments have short-term and possible adverse side effects, e.g. muscle weakness when motor and autonomic fibres are also blocked. Our goal is to develop a novel drug delivery approach to silence sensory neurons. We will test the hypothesis that the transient receptor potential cation channel subfamily V member 1 (TRPV1) found on nociceptors, can act as a nanophotonics-controllable gate for delivering cationic drugs. TRPV1 is a large-pore heat-sensing channel that is activated at 42-45 oC. Our strategy exploits selective TRPV1 opening with local heating, generated by light-triggered antibody-coated gold nanoparticles (Ab-AuNPs). We anticipate nociceptor silencing with single-cell selectivity thanks to the unique ability of AuNPs to confine heat at the nanoscale level (1-100 nm). We will use a membrane-impermeable positively charged lidocaine derivative (QX-314) to validate our hypothesis. Intracellular delivery of QX-314 blocks neuronal voltage gated sodium currents resulting in a highly targeted and long-lasting (>9h) silencing of nociceptors. Compared to conventional drug delivery approaches, this interdisciplinary strategy can potentially enable single-cell specificity, long-lasting activity, and limited side-effects. To further develop this strategy, we aim to: 

1)Develop a modeling framework for optimizing nanophotonics-controlled heat-activation of TRPV1+ nociceptors. 

2)Test whether in-vitro laser-activation of Ab-AuNPs enables QX-314 delivery and silencing of TRPV1+ nociceptors.

3)Test whether Ab-AuNP delivered QX-314 resolves burn-induced corneal inflammation.

If successful, the new ion-channel-based therapy can help to elucidate the contribution of sensory neurons subpopulations to autoimmune pathologies and with further efforts can be translatable into novel treatments.

While older adults heavily rely on opioids to manage chronic pain, opioids also suppress breathing. Moreover, many older adults have sleep apnea and frequently stop breathing during sleep. High prevalence of sleep apnea, suppression of respiration by opioids, and inadequate monitoring during sleep lead to cessation of breathing and death. Indeed, majority of opioid-related deaths occur between 12AM-6AM when caregivers, usually family members, are asleep. Therefore, instead of being relaxing, sleep becomes a major challenge for patients and caregivers, either in the hospital or at home.

97% of opioid-related deaths can be prevented by adequate monitoring and faster response. We propose to develop a wearable device to continuously monitor patient’s respiration and sedation during sleep. The system will predict respiratory depression in real-time, and stimulate the patient or caregiver to react.

Our proposed technology has two innovations to monitor older patients adequately. Our first innovation is to predict the onset of respiratory depression events during sleep. We will achieve this by employing an interdisciplinary approach that includes in-depth knowledge of sleep and opioid physiology, advanced sensor design, and machine-learning algorithms. Our second innovation is to alert the patient and caregiver through audio, visual, or mechanical stimulation to prevent respiratory depression. As older adults may have sensory disabilities, we will use various stimuli to alert the patient and caregiver. Alerting the caregiver and waking the patient up will allow for the interruption of respiration depression in a timely manner and minimize opioid-related death.

Our proposed technology will improve patient monitoring and help to reduce opioid-related death. We will predict when the patient is struggling to breathe during sleep, immediately alert the caregiver, and stimulate the patient or caregiver to wake them up. This will ultimately help older adults to live successfully, safely, and independently at home.

From the beginning of the study, we will have an advisory board composed of older patients, caregivers, and clinicians. We will consult the board to determine the main challenges of older patients on opioids and their concerns about the design of the proposed technology. We will share the research findings with the board to increase adherence to the proposed technology.

Despite many advances in science, much of chemical synthesis is still performed in a laborious, linear fashion that is inefficient, requires large amounts of time and relies heavily on scientific intuition. Breakthroughs in robotics and machine learning have the potential to have a significant impact on the way chemical synthesis is performed, and dramatically accelerate the pace of discovery and optimization.

We plan to apply machine learning-based chemical optimization to the synthesis of metal nanoclusters. These unique materials form a key link between molecules and materials. Unlike nanoparticles, which are characterized as a distribution of species, nanoclusters are single molecules with exactly known structures. This is important because molecules with precise structures are the best hope for understanding the complex relationship between structure and function. Our eventual aim is to predict properties prior to synthesis, and then prepare the desired materials.

Crudden is a pioneer in the use of organic ligands for metal surfaces. She recently described the first metal nanoclusters stabilized by carbon-based ligands, having much greater stability than previously known clusters, and the highest known photoluminescent quantum yields. The stability of the organometallic precursor she employs greatly simplifies nanocluster synthesis, making this an ideal system for autonomous optimization. Hein is a leader in mechanistic analysis of complex reaction mixtures. He has recently created the first broadly applicable autonomous synthetic platform, leveraging machine learning algorithms and in-situ analysis to achieve closed-loop optimization of batch reactions.

We will combine Crudden’s stable organometallic precursors with Hein’s autonomous reaction platform to achieve three goals. We will train the robot to execute fully automated synthesis, purification and analysis of a known nanocluster, replicating existing results. Next, the robot will explore experimental space, optimizing the synthesis and isolation of the target nanocluster, using online analysis to interrogate reactions. These studies will deliver insight into the mechanism of nanocluster formation, the effect of conditions on structure, and the effect of structure on properties. Finally, we will use the system to discover new nanoclusters with specific properties, starting with near IR photoluminescence–an important property for the use of nanostructures in photothermal therapy.

The alarming rise of atmospheric carbon dioxide (CO2) levels and the consequential global climate change demand the urgent development of new technologies for effective CO2 sequestration. Conventional CO2 capture techniques are inefficient due to high costs and serious operative environmental problems. Alternatively, enzyme-based technologies have been proven to be an effective and safe solution for CO2 capture. Carbonic anhydrase (CA), an innate metalloenzyme that effectively processes CO2 in humans and other organisms with a high turnover rate (~106 reactions per second), has particularly emerged as an attractive choice for this purpose. However, the native CA enzymes are known to optimally perform only at ~37°C; whereas, CO2 capture in industries involve elevated temperature (>87°C) and high alkaline (pH>9) conditions.

Our research program will focus on developing a scaffold of novel engineered CAs with improved thermal- and alkaline- stabilities that are suitable for the harsh conditions in industries. We will employ an innovative combination of techniques from bioinformatics, phylogenomics, computational biophysics, and nanotechnology to achieve this goal. It is widely acknowledged that ancestral proteins have existed in extremely hot conditions. Given the primordial presence of CAs, it is therefore highly likely that the ancestral states of this enzyme would have featured much higher stability than the current forms. Our team will trace the evolutionary trail of CAs using phylogenomics principles and reconstruct the sequences of ancestral CAs. Three-dimensional structures of the ancestral CAs will be constructed and their structural stability under varied temperature and pH settings will be tested using advanced modeling and molecular dynamics methods. Ancestral CAs showing high in silico stability will be synthesized and confirmed using different biochemical experiments. Further, we will develop suitable nanoparticles (NPs) for immobilizing our engineered CAs so as to optimize their stability and performance in CO2 sequestration. NP-supported enzymes are known to exhibit more robust performance than their free forms.

Thus, our project will develop novel evolution-inspired nano-biocatalyst for CO2 catalysis. This project aims to deliver an efficient, low-cost and eco-friendly CO2 capture technology for industrial scale translation in future.

As per Nobel Laureate Philip Sharp, the third revolution in life sciences can happen only through collaboration of life scientists, physical scientists and engineers.  Micro-nano technologies, is one way of implementing this convergence as proposed in this application. The problem that we try to understand in this application is very fundamental to the existence of life and needs more transdisciplinary minds to solve. Hence, a team of engineer, fine artist and cellular biologist decided to team up and understand the common lifeline that runs across microcosmos to macrocosmos and decipher the response in an artistic way. Humans evolved from Macrocosmos and inherited its nature, basic constituting elements and dynamics in every subtle way of existence. That is why humans, along with plants, animals, cells and other living things, form the Microcosmos.  The journey from macrocosmos to microcosmos which is the evolution from big bang to genetic coding and beyond has a common bridge in terms of music which is the manifestation vibrations or oscillations that are fundamental to the existence. Exploration into this life music needs a set of minds to work together that are open and beyond boundaries. As the New Frontiers Grant is an ideal platform to explore into this unconstrained continuum of knowledge which does not fall under any standard disciplines, this highly transdisciplinary project is applied through this grant.  The main objective of this project is to connect the fields of engineering, science and fine arts to understand and express emotions or outbursts of our common ancestors called cells in a microfluidic based Lab on Chip (LOC) platform. This project will (i) explore the integrated optical technology to trap, culture and study biological cells and to record their living oscillations and vibrations (ii) manipulate their signal in terms of sound recordings of music which will be later expressed through fine arts media to categorize their emotions of joy and suffering and (iii) relate their life music with their affecting environment. The future of studying and performing the musical journey of cells in microenvironment, will open a new transdisciplinary area that would try to address the ethical as well as technical issues behind bio harnessing, nature versus nurture, cellular psychology, pharmacology, drug development, etc.  This work is transdisciplinary with very high risk involving Fine Arts, Science and Engineering faculties.

It is clear that Indigenous housing across Canada is in crisis. Despite many initiatives, Indigenous communities still remain overwhelmed by poor housing construction, mould, fire, over-crowding, and long wait lists. Six Nations of the Grand River also faces many of these issues. Sewá:ko (Arriving Home) is an interdisciplinary research project that brings together Haudensaunee (Iroquois) cultural experts and knowledge keepers, and Haudensaunee and non-Haudensaunee historians, planners, policy makers, environmental scientists, and architects to examine this issue in the local cultural context of the Six Nations’ community and in the global context of climate change. At the centre of this project is the conviction that a home should be an integrated part of the landscape and community and that better houses can be designed with reference to the cultural, kinship, and historical traditions of the Six Nations. Thus, this housing prototype will be integrated with other planning initiatives, including the community’s innovative green-energy projects that align with the United Nations’ Clean Development Mechanism standards for certified emissions reduction. We ask, how can a house be better integrated into larger community initiatives during this period of climate change? How can housing contribute to the long term (seven generations) well-being of our community? Our goal is to design housing and landscaping—windows, heating, and cooling as well as the planting of Indigenous plants that support the local environment and economy—to be both energy efficient and culturally appropriate. Sewá:ko (Arriving Home) utilizes a multi-pronged research approach, including archival research of historic housing construction and policy, oral history interviews about the history of housing at Six Nations, quantitative surveys and community consultations in relation to contemporary and future housing requirements, and research about innovative construction materials and architectural design. This project is highly significant for the local Six Nations community, but it also develops a model for collaborations about housing that can be applied to other communities in Canada and beyond. It emphasizes the power and beauty of Indigenous architectural design that responds to local environmental and cultural factors. And on the national and global stage, Sewá:ko (Arriving Home) contributes to the larger critical public dialogue about climate change and the Indigenous housing crisis.

Introduction: Several communities in low-to-middle income countries (LMICs) lack access to quality healthcare. Some of these communities exist in conflict zones where health facilities have either been destroyed or are understaffed. Physicians do not like to locate to these communities because they lack basic amenities, are sparsely populated, and in some cases, unsafe.  This leaves the health facilities (HFs) with insufficiently qualified and ill-equipped front-line health workers (FHWs). There is need to provide a tool that would assist FHWs to effectively manage fever and other common morbidity, thus addressing the health access crisis in these communities.

Objectives: The overarching goal is to increase healthcare access for people living in LMICs. The specific objectives of the project are to: a) obtain experiential knowledge of medical experts who are experts in the diagnosis of following febrile diseases: malaria, enteric fever, dengue fever, yellow fever, zika virus, and chikungunya; b) develop a fuzzy cognitive map (FCM) model for differential diagnosis of these diseases; c) develop a decision support system that utilizes our FCM model as an aid to diagnosis and therapy the of diseases, and d) test the system for utility & efficiency.

Methodology: To accomplish the objectives stated above, we will: i) refine & validate our existing fuzzy-cognitive map model by obtaining experiential knowledge of 50 physicians and 2000 patient data in Nigeria; ii) develop an Android-based app for diagnosis, therapy & providing clinical advice. Our text- and icon-based user interface will be designed in consultation with potential users of the system; iii) recruit and train FHWs in app use; iv) deploy the app in select communities in Nigeria; v) assess the system adoption (using the medical app eval framework), and report project outcomes.

Novelty and significance: Our high risk project attempts to significantly refine our existing two-disease model  to: i) cover additional diseases, ii) accept low-cost test results (using local reagents) and patient risk factors as inputs to generate more reliable diagnosis outcomes, iii) provide guidance on complications, danger signs and disease management strategies, iv) save lives in communities with limited health resources by providing ability for FHWs to diagnose and treat patients in the absence of qualified doctors. This system can be implemented in rural communities in Africa and elsewhere with limited resources.

The objective of this research program is to develop a new way to “trap” a bacterial metabolite in the gut that feeds the host liver store fat and increase blood glucose. Gut bacteria produce almost all D-lactate. Host-derived lactate (L-lactate) is useful for many important functions, but bacterial-derived D-lactate is mainly used by the liver to form blood glucose or stored as liver fat. We have discovered that bacterial lactate is a key source of higher blood glucose and more fat storage during obesity in mice, which are the main two problems in diabetes and fatty liver disease. Usually, we think of blood glucose and liver fat coming from nutrients after eating food and the close connection to obesity. However, gut microbes are always present and always producing D-lactate, which may be one reason is so hard to lower blood glucose and liver fat by dieting.

We have devised a way to “trap” bacterial D-lactate in the gut that effectively excretes D-lactate in the feces thereby preventing it from entering the circulation. Our first-generation lactate trap is a polymer of host L-lactate that sequesters bacterial D-lactate in mouse models of obesity, prediabetes and fatty liver disease. This polymer is extremely safe since it is a natural, biodegradable compound that does not to cross the gut barrier. We will combine our expertise in host glucose/fat metabolism, microbiome engineering and polymer chemistry to build a better trap for bacterial D-lactate to safely lower blood glucose and liver fat.

The research approach involves chemical synthesis of new lactate polymers that can more effectively trap bacterial lactate and survive the journey from the mouth to the intestine to reach their target bacteria. Oral compounds are the preferred route for human drugs or dietary supplements. The research approach will also directly target microbial lactate by blocking its production and engineering microbes to eat and metabolize D-lactate into other beneficial compounds such as a short chain fatty acid.

There are already lots of scientific associations between the microbiome, obesity, diabetes or fatty liver disease. The proposed work is novel because we have found the first unique bacterial metabolite that provides a preferential fuel for blood glucose and liver fat. Safely trapping bacterial D-lactate or stopping its production from bacteria is positioned to help lower blood glucose and liver fat without changes in diet.

Climate change is the justice challenge of our century, and the transition from a high-carbon economy demands high-risk, high-stakes innovations across all sectors towards more sustainable development, backed by new rules and governance systems, public awareness and citizen engagement for compliance. To investigate how rules change can better support systems change, collaborative research and action across legal, economic and scientific disciplines will be harnessed to scale up efforts to achieve the global Sustainable Development Goals (SDGs) across Canada. Over two years (24m), this project will map science-based law and governance innovations, using economics and information systems to track their effectiveness for achieving key targets of the SDGs in Canada and internationally. Legal innnovations towards the 17 SDGs' targets and indicators will be analysed through application of an early-stage SDG-AI system and informed by expert legal, policy, economics, scientific and programming analysis. Engaging with Canada's new Sustainable Development Solutions Network's efforts to create communities of practice for achieving key SDG targets on climate change, biodiversity, oceans, energy and water, the project team will track federal, provincial and local law and governance innovations to identify innovative legal and policy experiments and effects. By activating civil society, firms and authorities to review implications and action, and by employing an experimental AI analysis to track innovative instrument effectiveness on the ground tied to scientific and economic indicators, the transformative potential increases exponentially. Research outcomes will be presented in iterative briefings shared across global and national treaty networks, and disseminated through an interactive web portal, allowing users to quickly identify science-based legal, economic and policy instruments searched by SDG target. Across new frontiers, we co-generate knowledge, awareness and engagement, enabling faster, more effective, more systemic responses to climate change mitigation and adaptation opportunities, providing incentives for a greener economy, and fostering more sustainable development. AI analysis tracks legal intersections within and across jurisdictions, overseen by international experts with deep knowledge of the SDGs and their assessment, ensuring accuracy and managing the inevitable risk given the breadth and complexity of the transformations sought for sustainability.

Sustainability of the beef industry and sustainability of temperate grasslands are equally challenging currently. Beef cattle don’t typically graze on tidy fields of managed pasture, but instead graze complex landscapes with highly diverse vegetation and plant species where they generate an ongoing variety of socio-economic benefits. Moderate grazing increases the ecosystem benefits of pastures such as carbon sequestration by forages and soil, and plant species diversity. Grazing also reduces shrub and tree encroachment, helping maintain grassland habitats required by many wildlife species. Grazing is regarded as the most beneficial use of this land from both an agricultural and ecological point of view. However the public is conflicted by the dire information on the environmental footprint of beef production and some individuals are beginning to make choices of alternate products – such as plant based meat products. Within these prairie grasslands, cattle grow well, eating and living naturally. Under sustainable grazing practices, grasslands provide critical habitat for co-habiting species, help maintain critical water resources and help sequester carbon, reducing greenhouse gases, thereby limiting the impacts of climate change. Canada’s grasslands are a vital and endangered resource and well managed cattle grazing can contribute to their sustainability. The challenge is how to quantify the totality of costs and benefits of raising cattle on temperate grasslands and to ensure the public, the industry and science are working on the same results.  If we cannot align the ecosystem benefits with public environmental concerns and maintain beef productivity to help achieve the benefits we could lose both the benefits and the unique grasslands themselves. Without a multidisciplinary approach we will miss the triggers of consumer behaviour and cow calf producer behaviour as they link to the scientific findings. In this project, we will use a variety of approaches to understand how variation in pastures, forage grasses, beef cattle, and the vast number of microbes they come in contact with, work together to influence sustainable beef production in a relationship that enhances ecosystem quality. We will develop tools that help farmers decide which types of cattle are best for the grasses on their land, while better aligning the availability of forage resources with cattle nutritional needs throughout the grazing season.

Artificial Intelligence (AI) application in the emerging smart manufacturing concepts (Industry 4.0) is meant to remarkably increase the forming processes productivity, customizability, and cost effectiveness. However, the burden of “limited data” in practice, still severely impedes leveraging AI-based solutions for digitization of such processes towards the Factories of Future, and it needs to be addressed at the frontier of basic research. Specifically, in this highly interdisciplinary project with both junior and senior team members from manufacturing/mechanical engineering and data science/informatics fields, we aim to develop a novel sim-to-real transfer-learning framework for predicting and mitigating defects in complex manufacturing processes, in the presence of highly limited data. Such process optimization tasks would otherwise be expensive to tackle experimentally by industries, and/or require extensive expertise and tedious manual tuning. To test the application of this new AI-based framework, an advanced automated thermoforming will be opted, where the goal, first, is to reduce the occurrence of current defects in the body of the thermoformed parts; and second, to maximize the quality of the final products by arriving at more uniform distribution of geometrical properties. The AI will be governed by a verity of factors in the forming process, from part shapes and material properties, to the process variables such as initial zone-based heating of incoming material plates.  In our approach, to enhance the performance of the targeted smart manufacturing models, the learned basic knowledge from previously developed models from auxiliary data sources (e.g. Finite Element simulations and/or lab-scale tests) can be transferred to the real-scale models with a minimum computational cost, which will then be fine-tuned for industrial-scale application purposes. If successful, the trained model can be eventually integrated within a multi-criteria optimization framework to serve as a decision support system for prominent industries such as aerospace and automotive to find optimal thermoforming process conditions given different part shapes.

A rapidly emerging area of age-onset neurodegeneration mechanism is the concept of defective DNA repair in diseases such as Huntington’s, Spinocerebellar ataxias (SCAs) and Parkinson’s disease (PD). DNA damage is being detected not only in disease, but in the premanifest stage for gene carriers decades before disease onset.  DNA damage triggering neurodegeneration is a fundamental new hypothesis for age-onset neurodegenerative diseases. The inability to repair DNA damage is the trigger of disease, linked to metabolic stresses of ageing. This suggests new drug targets in DNA repair may exist, and drugs may be quickly repurposed.

What is not known is the exact molecular mechanism of disease to precisely define new drug targets. Using live cells with Fluorescence Lifetime Imaging Measurement (FLIM) to quantify Forster Resonant Energy Transfer (FRET) with fluorescently labeled pure proteins, we seek to develop a real-time video speed observation of protein-protein and protein-DNA interactions. DNA damage response and resolution takes place in a temporal space of seconds, in proximal space of under 10nm to DNA damage, well within parameters for FLIM-FRET.

We will take recombinant, pure proteins, fluorescently labelled and transduced into cells. At the DNA, we will label DNA at sub-stoichiometric amounts of dye or use histone H2B-fluorescent protein fusions. This will merge biochemistry success at purifying large proteins (Edwards) with live cell imaging, biophysics and biophotonics technology (Truant).

The second aim is then to use a Chemical Biology approach to observe real-time DNA damage response in human live cells. We will use a series of specific DNA damage agents. This localization over time will be correlated to super-resolution imaging at 100nm resolution. This will additionally be done in primary patient-sourced cells.

The final aim is to make temporal observations to image the kinetics of disease protein recruitment and release to/from DNA damage. Within this context, we will test various DNA damage modulators defined as relevant to these diseases and in drug development for cancer to potentially re-purpose these drugs to an accelerated time frame for neurodegenerative diseases. This project will be done under the concept of Open Science and lay translation already established within our groups to bring this data as quickly and openly as possible to the drug discovery community.

The overall objective of this research initiative is to develop a highly accurate "fluid biopsy" that will allow a neurologist to perform early detection of Alzheimer's Disease and its precursor conditions with just a blood and/or urine sample. This "fluid biopsy" test would transform care for this disease because there is currently no effective biomarker for its earliest forms.

We will focus on developing biomarkers for patients exhibiting the earliest signs of neural cognition deficits leading to mild, moderate and severe forms of Alzheimer's Disease. These patient cohorts will be clinically characterized by Dr. Mario Masellis and Dr. Sandra Black, one of the world's foremost experts on developing the clinical guidelines for diagnosis of these early stage neurological disorders.  Blood and urine samples will be obtained from carefully chosen patients for each of these patient cohorts.

These biofluid samples will be processed and brain-derived cell fragments (also known as extracellular vesicles) will be isolated using a novel piece of equipment, called the NanoFACS.  This instrument will allow Dr. Leong to isolate EVs as small as 70nm in diameter, which is not possible with any other conventional FACS instrument. In this way, Dr. Leong will be able to isolate EVs that express multiple neuron markers such as CD171 and CD56 (L1CAM and NCAM respectively) from patient biofluids such as blood plasma and urine. Furthermore, we will be able to isolate these neuron-derived EVs that also contain only RNA. 

The isolation and generation of ultra-pure brain-derived EVs that contain RNA will then be submitted to sequencing by the Co-PI at Johns Hopkins who are experts in extracting RNA from microgram quantities of EVs. Dr. Sabunciyan then will use bioinformatics approaches to assemble protein and RNA based biomarker signatures that are specific for various neurological disorders ranging from mild cognitive impairment (MCI), to mild AD, moderate AD and severe AD.

A special focus will on spent on understanding the biomarkers and RNA species related to MCI and mild AD because these are the patients that would benefit from any new and upcoming treatment. These are also the best kind of patients to enroll patients into clinical trials, a strength of Dr. Black's, so that these patients can be prevented from progressing to moderate or severe AD.  A blood test that provides multiple independent biomarker sets (protein, RNA) would transform AD treatment.

Personalized therapy for patients with cancer remains one of the most important challenges facing clinicians and researchers. In this proposal we describe a point-of-care device that can diagnose disease, or provide prognostic information, by quantifying protein expression. We have patented a thin film platform that uses interference colours to quantify proteins, using designer antibodies, in patient tumours, blood or urine. Interference colours are generated when light enters a two component system where the upper component is semi-transparent, that is it reflects some light, and the bottom component is also reflective. Our diagnostic platform is applicable to all patients in which tissue biopsy is possible or required. Since the vast majority of all cancers require tissue diagnosis and/or surgical resection as part of treatment, this diagnostic platform could apply to virtually all of the 180,000 Canadians affected every year with a new diagnosis of malignancy. This platform may change the nature of cancer tissue diagnosis and pathology given that we can rapidly detect and quantify markers of disease progression or metastases at the time of surgery. Our first application will be a protein biomarker platelet derived growth factor receptor alpha (PDGFRA) that is strongly associated with metastatic disease in papillary thyroid cancer. Validated in paraffin, frozen and fresh tumours and clearly linked in vitro and in vivo to an aggressive disease phenotype, PDGFRA was patented as a molecular diagnostic and represents an excellent model for testing our platform. This biomarker will be tested using the thin film diagnostic platform and tissue isolation protocol developed by Drs. Burrell and McMullen. The combination of a clinically-proven disease marker with the novel thin-film technology will provide a point-of-care diagnostic device that will predict the risk of metastases in a timely and reproducible manner. The ability to identify patients at high risk of metastases would decrease the number of unnecessary lymph node dissections in thyroid cancer by up to 40% (nearly 1300 cases/year). Physicians would also be able to focus aggressive surgery and radioactive iodine treatment efforts on those patients with aggressive disease early on decreasing recurrence rates up to 25% and possibly improving overall survival by 5 to 10% based on the known relationship between recurrence rates and prognosis.

The spread of cancer beyond the initial site (metastasis) occurs frequently and is the cause of 90% of cancer-related deaths. Current cancer therapies fail to prevent metastasis in many patients with advanced cancers. Herein, we plan to unlock the potential of marine macrolide natural products that target the cellular engine driving metastasis, which is the rapid reorganization of the actin cytoskeleton. We have identified the key pharmacophore of a complex marine macrolide toxin that depolymerizes and severs actin filaments, which is uniquely positioned to develop multivalent forms for attachment to dendrimers that we predict will boost actin depolymerization and antimetastatic activities.

The main goal of the proposal is to define the impact of multivalency of synthetic actin toxins to enhance actin depolymerization and antimetastatic activities.  We will use optimal multivalent toxins to develop a new class of antibody-drug conjugates (ADCs) for preclinical testing in metastatic cancer models by pursuing the following objectives:

1. Design and prepare a series of dendrimers for attachment of the synthetic actin toxins for in vitro actin depolymerization and antimetastatic studies.

2. Attach the dendrimers to clinical-grade oncology antibodies for their evaluation in metastatic cancer models.

ADCs target antigens on the surface of cancer cells, leading to the localized release of cytotoxic payloads in tumours. Nevertheless, there have been limited attempts to deliver payloads beyond those that target rapidly dividing cells with microtubule disrupting toxins or genotoxic small molecules. While these ADCs can reduce tumour burden, they do not eliminate recurrence and cancer metastasis.  We propose that this is due to the failure to target "actin addiction" of resistant tumour cells.  Additionally, one of the major limitations with ADCs is the limitation of the number of copies of the warhead.  Hence, new strategies to enhance the diversity and payload of ADCs are urgently needed. 

We have demonstrated that metastatic HER2+ cancer cells are highly sensitive to simplified synthetic analogues of the natural product mycalolide B (MycB), with significant suppression of cell motility and invasion at sub-lethal doses (nM). Encouragingly, these simplified analogues also disrupt filamentous actin (F-actin) in live cancer cells and are amenable to large-scale synthesis and conjugation to antibodies that target tumour-associated antigens.

Almost 150 years after the identification of Parkinson's disease (PD), we have few treatments and no cures. By focussing on the contribution of non-neuron cells to this disease and employing novel, interdisciplinary techniques and approaches, this research will reveal new targets for treatment and a potential cure.

A great deal of work has focused on understanding dopamine cell neurodegeneration in Parkinson's disease. More recently, microglial and astroglial cells have surfaced as promising but understudied therapeutic target in neurodegenerative disease. Glial cells are the most abundant neural cell type and comprise of a heterogenous population identified by morphology, protein expression and function. Unlike neurons that form networks to communicate incoming sensory information and generate motor responses, glial cells conduct critical functions to support neurons: they are responsible for maintaining neuronal function and homeostasis and are key responders in injury, stress and disease. Perturbations of glial cells have been demonstrated in Parkinson's disease (PD) and in two recent studies, we found that 1) optogenetic stimulation of astroglial cells that neighbour nigral dopaminergic cell bodies reversed the behavioural deficits induced by a unilateral 6-OHDA lesion. Moreover, 2) inducing glial cells death is sufficient to induce Parkinson's like motor deficits in a rodent model. Because these data suggest that other cells types might be intimately involved in the pathophysiology (and related treatment) of Parkinson's disease, and because different cell types act together to produce and maintain neuronal activity, we propose that a more systems based approach that considers the phenotype of each cell individually is needed to understand the role of the substantial nigra in Parkinson's disease. The current proposal seeks to identify and classify subtypes of cells and their responses to dopamine neurodegeneration using both biologically driven and bioinformatic-driven hypotheses testing. To achieve this we will use bioinformatics in conjunction with single-cell RNASeq of human post-mortem tissue obtained from patients with Parkinson's Disease.

Efforts to eradicate polio have succeeded in reducing the global burden by 99%, yet recent years have seen the emergence and rising prevalence of a related wave of non-poliovirus paralysis around the world, whose clinical features resemble poliomyelitis. Known as Acute Flaccid Myelitis or Paralysis (AFM/AFP), it is characterized by progressive paralysis with accompanying inflammation and injury to the spinal cord. As with polio, affected individuals are predominantly children (average 7.8 years), after a bout of mild viral illness. Data suggests severe and irreversible disability in a large proportion of affected individuals. Thus, there is an urgent need for a new understanding of host-pathogen interactions in this cohort. Our team has unparalleled expertise in the management and epidemiological study of AFM/AFP, combined with a unique ability to provide a stem cell-based tissue-engineering approach to model interactions of pathogens with target organs, as demonstrated by previous work on the neurological effects of Zika and Dengue viruses. We will select severe cases to follow disease progression, identify possible molecular signatures, and isolate the most likely pathogens. We will engineer models of the spinal cord containing patient-derived nerve cells, and uniquely including the tissue-resident immune cells of the brain and spinal cord. In parallel, we will devise entirely novel tissue-culture models of viral interaction with the gut, replicating the interface between the mucosa and the underlying intestinal nervous system, complete with resident immune cells. Tissue-resident immune cells are needed to recapitulate the inflammatory cascades triggered by infections, locally in the gut, or acting at a distance to promote inflammation in the nervous system. This ambitious project requires challenging technical developments, from a diverse team of interdisciplinary experts (stem cell biologists, tissue engineers, biomaterials scientists, clinical neurologists and immunologists). The knowledge gained from this work will allow us to develop novel and targeted therapies for polio-like illnesses, and reward us with platforms to better understand inflammatory interactions between the gut, its nervous system, and the brain in several highly prevalent neurological disorders such as Autism or Alzheimer’s disease.

At the intestinal level, there is a fine balance between gut microbiota, miRNAs, and the host immune system necessary to drive immune surveillance against tumours.  This triad of mechanisms is crucial in early life establishment of gut microbiota and the mammary gland bud formation. Gut microbiota is recognized as potentially targetable by probiotics. In addition, subsequent depletion via antibiotics will consequently affect miRNA regulation and therefore exposes to higher risk of developing breast cancer later in life. Whether gut microbiota-directed interventions, such as diet enrichment with probiotics will also regulate miRNAs is an important question not yet studied in cancer prevention. Antibiotic use early in life was shown to have long-term effects on gut microbiota composition, inflammatory cytokines expression on sites distant from the intestine with a potential significant impact on pubescent mammary gland. Taken together, this may increase susceptibility to breast cancer later in life. We postulate that concomitant probiotic supplementation with antibiotic will correct disturbance in gut microbiota and miRNAs during mammary gland development. We have shown that probiotics increased many tumour suppressors and down-regulated cancer stem cells development. We aim to establish if antibiotic perturbation will be overcome by probiotic and microbiota-dependent regulation of miRNAs and therefore influence breast cancer development later in life. The bilateral research project between my lab and Dr. Herceg's lab (International Agency for Research on Cancer) will be to fully elucidate the mechanisms by which probiotics influence miRNAs, and consequently microbiome and tumour development of breast cancer. 1) to study if concomitant intake of probiotic and antibiotic early in life, will influence on the establishment of gut microbiota and tumour suppressor miRNAs at the intestine and at the pubertal mammary gland levels.

2) to investigate if probiotic intake will counteract the potential role of early-life antibiotic use in mitigating breast cancer development risk later in life.

We are aiming to study this question by using animal model of female mice exposed to antibiotics in utero and before weaning. We will investigate if antibiotic challenge will affect miRNA in the pubertal mammary gland, which might be translated to a higher risk of breast cancer later in life.

Despite increased focus on the ongoing housing crisis for Indigenous peoples in Canada, it remains understood as a homogeneous problem without clear solutions. The Nishnawbe Aski Nation Housing Strategy was initiated in response to the Chiefs-in-Assembly declaring a housing crisis and asserting the need for community-based solutions. Through the development of the Strategy, community members have shared the particular challenges facing youth throughout Nishnawbe Aski Nation (NAN) in obtaining safe and appropriate housing. Persistent shortages and the overrepresentation of family sized units contribute to this challenge as well as systemic failure of off reserve services including healthcare, education, child family services and justice. Rather than treating the crisis as a strictly physical, technical problem, Creating a Home for Our Youth: Creating housing systems change to address systemic failure for First Nations Youth in Nishnawbe Aski Nation recognizes the additional interconnected social, emotional and spiritual factors which create home.

Using a systems approach, this project looks to identify, from a community-youth perspective the challenges of obtaining housing both on and off reserve and their impacts on individual well-being and potential solutions. Journey mapping, and the co-development of an evaluation framework will lead to a better understanding of existing housing services, while design charrettes will propose alternative designs and service delivery models. A focus throughout is placed on the distinct and unique needs of NAN youth, demonstrating the need for specific rather than general understandings of Indigenous Housing.

This research project looks to approach housing for First Nations youth in the NAN territory holistically, understanding current experiences, mapping and evaluating systems and programs and visioning alternatives through the following objectives: 1. Record the lived experiences of NAN Youth, identify the outcomes of existing housing challenges and understand their visions for alternative appropriate housing systems; 2. Map existing housing services and programs targeted at NAN Youth both on- and off-reserve highlighting service gaps or duplication; 3. Develop an evaluation framework for existing housing services and programs based on youth priorities; and 4. Document best practices across the continuum and through lifecycles, with a focus on Indigenous contexts, in providing appropriate housing for youth.

Making sustainable decisions is hard. Sustainability permeates every decision we make and every relationship we maintain, but the connections between individual decisions and long-term outcomes are so complex and involve so many subjective comparisons that we rarely feel empowered to say, objectively, that we have made the best decision. The Montreal Sustainability Dashboard (MSD) addresses this challenge, transforming subjective decisions into objective ones using a range of data sources, integrated into meaningful relationships.

WHAT IS THE MSD? The MSD is an architecture for transforming raw data into meaningful metrics or comparisons for decision making. We maintain an ongoing simulation of urban land use and transportation under a number of alternative scenarios and then experiment on those simulations to measure the system’s response to different perturbations. This allows us to ask questions in the simulated environment and get answers to questions that we didn’t originally anticipate. Sus is also a hub for academic innovation. We use the questions generated by users to drive the research we do. This feedback creates something we’ve never seen before, a clearinghouse for sustainability decision making.

WHO IS THE MSD FOR? The MSD relies on a unified data infrastructure to help different people get different answers about common sustainability questions. A family considering a move may want to know which neighbourhoods support walkable lifestyles. Government planners may also be interested in neighbourhood walkability, but they want to understand aggregate patterns, and identify neighbourhoods which are outliers.

HOW DOES THE MSD WORK? The MSD is a set of multi-scale simulations designed as a flow of information controlled by modular functions. Our initial design includes 3 primary modules: ecological, residential, and transportation. The ecological module tracks the occupancy and abundance of different species to estimate extinction risk, community dynamics, and biodiversity function over time. The residential module tracks the economics of residential dwellings and the people who use resources there. The transportation module examines how individuals move through their environment, and with what environmental implications. The result is the ability to seamlessly move between social, ecological, and energetic sustainability questions without realizing that you’ve required the expertise of multiple academic disciplines to do so.

Therapeutic proteins, or biologics, represent 10 out of the 25 top grossing pharmaceuticals in 2018 and biologics alone are forecasted to reach a global market size of $500B in 2020. Of the top 10 grossing biologics in 2018, nine require post-translational modifications in the form of glycosylation. The structure of the glycan attached to a protein can affect the efficacy of the treatment, the stability of the protein, and could be immunogenic if incorrect. Although protein glycosylation is present amongst all eukaryotes (yeasts, plants, animals, etc.), each species generates proteins with a distinct glycosylation pattern. In order to circumvent concerns of reduced efficacy and possible issues with immunogenicity there has been a shift towards manufacturing human biologics using human cell lines rather than the mammalian cell systems previously preferred.  Unfortunately, human cell culture is one of the most expensive protein production platforms which contributes to the high costs of these biotherapeutics. In order to reduce the cost of manufacturing these critical medicines and increase the availability of these treatments, significant efforts have been directed into developing alternative biomanufacturing platforms with very limited success.

Eukaryotic microalgae such as Chlorella sp. are generally regarded as safe (GRAS) and are easily grown to higher cell densities than current human cell culture technologies at less than 1/100th of the cost. Microalgae produce glycosylated proteins with a pattern similar to the precursor structure found in human proteins. However a highly unusual DNA virus, PBCV-1; capable of infecting Chlorella NC64, is known to encode its own set of glycosylation enzymes which are used to glycosylate viral proteins.

The objective of this work is to adapt PBCV-1 to encode human glycosyltransferases which will allow the expression of human glycosylated biologics in microalgae at a fraction of the cost of human cell culture. The virus genome will be engineered in E. coli allowing the use routine cloning techniques and transfected into Chlorella NC64. The glycosylation pattern of the resulting proteins will be evaluated and compared to human proteins. If successful, this platform will be a major break-through in the field of protein biomanufacturing and drastically reduce the cost of biologics production, increasing the accessibility of these essential therapies to patients. 

This research program aims to document and assess the relationship between the permeation of medicine by knowledge in the form of data and aspects of medical care that involve touch. We will examine several specific domains in medicine and health care that illustrate the varied ways in which data is represented and made available in medical practice and the various kinds of touch and haptic skills that are important in medical care. The former can include, for example, clinical guidelines summarizing population-based research data, or information-aggregating remote sensors and devices. The latter can include how doctors touch patients in various types of encounters, or how touch is allocated between health care professionals in relation to diagnosis and treatment. We will undertake documentary analysis, interviews, and observations – including recording and representing touch in practice in novel ways. The research project complements emerging studies of how work and services that have traditionally required haptic skills are being reconfigured by the emphasis on data-driven decisions and planning. The project will be a contribution to understanding, documenting, and archiving contemporary changes to the sensory infrastructure of our society -- the nature of our embodied experiences and perceptions -- and resulting effects on our behaviour towards one another and sense of what it means to behave responsibly. The risks of the research primarily revolve around the difficulties of defining, operationalizing, and recording touch and data, especially since both are often conveyed, registered and incorporated into embodied practice in ways that are not entirely conscious or recognized as such. The benefits of this research are the re-orientation of medical education and work in order to enhance the care given to patients and the inspiration of new, creative ways of engagement and treatment in light of the powerful role of data in what we know and feel.

Entheogens are substances that promote altered mental states. The use of entheogens in spiritual practices has a rich history by indigenous peoples of every continent. Anecdotal, anthropological, and clinical evidence suggests that these compounds can promote mental health when used in the proper setting. Scientific study has been severely curtailed by legislation, but several studies indicate lasting positive effects. Moreover, the practice of ‘microdosing’ entheogens on a semi-regular basis is increasing among professionals. Thus, entheogens are used in spiritual, therapeutic, and professional contexts. A recent study has shown that they can promote neural growth, providing a mechanism for lasting brain changes. Yet we know very little about the effects of entheogens on the neural activity that underlies thoughts.

A common aim of entheogens use is to ‘expand the mind’. The purpose of this project is to begin to evaluate this claim at the cellular level using cutting-edge experimental and analytical techniques in animal models. Although not capable of human-like thought, the rodent brain is a widely-used model that provides valuable insights to interpreting data from humans. We will use high-density imaging techniques (2-photon imaging) to record the activity of thousands of neurons in the neocortex of awake behaving mice. We will then use techniques for the study of complex dynamical systems to map patterns of neural activity to behavior. We will test our novel hypothesis that entheogens will cause a long-lasting expansion of the repertoire of neural signaling, which facilitates future creative problem solving. We will test a paradigm of microdosing, as well as an acute treatment modeled after spiritual use. We will then relate this to human use, both historically and in in the modern context, by examining if the neural changes explain lived experience and therapy results. Our team involves experts in neuroscience (Gruber), nonlinear physical systems (Davidsen), and cultural use of entheogens as well as their legal/policy framework (Tupper). This project has high reward – in terms of cultural understanding, generating new knowledge about the neural basis of cognition, and informing policy about a potentially valuable way to promote mental health. Knowledge translation will occur in academic domains (Gruber, Davidsen) and policy domains (Tupper). This is a truly interdisciplinary project, and not likely to be funded by any one tri-council agency.

Emergency Department (ED) congestion is a very serious problem familiar to Canadians of all walks of life. This project will leverage recent advances in artificial intelligence (AI) and machine learning to develop an "Emergency Department AI Flow Assistant" that will help to alleviate ED congestion.

The AI Flow Assistant will safely accelerate patient movement through the emergency department by automatically and reliably identifying patient's needs very early during their ED stay and immediately notifying the relevant personnel and decision makers. This will allow patient care to be streamlined from the door of the ED to the patient's eventual admission to hospital or discharge home.

The Jewish General Hospital (JGH) ED is one of the largest in Canada and has a long history of innovation in optimizing patient flow. The department has collected over 7 years of high quality electronic data regarding patient visits, including data about triage, imaging, lab tests, consults and admissions.

This large amount of data will be used to train the AI Flow Assistant to reliably identify patients who are likely to:

- Be hospitalized

- Be discharged

- Require CT or X-ray imaging

- Require IV catheters or blood tests

- Require physiotherapy consults for early assessment of mobility

- Require the planning of home care visits after discharge from the ED

- Be frail and elderly, requiring specific interventions to avoid hospitalization

- Have congestive heart failure with a high risk of complications and hospitalization that may be avoided with early intervention

Once the AI Flow Assistant has been trained to recognize such patients, it will be deployed so that it can work on a live basis - automatically notifying relevant decision makers such as emergency physicians, nurses, bed and flow coordinators and discharge planning nurses.

This tool promises to significantly reduce ED congestion by reducing the length of stay for each patient. Once the concept is developed and tested at the JGH, it will be possible to easily adapt and implement the AI Flow Assistant at EDs across Canada - thereby benefiting hundreds of thousands to millions of patients per year.

The tool will be entirely novel and will serve as a proof of concept of the potential benefits of AI technology in healthcare resource management - laying the ground work for further applications of this new and exciting technology in the healthcare arena in a safe and responsible way.

AI has become part of society faster than the computer scientists and neuroscientists at its vanguard had expected. As a result, the bioethical implications of AI are not fully appreciated. In the context of oncology, AI is currently being applied by our group to create digital twins, a digital replica of a patient that can be used to predict the metastatic potential of any cancer at early stages that would radically transform our approach to cancer treatment. However, the foregoing work raises substantial social and ethical questions: even if we can make a digital twin, should we? What would you do if you were perfectly healthy, were diagnosed with cancer at an early stage, and your oncologist indicated your 5-year survival probability is <2%? Would you want to know? And what would you do with that information? To act on the information offered by the digital cancer twin throws into question the very nature of the self; the boundaries between the body of data and the fleshy body become porous.

Canadian AI pioneer and Turing Award winner Yoshua Bengio recently warned of the potential misuse of AIs by individuals, companies, and governments and that the only way to face this problem is to have a more just society where people care about the group more than their individual interests. We posit that the way to do this is to change the way humans in AI-driven contexts think of their place in the world with respect to all the other kinds of being in it. This involves highlighting two axes of human-AI interaction: 1.) We highlight how much we already ordinarily cede our decision-making power, outsource our memory, and share our intimate lives with AI algorithms. 2.) We leverage radical reformulations wrought by feminist and other science and technology studies scholars for how humans might consider their own being as, for example, “intra-active”, “ontologically multiple”, and not essentially different from other matter, even machine matter, which is more “vibrant” than conventionally understood. We will do so by appealing to the authority of neuroscientific evidence about the nature of self and consciousness, as well as philosophical thought on the nature of being.

This application leverages interdisciplinary collaboration between an oncologist, AI scientist, and a humanist to keep Canada on the vanguard not just of AI technology but a cultural, sociological, and philosophical defense against its worst excesses.

Rationale:

Intracellular aggregates of insoluble proteins & neuroinflammation are poorly understood characteristics of neurodegenerative diseases like Alzheimer disease (AD). However, practical considerations of studying brain biopsies have limited research advancements. 

Novelty and Expected Significance:

With our complementary expertise & convergent findings in AD genetics, brain & blood pathology, we will show how changes in cell-free & cell-contained DNA in blood contribute to AD pathophysiology.  A “liquid biopsy” could be a less invasive means of detecting AD & novel therapeutic targets.

Hypotheses:

1) Errors in neuronal cell division result from acquired DNA changes of important cell cycle regulators as well as in changes in chromosomal copy number that lead to aberrant expression of proteins associated with (AD) neuropathology; these copy number variants (CNV) will be detectable in cell-free DNA (cfDNA).

2) Acquired genetic mutations in blood cells directly or indirectly lead to neuroinflammation & pathology associated with AD; these changes are also readily detectable in blood cell-contained genomic DNA (gDNA).

Objective 1: Identify novel AD-associated CNV in cfDNA & validate in post-mortem brain tissue.

We will use next-generation sequencing (NGS) to perform a low-plex virtual karyotype. Software will identify CNV between cfDNA & gDNA of AD patients relative to age-matched controls.  We will validate brain-specific origin of cfDNA targets by quantitative PCR & in situ hybridization of tissue. As proof-of-principle, we found a novel gain of chromosome 19 (APOE genetic region, previously implicated in AD) detectable in cfDNA & brain of AD patients. We will study the effects of these CNV on neural growth & protein aggregate formation in vitro.

Objective 2: Identify acquired mutations in blood cells (gDNA) that may be associated with AD.

We identified age-associated, acquired mutations in cancer-associated genes in blood cells of healthy adults (called clonal hematopoiesis, or CHIP).  In mice & humans, blood cells carrying these mutations are hyper-inflammatory & able to infiltrate body tissues, including brain. We will use an NGS cancer hotspot panel to identify if AD patients have a higher rate of CHIP than controls (in blood cell gDNA), if there is an association between alterations in cfDNA & gDNA, & if there are shared targets or pathways. We will also study neuropathology & inflammation in our CHIP model mice.

Online hate is a growing concern. Recent alarming reports suggest that autistic youth are being targeted for recruitment in online hate speech forums (HSF). To date, there has been no systematic study of autistic people who participate in HSF. Clinical experts on our team find current approaches do not work with their autistic clients and are desperately seeking solutions.

Objectives:

1) Identify posts on HSF written by autistic participants using machine learning;

2) Explore how autistic participants in HSF describe autism and their societal context through: a) Analysis of HSF posts identified as being written by autistic participants; and b) Interviews with autistic people currently or formerly involved with HSF.

The data for Objectives 1 and 2a were generated for us by the Southern Poverty Law Centre and consist of public, online HSF posts that contain autism terminology.

Objective 1: We will use machine learning to train, test, and apply a classifier that will identify posts in which the participant identifies as autistic.

Objective 2a: We will read and code the posts identified in Objective 1 using a critical discourse analysis approach in order to understand certain autistic people’s involvement in HSF.

Objective 2b: We will interview autistic people who are current/former participants in HSF to examine the factors that influence their engagement in HSF. Participants will be recruited from the Free Radicals Project, an organization that helps people to exit HSF. We will use thematic analysis to analyze interview data and will compare findings with Objective 2a.

High risk: This groundbreaking work boasts a uniquely composed interdisciplinary team from fields not commonly combined, an exclusive data set, and access to hard-to-reach participants. Our team is singularly qualified for this task, including expertise in autism, extremist ideology, machine learning, and forensics.

High reward: Our work will open a new field of research in autism and extremism and offer unique training opportunities.  Our study products will focus on real-world applications, including: 1) evidence-based rehabilitation strategies for autistic people in HSF; 2) healthcare provider tools for early detection and appropriate steps to guarantee safety; and 3) an Internet safety campaign to prevent autistic people from becoming involved with HSF. This study will have global implications for the safety of autistic people, their families, and the general public.

In this project, we will generate a creative space for community-led policy engagement in the heart of Vancouver’s housing crisis. Using raw materials from archival, qualitative, and humanities-based methodologies gathered through four years of SSHRC Insight participatory action research, we propose a permanent exhibit that will tell the histories of governance, activism, and inhabitance surrounding Single Room Occupancy (SRO) Hotels in Vancouver’s Downtown Eastside. This exhibit space will be located within an SRO, or in close affiliation to SROs by way of our community partners. The exhibit will build on our work as part of the Right to Remain Collective, a group of SRO tenant leaders, academics, and community partners, that has explored the historical trajectory and inhabited realities from within SRO hotels in order to support tenants in asserting their rights. These SROs are historic buildings – often over a century old – and our research has demonstrated how decades of policy decisions made by all levels of government without meaningful input from SRO tenants has led to the precipitous decline in SRO stock, habitability, and tenant well-being. Today, SROs are in atrocious conditions and tenants must cope with exploitative, abusive, and even violent landlords, while in many cases managing multiple concurrent physical and mental health challenges. Working with current tenant leaders, the SRO exhibit space will be constructed to facilitate intense, relational sharing circles that bring decision-makers from all levels of government together with people with lived experience of SRO dwelling and rights-based leadership. Our purpose with curating this space and convening these sharing circles is to “flip the script,” challenging those in positions of power to learn from the grounded expertise of community leaders - a form of evidence that radically unsettles the dominant “evidence-based” decision-making rationale in housing policy today. We imagine our exhibit will bring to life stories and lessons from history, and true expert testimony – that is the lived or living experience of SRO tenants themselves. This project has the potential to develop innovative humanities and arts-based methods of knowledge co-creation and mobilization, and through these spaces to radically transform the political, policy and lived futures of this marginalized but crucially important housing stock.

The potential consequences of high doses of ionizing radiation have been well documented. These exposures pose an issue environmentally with respect to the long-term storage of nuclear waste, as well as medically where damage to healthy tissue can occur as a side effect of radiation therapy. Microorganisms have the potential to play a central role in mitigation strategies to combat radiogenic effects. Bacterial driven bioremediation has been explored for the management of spent nuclear fuel. Additionally, the gut microbiome has been implicated as a factor in bowel injury following radiotherapy of the abdominal region. However, research in these areas has relied on naturally present microorganisms and largely ignores modern advances in genetic engineering and molecular biology. These tools allow for genetic manipulation to generate new variants that are potentially more resistant to radiation, in addition to having increased bioremediation potential and/or heightened microbiome activity. This research program will investigate genetically modified bacteria as a novel approach to combating the effects of ionizing radiation. Six different bacterial species will be studied; three of which have been identified as potential candidates for nuclear waste bioremediation (Deinococcus radiodurans, Geobacter metallireducens, Pseudomonas fluorescens) and three which are present in the mammalian gastrointestinal tract (Ruminococcus gnavus, Lactobacillus rhamnosus, Bacteroides fragilis). Using CRISPR based gene editing, single gene-upregulated strains will be generated for each bacterial species. Initially these strains will be tested for their resistance to high dose ionizing radiation exposure. In aim #1, selected radioresistant variants will be tested for the ability to biotransform nuclear waste to less toxic products.  In aim #2, selected bacterial variants will be tested to determine whether radioresistant gastrointestinal bacteria can help prevent radiation induced small-intestine injury or accelerate recovery.  This study proposal is novel in that it brings together state-of-the-art molecular biology tools for generating genetically modified bacteria that can be utilized for both environmental remediation and human health care.

Background: Tumor-derived extracellular vesicles (EVs) contribute to the crosstalk between tumor cells and the microenvironment (ME), and can transfer bioactive molecules to recipient cells, promoting tumor progression and metastasis. However, uptake can differ depending on cell type and ME conditions, and this may be related to different parameters such as size and zeta potential. Understanding cancer cell-derived EVs and their context-dependent uptake may provide additional therapeutic avenues. Nanoparticle synthesis and modeling in microfluidic devices with different structures and ME conditions provides a novel approach to study EV uptake.

Hypothesis: Changes to ME contribute to EV uptake, thereby modulating the effect on recipient cells.

Aim: To characterize the uptake of cancer cell-derived EVs and assess how this is modulated by the ME, we will 1) characterize the size, size distribution and zeta potential of cancer-derived EVs; 2) synthesize EVs with different microstructures and flow rates and quantify their uptake by recipient cells; 3) modulate the zeta potential of EVs in different ME conditions.

Methods: EVs from cancer cells will be characterized using dynamic light scattering. Then, EV nanoparticles will be modeled and synthesized under different microstructure shapes with different flow rates of lipid/solvent and aqueous solutions, and ME variables such as temperature and humidity. Micromixers allow production of EVs under continuous-flow conditions, improving repeatability. Analytical models of the microfluidic structures will be validated against experimental results. Uptake will be compared for EVs synthesized under different conditions.

Impact: EV nanoparticle development combines efforts from different science domains to offer tools to combat and understand diseases. These studies will contribute to better understanding of the capabilities as well as limits of microfluidic structures, creating fundamental tools that could be further used in the systematic development of working microsystems for micromixing.

While cancer is well controlled in the primary setting, metastatic disease presents a major clinical challenge. Given the known role of EVs in metastasis, identifying key regulators of this process may help to elucidate why despite primary control, some patients develop metastasis while others do not, and further demonstrate that to improve patient survival, a systemic approach is needed to target tumour-derived molecules.

Incarcerated individuals suffer vast health and social inequities, many of which span generations. In Canada’s colonial context, Indigenous peoples are disproportionately impacted by barriers to health and social well-being, which are in turn correlated with crime. This results in the over-representation of Indigenous peoples - including children and youth, women, Elders and LGBTQ2+ peoples - in institutional contexts such as child welfare, youth detention, provincial/federal corrections and mental health and substance use treatment facilities. Despite widespread research attention, attempts to address these inequities often exist in disciplinary siloes. Additionally, assumptions regarding Indigenous peoples’ vulnerability often reduces meaningful input from those most impacted by intersecting colonial health, social and criminal justice systems, truncating opportunities to engage with community strengths. Our interdisciplinary and cross-sectoral team of scholars, Indigenous Elders, organizational representatives and community advocates will conduct Participatory Action Research to explore peer-led interventions to foster health and social equity, employment opportunities, and safe housing for people impacted by intersection health, social, and criminal justice systems. We will expand our network to engage additional Indigenous youth, adults, Elders and LGBTQ2+ peoples to collaboratively develop a peer-led intervention in Vancouver, BC, guided by pre-existing relationships with an advisory of Indigenous adults and Elders with lived experience of institutionalization. This work is timely given the ongoing calls for action amidst the overdose and housing crises, and increasing rates of detention and incarceration for Indigenous peoples. Providing paid research training and employment for Indigenous peoples, including youth, will foster opportunities for future scholars and advocates at the intersections of health, justice and social well-being. Drawing on arts-based methods (filmmaking, storytelling), we will explore the strengths, priorities and challenges facing Indigenous peoples in criminal justice contexts and collaboratively develop a pilot peer mentorship program. Future funding will support ongoing program evaluation and scalability across contexts. Drawing on community strengths and guided by Indigenous Elders, scholars and advocates, this Exploration Grant will support equity and the intersections of health, social well-being and criminal justice.