Innovative Projects Realized

Rational design of opioid analgesics for treatment of chronic pain

Opioids are the most efficacious analgesics known, and elective in the treatment of acute severe pain. In contrast, their use in the management of chronic pain syndromes remains limited, requiring a compromise between preserving analgesic efficacy and controlling side effects such as respiratory depression, somnolence, nausea, constipation as well as abuse, dependence and analgesic tolerance. Tolerance involves a self-perpetrating cycle of insufficient analgesia and increasing incidence of side effects as a result of dose escalation.

Mechanisms that contribute to tolerance take place at different organizational levels within the nervous system, including molecular, cellular and neuronal circuit adaptations. The focus of the project is on the adaptations that occur at the two first levels, namely opioid receptor regulation by endocytic/post-endocytic trafficking and the associated cellular changes (morphology and texture) that result from cytoskeletal rearrangements supporting receptor trafficking. By combining a number of new target-based approaches that we have developed to capture more of the relevant signals that control trafficking, together with a broader examination of cellular phenotypes using high content miscroscopy, it should be possible to identify clusters of opioid receptor ligands with the common ability to activate specific protein kinases and promote distinctive modalities of beta-arrestin1/2 recruitment that correlate with distinct trafficking phenotypes and tolerance profiles. To validate this notion we will pursue three aims:

SPECIFIC AIMS
a) Use resonance energy transfer-based assays to quantify i) ligand-specific patterns of kinase activation, ii) beta-arrestin1/2 recruitment to MORs/DORs and iii) their redistribution from the membrane to the endosomal compartment;
b) Monitor beta-arrestin1/2 mobilization and endocytic redistribution of receptor proteins with a high content microscopy platform
c) Correlate outcomes in a) and b) with high content-based readouts of cytoskeletal rearrangements and changes in cell morphology/texture analyses.

Integrating data obtained with phenotypic screens and target-based screening techniques will allow definition of a regulatory footprint for different ligands. Correlation of the latter with well described profiles of ligand potential for generating tolerance should establish the bases for simple drug stratification algorithms that are predictive of pharmacodynamic tolerance to the analgesic actions of opioid receptor ligands much earlier in the drug development pipeline.

Photochemical water-splitting with transition metal complexes

The objective of this particular project is the synthesis and characterisation of novel bimetallic photocatalysts which are able to produce hydrogen gas from water using sunlight. Currently, hydrogen is made through steam reforming, which produces carbon dioxide as a side-product, or by electrolysis, which uses more energy to produce hydrogen than you get from its use in fuel cells. Our goal is to use sunlight as the main energy source for the production of hydrogen for use in fuel cells.
The organic synthesis of novel heterocyclic ligands will allow us to bind them to various transition metals that introduce photochemical properties into the final complexes. The organic ligand will be synthesized using carbon-carbon and carbon-nitrogen bond forming reactions such as the Suzuki, Stille and Buchwald coupling reactions. The choice of metal ion will be dictated by the energy of light that we wish the complex to absorb. The use of Re(I) will lead to high energy light absorbers, whereas Ru(II) will lead to lower energy light absorbers. The ligands and their metal complexes will be studied using a wide variety of techniques available in our laboratory and the chemistry department, including 1H and 13C NMR, electrochemistry, UV-visible and emission spectroscopies, and X-ray crystallography.
The Re and Ru complexes will then be used as photosensitizers for the catalytic reduction of water to hydrogen gas in conjunction with Co and Pt-based catalysts. By varying the type of photosensitizer and catalyst, we will be able to optimize the photochemical reaction. This part of the project will entail careful analysis of H2 production using gas chromatography.

Redox-dependent mechanisms of the innate immune antiviral response

The molecular mechanisms that explain how the host triggers a first antiviral response against virus infection has been the focus of numerous studies over the past decades. This first line of response involves key signaling cascades that permit the expression of antiviral and proinflammatory genes. Recently we have demonstrated that the production of reactive oxygen species (ROS) plays a key role in the regulation of this response. These molecules are often associated with damage, but they are now well known to play a key role in the regulation of signaling events through oxidation of proteins. Having characterized the contribution of ROS to the innate antiviral response, we are now seeking to identify the proteins that are regulated by oxidation during this response. The project will involve culture of human cell lines and state-of-the art biochemistry and cellular biology techniques.

Optimizing Production of Biomass Fly Ash

Kruger Energy has built and commissioned a 23-MW biomass cogeneration plant at Kruger paper mill in Brompton (Québec) in 2007. The plant includes a hog boiler which burns papermill sludge, bark, and other wood residue (were firstly disposed in earth), as well as a steam turbine which generates electrical energy and provides steam required to dry the paper. This power station reduces 25 million litters/year of fuel oil and 83000 tons/year of gas emissions for greenhouse gas (GHG) (equal to a removal of 18000 vehicles from roads).The combustion of the residues of biomass generates 70 tons/day of fly ash (FA) and 30 tons/day of bottom ash (a coarse residue containing aggregates, metals, and ash). These ashes were initially hided in earth. Suitable FA is not always available near construction site, and transportation and storage costs may nullify any cost advantage (can reach 40% of total cost). The SFA is only available in provinces where electricity is primarily produced from coal-fired powers. Out of these provinces, as in Quebec where 96% of electricity generated hydraulically, the cement factories must import the SFA from Ontario, Maritimes region, or United States. Thus, the solution lies in producing and valorization of residual industrial materials as alternative cementing additives (ACA). The FA obtained from incineration of municipal residues is one of the examined alternatives to be used in concrete. The use of Kruger FA (KFA), like alternative to FA, represents a very promising solution for ecological concrete design with high performance. Indeed, 90% of KFA production is currently sold as cementitious additives (CA) for stabilization/solidification process of hazardous wastes and contaminated soils.
This study aims at making an optimal choice of source and content of combustible raw materials and combustion temperature used in the production of KFA. In addition, the research is to propose several KFA types of certain properties that confront the Standards’ requirements (CSA A3004, ASTM C 618, and AASHTO M 295) with ensuring batch-to-batch uniformity with periodical checkup.
This research will be of interest to the environmental performance, Kruger profitability, and Canadian industry of construction by finding new sources of FA. In addition, this project provides training for highly qualified person(s).

Evaluating In-situ Testing Properties of New Alternative Cementing

Use of fly ash (FA) in concrete started in United States in early 1930’s. Standardized FA (SFA) by Canadian Standard Association (CSA) is frequently used as partial replacement of cement in manufacturing binary or ternary concrete mixtures. In addition to economic and ecological benefits, use of FA in concrete (a) improves workability (due to increased paste volume and spherical form of particles), (b) reduces heat of hydration, permeability, segregation, and bleeding (by providing greater fines volume and lower water content), (c) reduces alkali-silica reaction (ASR) expansion (due to the capacity of FA to fix alkalis presented in interstitial solution), (d) enhances sulfate resistance, strength (FA exhibits very little cementing value at early age due to slow pozzolanic reaction of FA; however it contributes considerably to strength at later age), and durability.
Suitable FA is not always available near construction site, and transportation and storage costs may nullify any cost advantage (can reach 40% of total cost). The SFA is only available in provinces where electricity is primarily produced from coal-fired powers. Out of these provinces, as in Quebec where 96% of electricity generated hydraulically, the cement factories must import the SFA from other places such as Ontario, Maritimes region, or United States.
Kruger Energy has built and commissioned a 23-MW biomass cogeneration plant at Kruger paper mill in Brompton (Québec) in 2007. The combustion of the residues of biomass generates 70 tons/day of FA. This ash was initially hided in earth. The use of Kruger FA (KFA), as an alternative to SFA, represents a very promising solution for ecological concrete design. This can solve the lack of sources for the SFA.
The field validation is demanded for the acceptance of any new cementing materials to be used as a replacement of Portland cement. This is very important step towards standardization of any new product in the construction industry. The field study will make it possible to evaluate the behavior of concrete in service, to offer a technological window, and to give recommendations to the potential users of the construction industry. The ultimate objective is to ensure adequate lifespan for the infrastructures manufactured with the new materials as in our study is the Kruger Fly Ash (KFA).

Comparison of in vitro vs. in vivo formation of cis-platin DNA adducts

Comparison of in vitro vs. in vivo formation of cis-platin DNA adducts

INTRODUCTION: More than 50% of the compounds used in chemotherapy damage DNA. The most effective chemotherapeutic compounds induce DNA lesions that are slowly repaired, blocking DNA replication and cell cycle over a relatively long period of time after treatment. However cell cycle arrest induces events that promote DNA repair, making cells resistant to chemotherapeutic drugs. Among the most difficult DNA lesions to repair are DNA interstrand-crosslinks. Cis-platin induces multiple forms of DNA lesions: 1) intra-strand crosslinks (96%), 2) inter-strand crosslinks (1%), 3) mono adducts (~2%) and 4) DNA-protein crosslinks (<1%). The type of lesion formed by cis-platin depends on the DNA sequence. However, the torsion of DNA within the cell nucleus could also influence the DNA damage induced by cis-platin. Since in eukaryotic cells the DNA is heavily folded in a structure called chromatin, we propose that chromatin influences the type of DNA lesions induced by cis-platin. HYPOTHESIS: In the cell, DNA undergoes periodical torsions within a structure called chromatin. We hypothesize that cis-platin induced DNA lesions in naked DNA in vitro are different than those induced in chromatin in vivo. GOAL: To compare the formation of cis-platin induced DNA lesions in vitro vs. in vivo. METHOD: The student will isolate genomic DNA from yeast cells. The DNA will be damaged in vitro using increasing amounts of cis-platin and then sheared to obtain a population of fragmented DNA having, on average, a length of ~1 kbp. Thereafter, the damaged DNA will be analyzed by HPLC to determine the type of DNA lesions. In parallel, yeast cells will be treated with cis-platin. The DNA will be isolated, sheared and analyzed by HPLC. The results will be compared and the percentage for each type of DNA lesion determined for both, in vitro and in vivo treatments. In the laboratory we have the know-how to treat yeast cells with DNA damaging agents (Toussaint M and Conconi A (2006). High-throughput and sensitive assay to measure yeast cell growth: a bench protocol for testing genotoxic agents. NATURE Prot 1, 1922-1928). Moreover, Dr Richard Wagner - Department of radiobiology, Faculty of medicine, University of Sherbrooke - is a DNA chemist that studies DNA lesions by HPLC (Cadet J, Douki T, Ravanat JL, Wagner JR (2012). Measurement of oxidatively generated base damage to nucleic acids in cells: Facts and artifacts. Bioanal. Rev. 4, 55-74).

Contagion and contagions in financial markets: the application of network analysis in finance

The 2008 financial crisis highlighted the connectedness of financial institutions around the world. This networking can have important consequences, both positive and negative, for global and national financial systems. In this context, network theory and social network analysis (SNA) can provide helpful tools and measures to better understand the effects of networks or any other phenomena of finance or, to quote Allen and Babus (2009): “Mapping the networks between financial institutions is a first step towards gaining a better understanding of modern financial systems.”
The objective of this project is to study and analyse the topology and structure of different financial markets or networks, such as the mutual and pension funds networks, the syndicated loan market network and all the main securities markets. To do so, a comprehensive network theory approach that includes novel financial network analysis tools and metrics will offer an essential perspective on the underlying connections in the networks. Basic network structure metrics will be estimated, such as small-world statistic, scale-free parameters, etc. Further, novel network measures, which are typically developed in other fields, will be applied to the financial networks identified above: herd behavior, sources of diffusion, influential spreaders, bridges, adoption probabilities, mobility traces, etc. Because different networks can emerge from the same connections (e.g., dual-mode network, correlation network, etc.), the metrics will be estimated for a variety of networks.
The expected contributions of the project are both scientific and practical.

Quantum computation and quantum optics with circuit quantum electrodynamics

Quantum information is a new field of research that promises exponentially more powerful computers than those offered by current technology. To realize tasks that are impossible for their classical counterparts, quantum computers will harness effects that are fundamentally quantum mechanical. These effects (superposition of states, entanglement and interference) are at the heart of our understanding of quantum theory. As a result, a quantum computer would not only be a major technological advance, it would also represent a unique laboratory for the fundamental study of quantum mechanics. The realization of such a quantum information processor is however an extremely difficult task.

Josephson junction-based superconducting circuits are arguably amongst the most promising systems towards this goal. This research project will be focused on the physics of these mesoscopic devices, also known as superconducting qubits, and will be at the interface between mesoscopic physics, quantum information science and quantum optics. It will in particular focus on an architecture known as circuit quantum electrodynamics (circuit QED) where a superconducting qubit is strongly coupled to photons stored in a microwave resonator. In addition to being one of the most promising avenues for the realization of a full scale quantum computer, circuit QED opens the possibility to study the rich physics of quantum optics in the completely new parameter regime offered by a solid-state environment.

Depending on the student interest and background, this research project will be focused on one of the many outstanding challenges in the field of circuit QED:

a) High fidelity and rapid (~ 100 ns) qubit readout. The current state of the art relies on amplifying a weak microwave signal (~1 photon) going through the cQED setup using a superconducting amplifier, most commonly a Josephson junction parametric amplifier. While 95% single-shot readout fidelity has been achieved, this is not enough for full-scale quantum computation. The objective of this project is to understand what limits the fidelity of these devices, and suggest news quantum-limited amplifier designs reaching near ideal performances. Although theoretical, this work will be done in close collaboration with the experimental groups.

b) Quantum optics with circuit QED. The goal of this project is to find new ways to take advantage of the strong light-matter interaction and strong single photon nonlinearity that can be realized in circuit QED.

c) Quantum logical gates in circuit QED. While the fidelity of single-qubit quantum gates has increased over the last several years, this has not been the case of the two-qubit gates. These logical operations are however required to create entangled state and so for all quantum algorithms and protocols. The goal of this project will be to study a new type of two-qubit gate and to evaluate its potential performance.

For more information about circuit QED consult http://epiq.physique.usherbrooke.ca/data/files/publications/blais2011.pdf or http://www.youtube.com/watch?v=t5nxusm_Umk

A Simplified Life Cycle Approach for Assessing Environmental impact of Green Building

A full life cycle assessment (LCA) is usually a time, energy, and data-intensive process requiring sophisticated methodology. Moreover, rapid growth in LCA methodological developments applied to green building has generated a large body of work that may appear to lack direction.

This research project propose that environmental impact meta-analysis of green building highlights several key, sensitive parameters, provides a better understanding of the variability in LCA results, and then proposes a methodology to establish a simplified, streamlined approach based on regressions built on these key parameters.

Green Building environmental performance can be linked to three essential components: technological (e.g., material choices), geographical (e.g., electricity mix), and LCA methodology (e.g., system boundaries).

A regression will be derived based on detailed and published LCA results. Simple Environmental performance (i.e., emissions) curves depending on average on-site configurations and lifetime are proposed as a first step toward the proposed simplified and streamlined approach.

This research will present a simplified model as an alternative to detailed LCA. The methodology is applied as a first trial to green building and could be expended to other system such as energy systems.
Finally, the proposed approach will be helpful to identify research thrusts on how to further develop LCA methodology and improve obtained results in the field of green building.

Trainee position within the industrial Pfizer / UdeS Chair on process analysis (PAT) in pharmaceutical engineering technologies

Pfizer/Université de Sherbrooke Industrial Chair on PAT in pharmaceutical engineering
The internship will be offered in the framework of the Pfizer/Université de Sherbrooke industrial chair on process analytical technology (PAT) in pharmaceutical engineering. Led by Professors Nicolas Abatzoglou and Ryan Gosselin, this chair has the following objectives:
? Develop knowledge of: 1) the physical and chemical phenomena governing the behavior of processes involved in the production of pharmaceutical products, and 2) the criteria surrounding technology transfer based on phenomenological models or mathematics (e.g. the scaling and the introduction of new technologies);
? Implement improved processes and products based on PAT monitoring and control;
? Train highly qualified personnel, both in academia and industry;
? Build a critical research mass in the field of pharmaceutical process monitoring at the Department of Chemical Engineering at Université de Sherbrooke.

Aerodynamic measurements on airfoils in the wind tunnel

This research project is to better understand the flight dynamic characteristics of airfoils. The candidate will conduct an experimental study of the flow around airfoils in the wind tunnel. He will analyze the data to characterize the spatio-temporal dynamics of the vortex structures produced. The experimental study will be conducted in the wind tunnel located at the Université de Sherbrooke (UdeS). It has a closed test section of 1.82m×1.82m, and a maximum speed of 35 m/s. Some of these equipment’s will be used: Particle Image Velocimetry (PIV) and Hot Wire Anemometry (HWA).

Sustainable engineering / Développement durable pour l’ingénierie (Nouveau)

The project aims at the development of an approach to integrate sustainability principles and criteria in engineering projects. Awaiting more information from the professor. Please check back soon. Do not contact Globalink Research Internships.

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Le projet vise le développement d’une approche pour intégrer les principes et critères du développement durable dans les projets d’ingénierie.