Toronto, Canada
Toronto, Canada

The University of Toronto is a public research university in Toronto, Ontario, Canada, situated on the grounds that surround Queen's Park. It was founded by royal charter in 1827 as King's College, the first institution of higher learning in Upper Canada. Originally controlled by the Church of England, the university assumed the present name in 1850 upon becoming a secular institution. Wikipedia.


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A method and system for enhancing migration of precursor cells in a desired direction, comprising applying a biphasic monopolar electrical field to the precursor cells. The method and system can be used to treat injury or disease of neural or skin tissue.


Patent
University of Toronto | Date: 2015-04-23

The present invention relates to novel ruthenium-based triazole carbene complexes comprising specific ligands, their preparation and their use as catalysts in hydrogenation processes. Such complex catalysts are inexpensive, thermally robust, gel formation inhibiting and olefin selective.


Patent
University of Toronto | Date: 2016-09-13

Chitosan nanoparticles are provided for use in the in vivo treatment of connective tissues in root canal therapies. The nanoparticles are optionally linked with one or more photoactivatable compounds for providing antibacterial/antibiofilm properties, neutralizing bacterial byproducts and/or chemical/photodynamic crosslinking to achieve enhanced mechanical properties, chemical stability in connective tissues and/or to improve surface/interfacial integrity between filling material and connective tissue.


Patent
University of British Columbia, University of Toronto and Institute National Of Recherche En Informatique Et En Automatique | Date: 2015-04-16

A method is for estimating a three-dimensional (3D) representation of a set of two-dimensional (2D) curves of a concept drawing, the estimate of the 3D representation corresponding to a 3D object underlying the concept drawing. The method comprises: obtaining a representation of a set of 2D curves a concept drawing that represent a 3D object underlying the concept drawing; determining an energy function based on the set of 2D curves, the energy function comprising one or more terms, each term reflective of a preference for a 3D representation based on a characteristic of the 2D curves which reflects how concept drawings are commonly perceived to represent 3D objects; and performing an optimization which minimizes the energy function to thereby determine the 3D representation.


Patent
Samsung and University of Toronto | Date: 2016-06-22

A training method of training an illumination compensation model includes extracting, from a training image, an albedo image of a face area, a surface normal image of the face area, and an illumination feature, the extracting being based on an illumination compensation model; generating an illumination restoration image based on the albedo image, the surface normal image, and the illumination feature; and training the illumination compensation model based on the training image and the illumination restoration image.


Patent
University of Toronto | Date: 2017-03-29

Contemplated methods and devices comprise use of a charged probe and a pseudoligand in the electrochemical detection of a wide range of analytes, including nucleic acids, proteins and small molecules. In certain embodiments, the pseudoligand forms a complex with the probe that has a reduced charge magnitude compared to the probe itself, and is displaced from the probe when the complex is exposed to the analyte.


Patent
Samsung and University of Toronto | Date: 2017-04-19

A training method of training an illumination compensation model includes extracting, from a training image, an albedo image of a face area, a surface normal image of the face area, and an illumination feature, the extracting being based on an illumination compensation model; generating an illumination restoration image based on the albedo image, the surface normal image, and the illumination feature; and training the illumination compensation model based on the training image and the illumination restoration image.


Lo H.-K.,University of Toronto | Curty M.,University of Vigo | Tamaki K.,Nippon Telegraph and Telephone
Nature Photonics | Year: 2014

Secure communication is crucial in the Internet Age, and quantum mechanics stands poised to revolutionize cryptography as we know it today. In this Review, we introduce the motivation and the current state of the art of research in quantum cryptography. In particular, we discuss the present security model together with its assumptions, strengths and weaknesses. After briefly introducing recent experimental progress and challenges, we survey the latest developments in quantum hacking and countermeasures against it. © 2014 Macmillan Publishers Limited. All rights reserved.


Austin P.C.,Institute for Clinical Evaluative science | Austin P.C.,University of Toronto
Statistics in Medicine | Year: 2013

Propensity score methods are increasingly being used to reduce or minimize the effects of confounding when estimating the effects of treatments, exposures, or interventions when using observational or non-randomized data. Under the assumption of no unmeasured confounders, previous research has shown that propensity score methods allow for unbiased estimation of linear treatment effects (e.g., differences in means or proportions). However, in biomedical research, time-to-event outcomes occur frequently. There is a paucity of research into the performance of different propensity score methods for estimating the effect of treatment on time-to-event outcomes. Furthermore, propensity score methods allow for the estimation of marginal or population-average treatment effects. We conducted an extensive series of Monte Carlo simulations to examine the performance of propensity score matching (1:1 greedy nearest-neighbor matching within propensity score calipers), stratification on the propensity score, inverse probability of treatment weighting (IPTW) using the propensity score, and covariate adjustment using the propensity score to estimate marginal hazard ratios. We found that both propensity score matching and IPTW using the propensity score allow for the estimation of marginal hazard ratios with minimal bias. Of these two approaches, IPTW using the propensity score resulted in estimates with lower mean squared error when estimating the effect of treatment in the treated. Stratification on the propensity score and covariate adjustment using the propensity score result in biased estimation of both marginal and conditional hazard ratios. Applied researchers are encouraged to use propensity score matching and IPTW using the propensity score when estimating the relative effect of treatment on time-to-event outcomes. © 2012 John Wiley & Sons, Ltd.


Faulkner G.,University of Toronto
American Journal of Preventive Medicine | Year: 2013

Context Given its high prevalence and impact on quality of life, more research is needed in identifying factors that may prevent depression. This review examined whether physical activity (PA) is protective against the onset of depression. Evidence acquisition A comprehensive search was conducted up until December 2012 in the following databases: MEDLINE, Embase, PubMed, PsycINFO, SPORTDiscus, and Cochrane Database of Systematic Reviews. Data were analyzed between July 2012 and February 2013. Articles were chosen for the review if the study used a prospective-based, longitudinal design and examined relationships between PA and depression over at least two time intervals. A formal quality assessment for each study also was conducted independently by the two reviewers. Evidence synthesis The initial search yielded a total of 6363 citations. After a thorough selection process, 30 studies were included for analyses. Among these, 25 studies demonstrated that baseline PA was negatively associated with a risk of subsequent depression. The majority of these studies were of high methodologic quality, providing consistent evidence that PA may prevent future depression. There is promising evidence that any level of PA, including low levels (e.g., walking <150 minutes/weeks), can prevent future depression. Conclusions From a population health perspective, promoting PA may serve as a valuable mental health promotion strategy in reducing the risk of developing depression.


Lumba S.,University of Toronto | Cutler S.,University of California at Riverside | McCourt P.,University of Toronto
Annual Review of Cell and Developmental Biology | Year: 2010

Plant hormones are a group of chemically diverse small molecules that direct processes ranging from growth and development to biotic and abiotic stress responses. Surprisingly, genome analyses suggest that classic animal nuclear hormone receptor homologs do not exist in plants. It now appears that plants have co-opted several protein families to perceive hormones within the nucleus. In one solution to the problem, the hormones auxin and jasmonate ( JA) act as "molecular glue" that promotes protein-protein interactions between receptor F-boxes and downstream corepressor targets. In another solution, gibberellins (GAs) bind and elicit a conformational change in a novel soluble receptor family related to hormone-sensitive lipases. Abscisic acid (ABA), like GA, also acts through an allosteric mechanism involving a START-domain protein. The molecular identification of plant nuclear hormone receptors will allow comparisons with animal nuclear receptors and testing of fundamental questions about hormone function in plant development and evolution. Copyright © 2010 by Annual Reviews. All rights reserved.


Austin P.C.,Institute for Clinical Evaluative science | Austin P.C.,University of Toronto
Statistics in Medicine | Year: 2014

Propensity score methods are increasingly being used to estimate causal treatment effects in observational studies. In medical and epidemiological studies, outcomes are frequently time-to-event in nature. Propensity-score methods are often applied incorrectly when estimating the effect of treatment on time-to-event outcomes. This article describes how two different propensity score methods (matching and inverse probability of treatment weighting) can be used to estimate the measures of effect that are frequently reported in randomized controlled trials: (i) marginal survival curves, which describe survival in the population if all subjects were treated or if all subjects were untreated; and (ii) marginal hazard ratios. The use of these propensity score methods allows one to replicate the measures of effect that are commonly reported in randomized controlled trials with time-to-event outcomes: both absolute and relative reductions in the probability of an event occurring can be determined. We also provide guidance on variable selection for the propensity score model, highlight methods for assessing the balance of baseline covariates between treated and untreated subjects, and describe the implementation of a sensitivity analysis to assess the effect of unmeasured confounding variables on the estimated treatment effect when outcomes are time-to-event in nature. The methods in the paper are illustrated by estimating the effect of discharge statin prescribing on the risk of death in a sample of patients hospitalized with acute myocardial infarction. In this tutorial article, we describe and illustrate all the steps necessary to conduct a comprehensive analysis of the effect of treatment on time-to-event outcomes. © 2013 The authors.


Guttman D.S.,University of Toronto | McHardy A.C.,Heinrich Heine University Düsseldorf | Schulze-Lefert P.,Cluster of Excellence on Plant science CEPLAS | Schulze-Lefert P.,Max Planck Institute for Plant Breeding Research
Nature Reviews Genetics | Year: 2014

Advances in genome-based studies on plant-associated microorganisms have transformed our understanding of many plant pathogens and are beginning to greatly widen our knowledge of plant interactions with mutualistic and commensal microorganisms. Pathogenomics has revealed how pathogenic microorganisms adapt to particular hosts, subvert innate immune responses and change host range, as well as how new pathogen species emerge. Similarly, culture-independent community profiling methods, coupled with metagenomic and metatranscriptomic studies, have provided the first insights into the emerging field of research on plant-associated microbial communities. Together, these approaches have the potential to bridge the gap between plant microbial ecology and plant pathology, which have traditionally been two distinct research fields.


Hsieh Y.H.,Tzu Chi University | Koo M.,University of Toronto | Leung F.W.,1 Sepulveda Ambulatory Care Center
The American journal of gastroenterology | Year: 2014

Minimal sedation obviates patient recovery burdens, but intolerable pain limits success of cecal intubation. Painless or minimally uncomfortable insertion ensures success of cecal intubation, current patient satisfaction, and willingness to repeat future colonoscopy with minimal sedation. Water immersion (WI) and water exchange (WE), when separately compared with air insufflation (AI), significantly reduced insertion pain. To assess comparative effectiveness, we conducted a randomized controlled trial with head-to-head comparison of these three methods. We hypothesized that WE could produce the highest proportion of patients reporting painless insertion. This prospective patient-blinded trial (NCT01535326) enrolled minimally sedated (25 mg intramuscular meperidine) patients randomized to AI, WI, or WE (90 patients/group) to aid insertion. The previously validated primary outcome was the proportion of patients reporting painless insertion. Painless insertion was reported by 30.0% (AI), 43.3% (WI), and 61.1% (WE) of patients (P<0.001). Multivariate logistic regression analysis revealed that, after adjusting for gender, body mass index, abdominal compression, position change, insertion time to cecum, and length of scope at cecum, only WE was significantly associated with painless insertion compared with AI (odds ratio (OR)=0.08, 95% confidence interval (CI)=0.03-0.24, P<0.001) or WI (OR=0.14, 95% CI=0.05-0.40, P<0.001). Adenoma detection rate (ADR) in the right (cecum and ascending) colon was 11.1% (AI), 14.4% (WI), and 26.7% (WE) (P=0.015). The limitations included single site study with unblinded colonoscopist and assistant. This head-to-head comparison of AI vs. WI vs. WE confirmed that WE was superior to WI and AI, with a significantly greater proportion of patients reporting painless insertion. The significantly higher ADR in the right colon in the WE group warrants further investigations.


Bazinet R.P.,University of Toronto | Laye S.,French National Institute for Agricultural Research | Laye S.,University of Bordeaux 1
Nature Reviews Neuroscience | Year: 2014

The brain is highly enriched with fatty acids. These include the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid, which are largely esterified to the phospholipid cell membrane. Once PUFAs are released from the membrane, they can participate in signal transduction, either directly or after enzymatic conversion to a variety of bioactive derivatives ('mediators'). PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signalling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders. © 2015 Macmillan Publishers Limited.


Peerani R.,University of Toronto | Zandstra P.W.,University of Toronto
Journal of Clinical Investigation | Year: 2010

Enabling stem cell-targeted therapies requires an understanding of how to create local microenvironments (niches) that stimulate endogenous stem cells or serve as a platform to receive and guide the integration of transplanted stem cells and their derivatives. In vivo, the stem cell niche is a complex and dynamic unit. Although components of the in vivo niche continue to be described for many stem cell systems, how these components interact to modulate stem cell fate is only beginning to be understood. Using the HSC niche as a model, we discuss here microscale engineering strategies capable of systematically examining and reconstructing individual niche components. Synthetic stem cell-niche engineering may form a new foundation for regenerative therapies.


Rosenzweig R.,University of Toronto | Kay L.E.,University of Toronto | Kay L.E.,Hospital for Sick Children
Annual Review of Biochemistry | Year: 2014

Large macromolecular assemblies, so-called molecular machines, are critical to ensuring proper cellular function. Understanding how proper function is achieved at the atomic level is crucial to advancing multiple avenues of biomedical research. Biophysical studies often include X-ray diffraction and cryo-electron microscopy, providing detailed structural descriptions of these machines. However, their inherent flexibility has complicated an understanding of the relation between structure and function. Solution NMR spectroscopy is well suited to the study of such dynamic complexes, and continued developments have increased size boundaries; insights into function have been obtained for complexes with masses as large as 1 MDa. We highlight methyl-TROSY (transverse relaxation optimized spectroscopy) NMR, which enables the study of such large systems, and include examples of applications to several cellular machines. We show how this emerging technique contributes to an understanding of cellular function and the role of molecular plasticity in regulating an array of biochemical activities. Copyright © 2014 by Annual Reviews. All rights reserved.


Van Leuven J.T.,University of Montana | Meister R.C.,University of Connecticut | Simon C.,University of Connecticut | McCutcheon J.P.,University of Toronto
Cell | Year: 2014

Mutualisms that become evolutionarily stable give rise to organismal interdependencies. Some insects have developed intracellular associations with communities of bacteria, where the interdependencies are manifest in patterns of complementary gene loss and retention among members of the symbiosis. Here, using comparative genomics and microscopy, we show that a three-member symbiotic community has become a four-way assemblage through a novel bacterial lineage-splitting event. In some but not all cicada species of the genus Tettigades, the endosymbiont Candidatus Hodgkinia cicadicola has split into two new cytologically distinct but metabolically interdependent species. Although these new bacterial genomes are partitioned into discrete cell types, the intergenome patterns of gene loss and retention are almost perfectly complementary. These results defy easy classification: they show genomic patterns consistent with those observed after both speciation and whole-genome duplication. We suggest that our results highlight the potential power of nonadaptive forces in shaping organismal complexity. Copyright © 2014 Elsevier Inc. All rights reserved.


Miller R.J.D.,Max Planck Institute for the Structure and Dynamics of Matter | Miller R.J.D.,University of Toronto
Science | Year: 2014

With the recent advances in ultrabright electron and x-ray sources, it is now possible to extend crystallography to the femtosecond time domain to literally light up atomic motions involved in the primary processes governing structural transitions. This review chronicles the development of brighter and brighter electron and x-ray sources that have enabled atomic resolution to structural dynamics for increasingly complex systems. The primary focus is on achieving sufficient brightness using pump-probe protocols to resolve the far-from-equilibrium motions directing chemical processes that in general lead to irreversible changes in samples. Given the central importance of structural transitions to conceptualizing chemistry, this emerging field has the potential to significantly improve our understanding of chemistry and its connection to driving biological processes.


Patent
Nippon Telegraph, Telephone and University of Toronto | Date: 2014-06-11

Provided is a quantum repeater network system that does not need any matter qubit. According to the quantum repeater network system for performing quantum communication between one transmitter/receiver and the other transmitter/receiver via transmission repeaters and reception repeaters, each of the transmission repeaters prepares quantum systems in an irreducibly entangled state, each of said quantum systems being associated with a reception repeater as a transmission destination, and transmits, to the associated reception repeater, each of the quantum systems in the irreducibly entangled state together with a quantum system entangled with the quantum system.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2011.2.1.1-2 | Award Amount: 15.99M | Year: 2011

PRIMES focuses on the role of protein interactions to assemble dynamic molecular machines that receive and process information to coordinate cellular responses. PRIMES investigates the following: (i) How do protein interactions contribute to the generation of biological specificity in signalling? (ii) How do pathogenetic perturbations affect protein interaction networks? (iii) How can we exploit protein interactions as therapeutic targets? We focus on the EGFR/ERBB signalling network and its role in colorectal cancer (CRC), the third most frequent cancer. The ERBB network is frequently altered in CRC either through overexpression or mutation of the receptors or downstream components. Network components have become important drug targets. Poor response rates and resistance demonstrate we lack sufficient insight to design efficacious therapies. Using proteomics, structural biology, advanced imaging and mathematical modelling we (i) map static and dynamic protein interactions in the ERBB network (ii) unravel the design principles and emergent network properties conferred by protein interactions; and (iii) validate these findings in genetic mouse models of CRC and human tissues. PRIMES aims to (i) enhance the functional pathogenetic understanding of CRC (ii) identify mechanisms of drug resistance and drug efficacy; and (iii) identify drugs that affect protein interactions to rationally manipulate network functions related to individual genetic mutations. Outcomes include (i) a dynamic, mechanistic flowchart of how protein interactions compute biochemical and biological specificity in signalling networks (ii) a functional protein interaction network of healthy and oncogenic ERBB signalling validated in mouse models of CRC and human tissues (iii) network level insights towards personalised CRC treatment based on genotype-phenotype relationships; and (iv) chemical compounds targeting protein interactions to restore normal ERBB network function or break oncogenic circuits.


Grant
Agency: Cordis | Branch: FP7 | Program: CSA-CA | Phase: HEALTH.2012.4.1-6 | Award Amount: 2.81M | Year: 2012

The MDGs succeeded in generating consensus on and mobilising resources towards agreed goals. They were less successful at clarifying responsibilities for achieving them. The MDG target on sharing global health innovation is particularly ambiguous about the allocation of responsibilities. The members of the consortium behind this proposal assume that the new goals for global health will need to be based on a broad global consensus on the goals, on accepted national and international responsibilities to achieve those goals, and on the kind of governance that is needed to ensure accountability for accepted responsibilities. They believe that the internationally agreed right to health provides a useful point of departure for the formulation of such a global consensus, that the goals should incorporate universal coverage, and that community input is critical to designing the goals. Consortium members will: * Assess the achievements and shortcomings of the MDG approach; * Consult communities whose health is most compromised on their essential needs and their perception of their entitlements under the right to health; * Assess the capacity of low and middle income countries to meet those needs and entitlements, including to identify where international assistance (financial and technical) or cooperation (on sharing innovation or avoiding the brain drain of health workers) is needed; * Analyse the international political economy of global health and global governance for health, to formulate international responsibility for global health; * Analyse, clarify, and re-affirm national responsibility for health, in the light of international responsibility for global health; * Propose new goals for global health, clarifying national and international responsibilities; * Provide suggestions for governance for global health to effectuate these responsibilities.


INMARE stands for Industrial Applications of Marine Enzymes: Innovative screening and expression platforms to discover and use the functional protein diversity from the sea. It is a collaborative Innovation Action to streamline the pathways of discovery and industrial applications of new marine enzymes and bioactives for targeted production of fine chemicals, drugs and in environmental clean-up applications. The INMARE consortium will unify the multidisciplinary expertise and facilities of academic and industry partners. This will include integrating the following core activities: advanced technologies to access and sample unique marine biodiversity hot-spots; state-of-the art technologies for construction of metagenomic libraries; innovative enzyme screening assays and platforms; cutting-edge sequence annotation pipelines and bioinformatics resources; high-end activity screening technology; bioanalytical and bioprocess engineering facilities and expertise, nanoparticle-biocatalysts; high-quality protein crystallization and structural analysis facilities and experts in IP management for biotechnology. The companies involved in the project are market leaders in enzyme production and biocatalysis processes designed to efficiently deliver safer (pharmaceuticals) cheaper (agriculture) and biobased (biopolymers) products. They also have impressive track record in environmental clean-up technologies and are committed to promoting public understanding, awareness and dissemination of scientific research. The main emphasis will be focused on streamlining and shortening the pipelines for enzyme and bioactive compound discovery towards industrial applications through the establishing of marine enzyme collections with a high proportion of enzymes-allrounders. The project will also prioritize the identification of novel lead products and the delivery of improved prototypes for new biocatalytic processes.


Grant
Agency: GTR | Branch: EPSRC | Program: | Phase: Training Grant | Award Amount: 3.99M | Year: 2014

The Scottish Doctoral Training Centre in Condensed Matter Physics, known as the CM-DTC, is an EPSRC-funded Centre for Doctoral Training (CDT) addressing the broad field of Condensed Matter Physics (CMP). CMP is a core discipline that underpins many other areas of science, and is one of the Priority Areas for this CDT call. Renewal funding for the CM-DTC will allow five more annual cohorts of PhD students to be recruited, trained and released onto the market. They will be highly educated professionals with a knowledge of the field, in depth and in breadth, that will equip them for future leadership in a variety of academic and industrial careers. Condensed Matter Physics research impacts on many other fields of science including engineering, biophysics, photonics, chemistry, and materials science. It is a significant engine for innovation and drives new technologies. Recent examples include the use of liquid crystals for displays including flat-screen and 3D television, and the use of solid-state or polymeric LEDs for power-saving high-illumination lighting systems. Future examples may involve harnessing the potential of graphene (the worlds thinnest and strongest sheet-like material), or the creation of exotic low-temperature materials whose properties may enable the design of radically new types of (quantum) computer with which to solve some of the hardest problems of mathematics. The UKs continued ability to deliver transformative technologies of this character requires highly trained CMP researchers such as those the Centre will produce. The proposed training approach is built on a strong framework of taught lecture courses, with core components and a wide choice of electives. This spans the first two years so that PhD research begins alongside the coursework from the outset. It is complemented by hands-on training in areas such as computer-intensive physics and instrument building (including workshop skills and 3D printing). Some lecture courses are delivered in residential schools but most are videoconferenced live, using the well-established infrastructure of SUPA (the Scottish Universities Physics Alliance). Students meet face to face frequently, often for more than one day, at cohort-building events that emphasise teamwork in science, outreach, transferable skills and careers training. National demand for our graduates is demonstrated by the large number of companies and organisations who have chosen to be formally affiliated with our CDT as Industrial Associates. The range of sectors spanned by these Associates is notable. Some, such as e2v and Oxford Instruments, are scientific consultancies and manufacturers of scientific equipment, whom one would expect to be among our core stakeholders. Less obviously, the list also represents scientific publishers, software houses, companies small and large from the energy sector, large multinationals such as Solvay-Rhodia and Siemens, and finance and patent law firms. This demonstrates a key attraction of our graduates: their high levels of core skills, and a hands-on approach to problem solving. These impart a discipline-hopping ability which more focussed training for specific sectors can complement, but not replace. This breadth is prized by employers in a fast-changing environment where years of vocational training can sometimes be undermined very rapidly by unexpected innovation in an apparently unrelated sector. As the UK builds its technological future by funding new CDTs across a range of priority areas, it is vital to include some that focus on core discipline skills, specifically Condensed Matter Physics, rather than the interdisciplinary or semi-vocational training that features in many other CDTs. As well as complementing those important activities today, our highly trained PhD graduates will be equipped to lay the foundations for the research fields (and perhaps some of the industrial sectors) of tomorrow.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: KBBE.2011.2.2-02 | Award Amount: 7.84M | Year: 2012

NutriTech will build on the foundations of traditional human nutrition research using cutting-edge analytical technologies and methods to comprehensively evaluate the diet-health relationship and critically assess their usefulness for the future of nutrition research and human well-being. Technologies include genomics, transcriptomics, proteomics, metabolomics, laser scanning cytometry, NMR based lipoprotein profiling and advanced imaging by MRI/MRS. All methods will be applied in an integrated manner to quantify the effect of diet on phenotypic flexibility, based on metabolic flexibility (the capacity for the organism to adapt fuel oxidation to fuel availability). However, NutriTech will move beyond the state-of-the-art by applying these integrated methods to assess the underlying and related cell biological and genetic mechanisms and multiple physiological processes of adaptation when homeostasis is challenged. Methods will in the first instance be evaluated within a human intervention study, and the resulting optimal methods will be validated in a number of existing cohorts against established endpoints. NutriTech will disseminate the harmonised and integrated technologies on a global scale by a large academic network including 6 non-EU partners and by providing an integrated and standardised data storage and evaluation platform. The impact of NutriTech will be multifold and exploitation is crucial as major breakthroughs from our technology and research are expected. This will be achieved by collaboration with a consortium of 8 major food industries and by exploitation of specific technologies by our 6 SME partners. Overall, NutriTech will lay the foundations for successful integration of emerging technologies intro nutrition research.


Siler K.,University of Toronto | Lee K.,University of California at San Francisco | Bero L.,University of Sydney
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Peer review is the main institution responsible for the evaluation and gestation of scientific research. Although peer review is widely seen as vital to scientific evaluation, anecdotal evidence abounds of gatekeeping mistakes in leading journals, such as rejecting seminal contributions or accepting mediocre submissions. Systematic evidence regarding the effectiveness-or lack thereof-of scientific gatekeeping is scant, largely because access to rejected manuscripts from journals is rarely available. Using a dataset of 1,008 manuscripts submitted to three elite medical journals, we show differences in citation outcomes for articles that received different appraisals from editors and peer reviewers. Among rejected articles, desk-rejected manuscripts, deemed as unworthy of peer review by editors, received fewer citations than those sent for peer review. Among both rejected and accepted articles, manuscripts with lower scores from peer reviewers received relatively fewer citations when they were eventually published. However, hindsight reveals numerous questionable gatekeeping decisions. Of the 808 eventually published articles in our dataset, our three focal journals rejected many highly cited manuscripts, including the 14 most popular; roughly the top 2 percent. Of those 14 articles, 12 were deskrejected. This finding raises concerns regarding whether peer review is ill-suited to recognize and gestate the most impactful ideas and research. Despite this finding, results show that in our case studies, on the whole, there was value added in peer review. Editors and peer reviewers generally-but not always-made good decisions regarding the identification and promotion of quality in scientific manuscripts.


Prevots D.R.,National Institute of Allergy and Infectious Diseases | Marras T.K.,University of Toronto
Clinics in Chest Medicine | Year: 2015

Population-based data have documented a worldwide increase in the prevalence of human nontuberculous mycobacterial (NTM) infections since 2000. Mycobacterium avium complex is predominant in North America and East Asia, whereas in regions within Europe, M kansasii, M xenopi, and M malmoense are more common. Host factors important to the current epidemiology of NTM pulmonary disease include thoracic skeletal abnormalities, rheumatoid arthritis, and use of immunomodulatory drugs. Clustering of disease within families suggests a heritable genetic predisposition to disease susceptibility. Warm, humid environments with high atmospheric vapor pressure contribute to population risk. © 2015 Elsevier Inc.


Patent
University of Toronto and President And Fellows Of Harvard College | Date: 2012-11-16

A microfluidic method and device for focusing and/or forming discontinuous sections of similar or dissimilar size in a fluid is provided. The device can be fabricated simply from readily-available, inexpensive material using simple techniques.


Patent
Université de Sherbrooke, President And Fellows Of Harvard College and University of Toronto | Date: 2014-05-30

Techniques for use in connection with performing optimization using an objective function. The techniques include using at least one computer hardware processor to perform: beginning evaluation of the objective function at a first point; before evaluating the objective function at the first point is completed: identifying, based on likelihoods of potential outcomes of evaluating the objective function at the first point, a second point different from the first point at which to evaluate the objective function; and beginning evaluation of the objective function at the second point.


Patent
President And Fellows Of Harvard College and University of Toronto | Date: 2014-05-30

Techniques for use in connection with performing optimization using a plurality of objective functions associated with a respective plurality of tasks. The techniques include using at least one computer hardware processor to perform: identifying, based at least in part on a joint probabilistic model of the plurality of objective functions, a first point at which to evaluate an objective function in the plurality of objective functions; selecting, based at least in part on the joint probabilistic model, a first objective function in the plurality of objective functions to evaluate at the identified first point; evaluating the first objective function at the identified first point; and updating the joint probabilistic model based on results of the evaluation to obtain an updated joint probabilistic model.


Grant
Agency: GTR | Branch: NERC | Program: | Phase: Research Grant | Award Amount: 150.55K | Year: 2013

Forecasting the weather from days to two weeks in advance has typically focused on the troposphere, the layer of the atmosphere closest to the ground. A typical weather forecast first attempts to estimate what the atmosphere is like now, and then extrapolates forward in time, using a complex model of the atmosphere based on the basic physical laws of motion. Over the last 15 years, evidence has been growing that different parts of the atmosphere and Earth system can also be exploited to improve weather forecasts. One of these regions is the stratosphere, the layer directly above the troposphere. Because, temperatures increase with height in the stratosphere, winds and weather systems are quite different, and a distinct community of scientific researchers who study the stratosphere exists around the world. Through the work of this community, many weather forecasting centres have been encouraged to look to the stratosphere to improve their weather forecasts and have been modifying their weather forecasting models accordingly. What has been missing, however, is a concerted effort to understand how best to make use of the stratosphere to improve weather forecasts and to determine how much weather forecasts might benefit. This proposal will fund a new international scientific network which will bring scientists from around the world together to study the stratosphere and how it might be used to improve weather forecasts. The network is made up of scientists from universities and weather forecasting centres around the world and is supported by two other international scientific research bodies. The network will allow scientists to come together to discuss current research in this area and to plan and carry out a new experiment which will compare the stratosphere and its impact on weather forecasts in their weather forecasting models. At the end of the research project, the network members will work together to produce a report which will provide guidance to all weather forecasting centres on the use of the stratosphere for weather forecasting.


Grant
Agency: Cordis | Branch: H2020 | Program: CSA | Phase: ICT-38-2015 | Award Amount: 2.22M | Year: 2016

DISCOVERY aims at supporting dialogues between Europe and North America (US and Canada); and fostering cooperation in collaborative ICT R&I, both under Horizon 2020 and under US and Canada funding programmes. With this purpose, DISCOVERY proposes a radically new approach to engage more actively and strategically in supporting dialogues and partnership building for ICT R&I cooperation. At the core of the DISCOVERY action is the Transatlantic ICT Forum that will be established as a sustainable mechanism to support policy debate and to provide opinions and recommendations furthering meaningful dialogues for purpose-driven and mutually beneficial cooperation between Europe and North America in the field of ICT. DISCOVERY will specifically focus on key aspects that until now have not been properly addressed in the political dialogue, such as funding mechanisms, ICT policy and regulations, and cybersecurity, as well as ICT priority areas of strategic interest for future partnerships in R&I. DISCOVERY will also stimulate industry engagement and innovation partnerships between the industry, research and academia, by reinforcing networking between ICT ETPs and US/Canada innovation partnerships; providing a new partner search tool; implementing Doorknock outreach to relevant US and Canada funding programmes; and using a unique set of participatory and co-creative methods and people-centric facilitation techniques to stimulate interaction among the groups of participants in project events, such as the ICT Discovery Lab and well-targeted capacity-building workshops. The DISCOVERY consortium is in the best position to leverage the required expertise, engagement with ICT dialogues, shared vision, networking capacity, access to a wide range of political, industry and economic thought-leaders throughout EU, US and Canada, and resources towards action and result-oriented dialogues, and significantly contributing to reinforce ICT R&I cooperation between Europe and North America.


Ameis S.H.,University of Toronto | Catani M.,King's College London
Cortex | Year: 2015

Background: Autism Spectrum Disorder (ASD) symptoms have been hypothesized to result from altered brain connectivity. The 'disconnectivity' hypothesis has been used to explain characteristic impairments in socio-emotional function, observed clinically in ASD. Here, we review the evidence for impaired white matter connectivity as a neural substrate for socio-emotional dysfunction in ASD. A review of diffusion tensor imaging (DTI) studies, and focused discussion of relevant post-mortem, structural, and functional neuroimaging studies, is provided. Methods: Studies were identified using a sensitive search strategy in MEDLINE, Embase and PsycINFO article databases using the OvidSP database interface. Search terms included database subject headings for the concepts of pervasive developmental disorders, and DTI. Seventy-two published DTI studies examining white matter microstructure in ASD were reviewed. A comprehensive discussion of DTI studies that examined white matter tracts linking socio-emotional structures is presented. Results: Several DTI studies reported microstructural differences indicative of developmental alterations in white matter organization, and potentially myelination, in ASD. Altered structure within long-range white matter tracts linking socio-emotional processing regions was implicated. While alterations of the uncinate fasciculus and frontal and temporal thalamic projections have been associated with social symptoms in ASD, few studies examined association of tract microstructure with core impairment in this disorder. Conclusions: The uncinate fasciculus and frontal and temporal thalamic projections mediate limbic connectivity and integrate structures responsible for complex socio-emotional functioning. Impaired development of limbic connectivity may represent one neural substrate contributing to ASD social impairments. Future efforts to further elucidate the nature of atypical white matter development, and its relationship to core symptoms, may offer new insights into etiological mechanisms contributing to ASD impairments and uncover novel opportunities for targeted intervention. © 2014 Elsevier Ltd.


Patent
President And Fellows Of Harvard College and University of Toronto | Date: 2014-05-30

Techniques for use in connection with performing optimization using an objective function that maps elements in a first domain to values in a range. The techniques include using at least one computer hardware processor to perform: identifying a first point at which to evaluate the objective function at least in part by using an acquisition utility function and a probabilistic model of the objective function, wherein the probabilistic model depends on a non-linear one-to-one mapping of elements in the first domain to elements in a second domain; evaluating the objective function at the identified first point to obtain a corresponding first value of the objective function; and updating the probabilistic model of the objective function using the first value to obtain an updated probabilistic model of the objective function.


Patent
President And Fellows Of Harvard College and University of Toronto | Date: 2014-05-30

Techniques for use in connection with performing optimization using an objective function. The techniques include using at least one computer hardware processor to perform: identifying, using an integrated acquisition utility function and a probabilistic model of the objective function, at least a first point at which to evaluate the objective function; evaluating the objective function at least at the identified first point; and updating the probabilistic model of the objective function using results of the evaluating to obtain an updated probabilistic model of the objective function.


Lanner F.,Hospital for Sick Children Research Institute | Rossant J.,Hospital for Sick Children Research Institute | Rossant J.,University of Toronto
Development | Year: 2010

Fibroblast growth factor (FGF) signaling controls fundamental processes such as proliferation, differentiation and migration throughout mammalian development. Here we discuss recent discoveries that implicate FGF/Erk signaling in the control of pluripotency and lineage specification in several different stem cell states, including the separation of pluripotent epiblast and primitive endoderm in the blastocyst, the lineage priming of embryonic stem (ES) cells, and in the stabilization of the metastable state of mouse epiblast and human ES cells. Understanding how extrinsic signals such as FGF regulate different stem cell states will be crucial to harvest the clinical promise of induced pluripotent and embryo-derived stem cells.


McLeod D.S.A.,Royal Brisbane and Womens Hospital | McLeod D.S.A.,Queensland Institute of Medical Research | Sawka A.M.,University of Toronto | Cooper D.S.,Johns Hopkins University
The Lancet | Year: 2013

In many parts of the world, incidence of papillary thyroid cancer is increasing faster than any other malignancy. Most papillary thyroid cancers that are diagnosed are small and are generally regarded as being low risk, with little or no effect on mortality. Papillary thyroid cancer is a clinical challenge because it is difficult to prove benefit from the traditional therapeutic triad for this disorder (ie, total thyroidectomy with or without prophylactic central neck dissection, radioiodine remnant ablation, and suppression of serum thyroid-stimulating hormone with levothyroxine). However, risk of disease recurrence might be reduced by these therapies in a subset of patients with more aggressive disease. In the past decade, professional societies and other groups have established evidence-based clinical practice guidelines for management of papillary thyroid cancer, but these efforts have been made difficult by a paucity of randomised controlled trials. In this review, we summarise epidemiological data for disease incidence, discuss some controversies in disease management, and outline a therapeutic framework founded in the best available medical evidence and existing recommendations from clinical practice guidelines.


Cockburn K.,University of Toronto | Rossant J.,Hospital for Sick Children Research Institute
Journal of Clinical Investigation | Year: 2010

Mammalian preimplantation development, which is the period extending from fertilization to implantation, results in the formation of a blastocyst with three distinct cell lineages. Only one of these lineages, the epiblast, contributes to the embryo itself, while the other two lineages, the trophectoderm and the primitive endoderm, become extraembryonic tissues. Significant gains have been made in our understanding of the major events of mouse preimplantation development, and recent discoveries have shed new light on the establishment of the three blastocyst lineages. What is less clear, however, is how closely human preimplantation development mimics that in the mouse. A greater understanding of the similarities and differences between mouse and human preimplantation development has implications for improving assisted reproductive technologies and for deriving human embryonic stem cells.


Ghaznavi F.,University of Toronto | Evans A.,University of Toronto | Madabhushi A.,Rutgers University | Feldman M.,University of Pennsylvania
Annual Review of Pathology: Mechanisms of Disease | Year: 2013

Digital imaging in pathology has undergone an exponential period of growth and expansion catalyzed by changes in imaging hardware and gains in computational processing. Today, digitization of entire glass slides at near the optical resolution limits of light can occur in 60 s. Whole slides can be imaged in fluorescence or by use of multispectral imaging systems. Computational algorithms have been developed for cytometric analysis of cells and proteins in subcellular locations by use of multiplexed antibody staining protocols. Digital imaging is unlocking the potential to integrate primary image features into high-dimensional genomic assays by moving microscopic analysis into the digital age. This review highlights the emerging field of digital pathology and explores the methods and analytic approaches being developed for the application and use of these methods in clinical care and research settings. © 2013 by Annual Reviews. All rights reserved.


Gilbert R.E.,University of Toronto | Krum H.,Monash University
The Lancet | Year: 2015

Individuals with diabetes are not only at high risk of developing heart failure but are also at increased risk of dying from it. Fortunately, antiheart failure therapies such as angiotensin-converting-enzyme inhibitors, β blockers and mineralocorticoid-receptor antagonists work similarly well in individuals with diabetes as in individuals without the disease. Response to intensive glycaemic control and the various classes of antihyperglycaemic agent therapy is substantially less well understood. Insulin, for example, induces sodium retention and thiazolidinediones increase the risk of heart failure. The need for new glucose-lowering drugs to show cardiovascular safety has led to the unexpected finding of an increase in the risk of admission to hospital for heart failure in patients treated with the dipeptidylpeptidase-4 (DPP4) inhibitor, saxagliptin, compared with placebo. Here we review the relation between glycaemic control and heart failure risk, focusing on the state of knowledge for the various types of antihyperglycaemic drugs that are used at present. © 2015 Elsevier Ltd.


Dzavik V.,University of Toronto | Colombo A.,San Raffaele Scientific Institute
JACC: Cardiovascular Interventions | Year: 2014

Objectives This study sought to evaluate the feasibility of performing contemporary bifurcation techniques with the Absorb everolimus-eluting bioresorbable vascular scaffold (Abbott Vascular, Santa Clara, California) (BVS). Background The feasibility of using the BVS in bifurcation lesions is unknown. Methods We performed bifurcation stenting procedures including main-vessel stenting with ballooning of the side branch through the BVS struts, T-stenting and crush and culotte procedures, in a synthetic arterial model. Low-pressure final kissing balloon (FKB) inflation was performed to complete the procedures. Results Single-stent procedures optimally opened the side-branch ostium without deforming the main vessel BVS. T-stenting completely covered the side-branch ostium. In crush cases, we could easily re-cross the crushed BVS with the wire and balloon and achieve good results after deployment of the main-vessel BVS and FKB inflation. A 2-BVS culotte resulted in good paving of the main vessel. Disruption of 1 BVS strut was observed after FKB inflation with the 2 balloons inflated beyond the recommended limit of the BVS, as calculated by Finet's law. Conclusions Intervention of bifurcation lesions using the Absorb BVS using modern bifurcation techniques appears feasible in a coronary bifurcation model. Provisional stenting is recommended in the majority, with sequential balloon inflations and FKB inflation only when necessary. T or T-stenting and small protrusion stenting with a metal drug-eluting stent is preferable in case of crossover. A 2-BVS, T-stent technique can be performed in a high-angle bifurcation; otherwise, crush or culotte should be considered, using metal DES in the side branch. Two-BVS crush and culotte require careful evaluation, and should only be considered in patients with large-caliber main vessels. © 2014 by the American College of Cardiology Foundation.


Jones J.A.,University of Pennsylvania | Lutz S.T.,Blanchard Valley Regional Cancer Center | Chow E.,University of Toronto | Johnstone P.A.,Indiana University
CA Cancer Journal for Clinicians | Year: 2014

When delivered with palliative intent, radiotherapy can help to alleviate a multitude of symptoms related to advanced cancer. In general, time to symptom relief is measured in weeks to months after the completion of radiotherapy. Over the past several years, an increasing number of studies have explored rates of radiotherapy use in the final months of life and have found variable rates of radiotherapy use. The optimal rate is unclear, but would incorporate anticipated efficacy in patients whose survival allows it and minimize overuse among patients with expected short survival. Clinician prediction has been shown to overestimate the length of survival in repeated studies. Prognostic indices can provide assistance with estimations of survival length and may help to guide treatment decisions regarding palliative radiotherapy in patients with potentially short survival times. This review explores the recent studies of radiotherapy near the end of life, examines general prognostic models for patients with advanced cancer, describes specific clinical circumstances when radiotherapy may and may not be beneficial, and addresses open questions for future research to help clarify when palliative radiotherapy may be effective near the end of life. © 2014 American Cancer Society.


Siderowf A.,University of Pennsylvania | Lang A.E.,University of Toronto
Movement Disorders | Year: 2012

Parkinson's disease (PD) has a prodromal phase during which nonmotor clinical features as well as physiological abnormalities may be present. These premotor markers could be used to screen for PD before motor abnormalities are present. The technology to identify PD before it reaches symptomatic Braak Stage 3 (substantia nigra compacta [SNc] involvement) already exists. The current challenge is to define the appropriate scope of use of predictive testing for PD. Imaging technologies such as dopamine transporter imaging currently offer the highest degree of accuracy for identifying premotor PD, but they are expensive as screening tools, and abnormalities on these studies would only be evident at Braak Stage 3 or higher. Efficiency is greatly enhanced by combining imaging with a prescreening test such as olfactory testing. This 2-step process has the potential to greatly reduce costs while retaining diagnostic accuracy. Alternatively, or in concert with this approach, evaluating high-risk populations (eg, patients with rapid eye movement behavior disorder or LRRK2 mutations) would enrich the sample for cases with underlying PD. Ultimately, the role of preclinical detection of PD will be determined by the ability of emerging therapies to influence clinical outcomes. As such, implementation of large-scale screening strategies awaits the arrival of clearly safe and effective therapies that address the underlying pathogenesis of PD. Future research will establish more definitive biomarkers capable of revealing the presence of disease in advance of SNc involvement with the promise of the potential for introducing disease-modifying therapy even before the development of evidence of dopamine deficiency. © 2012 Movement Disorder Society.


Chatterjee A.,University of Pennsylvania | Vartanian O.,University of Toronto
Trends in Cognitive Sciences | Year: 2014

Neuroaesthetics is an emerging discipline within cognitive neuroscience that is concerned with understanding the biological bases of aesthetic experiences. These experiences involve appraisals of natural objects, artifacts, and environments. Because aesthetic encounters are common in everyday life, exploration of their biological bases can deepen our understanding of human behavior in important domains such as mate selection, consumer behavior, communication, and art. We review recent evidence showing that aesthetic experiences emerge from the interaction between sensory-motor, emotion-valuation, and meaning-knowledge neural systems. Neuroaesthetics draws from and informs traditional areas of cognitive neuroscience including perception, emotion, semantics, attention, and decision-making. The discipline is at a historical inflection point and is poised to enter the mainstream of scientific inquiry. © 2014 Elsevier Ltd.


Back S.A.,Oregon Health And Science University | Miller S.P.,Hospital for Sick Children | Miller S.P.,University of Toronto
Annals of Neurology | Year: 2014

With advances in neonatal care, preterm neonates are surviving with an evolving constellation of motor and cognitive disabilities that appear to be related to widespread cellular maturational disturbances that target cerebral gray and white matter. Whereas preterm infants were previously at high risk for destructive brain lesions that resulted in cystic white matter injury and secondary cortical and subcortical gray matter degeneration, contemporary cohorts of preterm survivors commonly display less severe injury that does not appear to involve pronounced glial or neuronal loss. Nevertheless, these milder forms of injury are also associated with reduced cerebral growth. Recent human and experimental studies support that impaired cerebral growth is related to disparate responses in gray and white matter. Myelination disturbances in cerebral white matter are related to aberrant regeneration and repair responses to acute death of premyelinating late oligodendrocyte progenitors (preOLs). In response to preOL death, early oligodendrocyte progenitors rapidly proliferate and differentiate, but the regenerated preOLs fail to normally mature to myelinating cells required for white matter growth. Although immature neurons appear to be more resistant to cell death from hypoxia-ischemia than glia, they display widespread disturbances in maturation of their dendritic arbors, which further contribute to impaired cerebral growth. These complex and disparate responses of neurons and preOLs thus result in large numbers of cells that fail to fully mature during a critical window in development of neural circuitry. These recently recognized forms of cerebral gray and white matter dysmaturation raise new diagnostic challenges and suggest new therapeutic directions centered on reversal of the processes that promote dysmaturation. Ann Neurol 2014;75:469-486 © 2014 American Neurological Association.


Patent
Roche Holding AG, Hoffmann-La Roche and University of Toronto | Date: 2012-09-12

The invention relates to a method for assessing heart failure in vitro comprising the steps of measuring in a sample the concentration of the marker IGFBP-7, of optionally measuring in the sample the concentration of one or more other marker(s) of heart failure, and of assessing heart failure by comparing the concentration determined in for IGFBP-7 and the concentration(s) determined for the optionally one or more other marker to the concentration of this marker or these markers as established in a reference population. Also disclosed are the use of IGFBP-7 as a marker protein in the assessment of heart failure, a marker combination comprising IGFBP-7 and a kit for measuring IGFBP-7.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: KBBE-2009-3-5-01 | Award Amount: 4.52M | Year: 2010

MAGICPAH aims to explore, understand and exploit the catalytic activities of microbial communities involved in the degradation of persistent PAHs. It will integrate (meta-) genomic studies with in-situ activity assessment based on stable isotope probing particularly in complex matrices of different terrestrial and marine environments. PAH degradation under various conditions of bioavailability will be assessed as to improve rational exploitation of the catalytic properties of bacteria for the treatment and prevention of PAH pollution. We will generate a knowledge base not only on the microbial catabolome for biodegradation of PAHs in various impacted environmental settings based on genome gazing, retrieval and characterization of specific enzymes but also on systems related bioavailability of contaminant mixtures. MAGICPAH takes into account the tremendous undiscovered metagenomic resources by the direct retrieval from genome/metagenome libraries and consequent characterization of enzymes through activity screens. These screens will include a high-end functional small-molecule fluorescence screening platform and will allow us to directly access novel metabolic reactions followed by their rational exploitation for biocatalysis and the re-construction of biodegradation networks. Results from (meta-) genomic approaches will be correlated with microbial in situ activity assessments, specifically dedicated to identifying key players and key reactions involved in anaerobic PAH metabolism. Key processes for PAH metabolism particularly in marine and composting environments and the kinetics of aerobic degradation of PAH under different conditions of bioavailability will be assessed in model systems, the rational manipulation of which will allow us to deduce correlations between system performance and genomic blueprint. The results will be used to improve treatments of PAH-contaminated sites.


Patent
Reflexion Pharmaceuticals Inc. and University of Toronto | Date: 2016-02-29

GB1 peptidic compounds that specifically bind to a hemagglutinin target protein, and libraries that include the same, as well as methods of making and using the same, are provided. Also provided are methods and compositions for making and using the compounds. Also provided are hemagglutinin mimics and fragments and methods of using the same, including methods of screening for GB1 peptidic compounds and methods of using conjugates the mimics as influenza A vaccines. Aspects of the invention include methods of screening libraries of L-peptidic compounds for specific binding to a D-peptidic hemagglutinin target protein. Once a L-peptidic compound has been identified that specifically binds to the D-peptidic hemagglutinin target protein, the D-enantiomer of the selected L-peptidic compound may be produced. In some embodiments, the D-enantiomer of the selected L-peptidic compound binds to, and in some instances, neutralizes influenza virus particles.


Patent
Reflexion Pharmaceuticals Inc. and University of Toronto | Date: 2016-02-01

Methods and compositions for identifying D-peptidic compounds that specifically bind target proteins are provided. Aspects of the methods include screening libraries of 20 residue or more L-peptidic compounds for specific binding to 40 residue or more D-target proteins. Once a L-peptidic compound has been identified that specifically binds to the D-target protein, the D-enantiomer of that compound may be produced.


Toplak M.E.,York University | West R.F.,James Madison University | Stanovich K.E.,University of Toronto
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2013

Background: Both performance-based and rating measures are commonly used to index executive function in clinical and neuropsychological assessments. They are intended to index the same broad underlying mental construct of executive function. The association between these two types of measures was investigated in the current article. Method and Results: We examined the association between performance-based and rating measures of executive function in 20 studies. These studies included 13 child and 7 adult samples, which were derived from 7 clinical, 2 nonclinical, and 11 combined clinical and nonclinical samples. Only 68 (24%) of the 286 relevant correlations reported in these studies were statistically significant, and the overall median correlation was only.19. Conclusions: It was concluded that performance-based and rating measures of executive function assess different underlying mental constructs. We discuss how these two types of measures appear to capture different levels of cognition, namely, the efficiency of cognitive abilities and success in goal pursuit. Clinical implications of using performance-based and rating measures of executive function are discussed, including the use of these measures in assessing ADHD. © 2012 Association for Child and Adolescent Mental Health.


Hansen B.M.S.,University of California at Los Angeles | Murray N.,University of Toronto
Astrophysical Journal | Year: 2013

We present a Monte Carlo model for the structure of low-mass (total mass <25 M ⊕) planetary systems that form by the in situ gravitational assembly of planetary embryos into final planets. Our model includes distributions of mass, eccentricity, inclination, and period spacing that are based on the simulation of a disk of 20 M ⊕, forming planets around a solar-mass star, and assuming a power-law surface density distribution that drops with distance a as a -1.5. The output of the Monte Carlo model is then subjected to the selection effects that mimic the observations of a transiting planet search such as that performed by the Kepler satellite. The resulting comparison of the output to the properties of the observed sample yields an encouraging agreement in terms of the relative frequencies of multiple-planet systems and the distribution of the mutual inclinations when moderate tidal circularization is taken into account. The broad features of the period distribution and radius distribution can also be matched within this framework, although the model underpredicts the distribution of small period ratios. This likely indicates that some dissipation is still required in the formation process. The most striking deviation between the model and observations is in the ratio of single to multiple systems in that there are roughly 50% more single-planet candidates observed than are produced in any model population. This suggests that some systems must suffer additional attrition to reduce the number of planets or increase the range of inclinations. © 2013. The American Astronomical Society. All rights reserved.


Oishi S.,University of Virginia | Schimmack U.,University of Toronto
Journal of Personality and Social Psychology | Year: 2010

We tested the relation between residential mobility and well-being in a sample of 7,108 American adults who were followed for 10 years. The more residential moves participants had experienced as children, the lower the levels of well-being as adults. As predicted, however, the negative association between the number of residential moves and well-being was observed among introverts but not among extraverts. We further demonstrated that the negative association between residential mobility and well-being among introverts was explained by the relative lack of close social relationships. Finally, we found that introverts who had moved frequently as children were more likely to have died during the 10-year follow-up. Among extraverts, childhood residential mobility was unrelated to their mortality risk as adults. These findings indicate that residential moves can be a risk factor for introverts and that extraversion can be an interpersonal resource for social relationships and well-being in mobile societies. © 2010 American Psychological Association.


Heusch G.,University of Duisburg - Essen | Botker H.E.,Aarhus University Hospital | Przyklenk K.,Wayne State University | Redington A.,University of Toronto | Yellon D.,University College London
Journal of the American College of Cardiology | Year: 2015

In remote ischemic conditioning (RIC), brief, reversible episodes of ischemia with reperfusion in one vascular bed, tissue, or organ confer a global protective phenotype and render remote tissues and organs resistant to ischemia/reperfusion injury. The peripheral stimulus can be chemical, mechanical, or electrical and involves activation of peripheral sensory nerves. The signal transfer to the heart or other organs is through neuronal and humoral communications. Protection canbe transferred, even across species, with plasma-derived dialysate and involves nitric oxide, stromal derived factor-1a, microribonucleic acid-144, but also other, not yet identified factors. Intracardiac signal transduction involves: adenosine, bradykinin, cytokines, and chemokines, which activate specific receptors; intracellular kinases; and mitochondrial function. RIC by repeated brief inflation/deflation of a blood pressure cuff protects against endothelial dysfunction and myocardial injury in percutaneous coronary interventions, coronary artery bypass grafting, and reperfused acute myocardial infarction. RIC is safe and effective, noninvasive, easily feasible, and inexpensive. © 2015 by the American College of Cardiology Foundation.


Forman-Kay J.D.,Hospital for Sick Children | Forman-Kay J.D.,University of Toronto | Mittag T.,St Jude Childrens Research Hospital
Structure | Year: 2013

Intrinsically disordered proteins (IDPs), which lack persistent structure, are a challenge to structural biology due to the inapplicability of standard methods for characterization of folded proteins as well as their deviation from the dominant structure/function paradigm. Their widespread presence and involvement in biological function, however, has spurred the growing acceptance of the importance of IDPs and the development of new tools for studying their structure, dynamics, and function. The interplay of folded and disordered domains or regions for function and the existence of a continuum of protein states with respect to conformational energetics, motional timescales, and compactness are shaping a unified understanding of structure-dynamics-disorder/ function relationships. In the 20th anniversary of Structure, we provide a historical perspective on the investigation of IDPs and summarize the sequence features and physical forces that underlie their unique structural, functional, and evolutionary properties. © 2013 Elsevier Ltd.


Hui C.-C.,Hospital for Sick Children | Hui C.-C.,University of Toronto | Angers S.,University of Toronto
Annual Review of Cell and Developmental Biology | Year: 2011

Gli zinc-finger proteins are transcription factors involved in the intracellular signal transduction controlled by the Hedgehog family of secreted molecules. They are frequently mutated in human congenital malformations, and their abnormal regulation leads to tumorigenesis. Genetic studies in several model systems indicate that their activity is tightly regulated by Hedgehog signaling through various posttranslational modifications, including phosphorylation, ubiquitin-mediated degradation, and proteolytic processing, as well as through nucleocytoplasmic shuttling. In vertebrate cells, primary cilia are required for the sensing of Hedgehog pathway activity and involved in the processing and activation of Gli proteins. Two evolutionarily conserved Hedgehog pathway components, Suppressor of fused and Kif7, are core intracellular regulators of mammalian Gli proteins. Recent studies revealed that Gli proteins are also regulated transcriptionally and posttranslationally through noncanonical mechanisms independent of Hedgehog signaling. In this review, we describe the regulation of Gli proteins during development and discuss possible mechanisms for their abnormal activation during tumorigenesis. © 2011 by Annual Reviews. All rights reserved.


Sellwood J.A.,Rutgers University | Carlberg R.G.,University of Toronto
Astrophysical Journal | Year: 2014

We present evidence that recurrent spiral activity, long manifested in simulations of disk galaxies, results from the superposition of a few transient spiral modes. Each mode lasts between 5 and 10 rotations at its corotation radius where its amplitude is greatest. The scattering of stars as each wave decays takes place over narrow ranges of angular momentum, causing abrupt changes to the impedance of the disk to subsequent traveling waves. Partial reflections of waves at these newly created features allows new standing-wave instabilities to appear that saturate and decay in their turn, scattering particles at new locations, creating a recurring cycle. The spiral activity causes the general level of random motion to rise, gradually decreasing the ability of the disk to support further activity unless the disk contains a dissipative gas component from which stars form on near-circular orbits. We also show that this interpretation is consistent with the behavior reported in other recent simulations with low-mass disks. © 2014. The American Astronomical Society. All rights reserved..


Fasano A.,Toronto Western Hospital | Lozano A.M.,University of Toronto
Current Opinion in Neurology | Year: 2015

Purpose of review The purpose of this review was to review the recent and future developments of deep brain stimulation (DBS) for movement disorders. Recent findings In the last 2 years, we have gained a better understanding of established indications, particularly with respect to the debate on whether subthalamus or globus pallidus pars interna should be the target of choice for Parkinson's disease. In addition, the role of DBS for dystonia has been further defined in terms of patients' selection and outcome of surgery. Other established (e.g. essential tremor) and novel indications (e.g. Tourette syndrome) have been addressed. Along with the evolving knowledge of the clinical aspects of DBS, technological advances are also shaping the present and the future of DBS. New implantable pulse generators (e.g. allowing storage of electrophysiological data and eventual adaptive stimulation) as well as new electrode configurations are now available. Furthermore, high-resolution structural imaging, including high-field MRI and diffusion tensor tractography, will facilitate both the planning of DBS procedures, and the optimization of postoperative outcomes by aiding stimulation programming. Summary The recent successes of DBS along the clinical and technological directions are changing the current practice of neuromodulation and, more importantly, will also drive future developments of this fascinating treatment. © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Weiss M.W.,University of Toronto | Bidelman G.M.,University of Memphis
Journal of Neuroscience | Year: 2015

Auditory experiences including musicianship and bilingualism have been shown to enhance subcortical speech encoding operating below conscious awareness. Yet, the behavioral consequence of such enhanced subcortical auditory processing remains undetermined. Exploiting their remarkable fidelity, we examined the intelligibility of auditory playbacks (i.e., “sonifications”) of brainstem potentials recorded in human listeners. We found naive listeners’ behavioral classification of sonifications was faster and more categorical when evaluating brain responses recorded in individuals with extensive musical training versus those recorded in nonmusicians. These results reveal stronger behaviorally relevant speech cues in musicians’ neural representations and demonstrate causal evidence that superior subcortical processing creates a more comprehensible speech signal (i.e., to naive listeners). We infer that neural sonifications of speech-evoked brainstem responses could be used in the early detection of speech–language impairments due to neurodegenerative disorders, or in objectively measuring individual differences in speech reception solely by listening to individuals’ brain activity. ©2015 the authors.


Connolly B.S.,Hamilton Health Sciences | Lang A.E.,Toronto Western Hospital | Lang A.E.,University of Toronto
JAMA - Journal of the American Medical Association | Year: 2014

IMPORTANCE: Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life. OBJECTIVE: To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eyemovement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea. EVIDENCE REVIEW: References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic. RESULTS: Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, β-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies. CONCLUSIONS AND RELEVANCE: Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established. Copyright 2014 American Medical Association. All rights reserved.


Simor A.E.,Sunnybrook Health science Center | Simor A.E.,University of Toronto
The Lancet Infectious Diseases | Year: 2011

Staphylococcus aureus decolonisation-treatment to eradicate staphylococcal carriage-is often considered as a measure to prevent S aureus infection. The most common approach to decolonisation has been intranasal application of mupirocin either alone or in combination with antiseptic soaps or systemic antimicrobial agents. Some data support the use of decolonisation in surgical patients colonised with S aureus, particularly in those undergoing cardiothoracic procedures. Although this intervention has been associated with low rates of postoperative S aureus infection, whether overall rates of infection are also decreased is unclear. Patients undergoing chronic haemodialysis or peritoneal dialysis might benefit from decolonisation, although repeated courses of treatment are needed, and the effects are modest. Eradication of meticillin-resistant S aureus (MRSA) carriage has generally been difficult, and the role of decolonisation as an MRSA infection control measure is uncertain. The efficacy of decolonisation of patients with community-associated MRSA has not been established, and the routine use of decolonisation of non-surgical patients is not supported by data. © 2011 Elsevier Ltd.


Patent
Sunnybrook Health Science Center and University of Toronto | Date: 2013-07-22

The present disclosure discloses a bone stabilization device (also referred to as a bone tape), which includes a composite flexible construct including a rigidifiable biocompatible sheet structure having first and second opposed surfaces. A biocompatible cement is located on the first surface. In use the composite flexible construct is applied to a bone with the cement contacted directly to the bone. The cement is made of a material that, once adhered to the bone, is curable to mechanically and/or ionically bond to the sheet structure and to chemically bond to the bone to achieve a permanent bond. The bone tape allows simultaneous alignment and stabilization of multiple articulated fragments for successful 3D reconstruction of shattered bones. Initial flexibility and translucency provided by the bone tape can facilitate the temporary stabilization and alignment adjustment of multiple fragments, prior to permanent rigid bonding.


Sigmond M.,University of Toronto | Scinocca J.F.,Canadian Center for Climate Modelling and Analysis
Journal of Climate | Year: 2010

Employing a comprehensive atmospheric general circulation model, the authors have shown in a previous study that the time-mean Northern Hemisphere (NH) winter circulation response to a CO2 doubling perturbation depends significantly on parameterized orographic gravity wave drag (OGWD) parameter settings, which are essentially related to the strength of OGWD. A possible implication is that aspects of the greenhouse gas-induced circulation response could depend directly on the formulation and internal parameters settings of the OGWD scheme. Such a result would further heighten the importance of OGWD parameterizations for climate studies and have far-reaching implications for modeled projections of future climate change. In this study the causal relationship between OGWD and changes in time-mean NH wintertime circulation response to CO2 doubling is investigated. This is accomplished by introducing a methodology that allows one to hold the OGWD forcing fixed to its 1 × CO2 value when CO2 is doubled. Employing this methodology for perturbation experiments with different strengths of OGWD, the authors find that the changes in OGWD forcing due to CO2 doubling have essentially no impact on the time-mean zonal-mean zonal wind response. The primary conclusion is that the OGWD influence is limited to its impact on the 1 × CO2 basic-state climatology, which defines the propagation characteristics of resolved waves. Different strengths of OGWD result in control basic states with different refractive properties for the resolved waves. It is shown that the action of resolved waves, as well as their sensitivity to such differences in the control climatology, explains essentially all of the NH wintertime circulation sensitivity identified here and in a previous study. Implications for climate change projections and climate-model development are discussed. © 2010 American Meteorological Society.


Ting J.J.,University of Toronto | Ting J.J.,University of Maryland University College
PLoS biology | Year: 2014

Conflict between the sexes over reproductive interests can drive rapid evolution of reproductive traits and promote speciation. Here we show that inter-species mating between Caenorhabditis nematodes sterilizes maternal individuals. The principal effectors of male-induced harm are sperm cells, which induce sterility and shorten lifespan by displacing conspecific sperm, invading the ovary, and sometimes breaching the gonad to infiltrate other tissues. This sperm-mediated harm is pervasive across species, but idiosyncrasies in its magnitude implicate both independent histories of sexually antagonistic coevolution within species and differences in reproductive mode (self-fertilizing hermaphrodites versus females) in determining its severity. Consistent with this conclusion, in androdioecious species the hermaphrodites are more vulnerable, the males more benign, or both. Patterns of assortative mating and a low incidence of invasive sperm occurring with conspecific mating are indicative of ongoing intra-specific sexual conflict that results in inter-species reproductive incompatibility.


Nishiyama A.,French National Center for Scientific Research | Frappier L.,University of Toronto | Mechali M.,French National Center for Scientific Research
Genes and Development | Year: 2011

Origins of DNA replication are licensed by recruiting MCM2-7 to assemble the prereplicative complex (pre-RC). How MCM2-7 is inactivated or removed from chromatin at the end of S phase is still unclear. Here, we show that MCM-BP can disassemble the MCM2-7 complex and might function as an unloader of MCM2-7 from chromatin. In Xenopus egg extracts, MCM-BP exists in a stable complex with MCM7, but is not associated with the MCM2-7 hexameric complex. MCM-BP accumulates in nuclei in late S phase, well after the loading of MCM2-7 onto chromatin. MCM-BP immunodepletion in Xenopus egg extracts inhibits replication-dependent MCM dissociation without affecting pre-RC formation and DNA replication. When excess MCM-BP is incubated with Xenopus egg extracts or immunopurified MCM2-7, it binds to MCM proteins and promotes disassembly of the MCM2-7 complex. Recombinant MCM-BP also releases MCM2-7 from isolated late-S-phase chromatin, but this activity is abolished when DNA replication is blocked. MCM-BP silencing in human cells also delays MCM dissociation in late S phase. We propose that MCM-BP plays a key role in the mechanism by which pre-RC is cleared from replicated DNA in vertebrate cells. © 2011 by Cold Spring Harbor Laboratory Press.


Jeschke M.G.,University of Toronto | Jeschke M.G.,Sunnybrook Research Institute | Herndon D.N.,University of Texas Medical Branch
The Lancet | Year: 2014

Outcomes of patients with burns have improved substantially over the past two decades. Findings from a 2012 study in The Lancet showed that a burn size of more than 60% total body surface area burned (an increase from 40% a decade ago) is associated with risks and mortality. Similar data have been obtained in adults and elderly people who have been severely burned. We discuss recent and future developments in burn care to improve outcomes of children.


Patent
University of Toronto and Roche Holding AG | Date: 2012-01-26

The disclosure relates to assessing heart failure in vitro by measuring the concentration of the marker mimecan in a sample, and optionally measuring in the sample the concentration of one or more other marker(s) of heart failure, and of assessing heart failure by comparing the concentration of mimecan and the one or more other marker(s) to reference concentrations of this (or these) marker(s) as established in a reference population. The one or more markers may be selected from the group comprising a natriuretic peptide marker, a cardiac troponin marker, and a marker of inflammation. Also disclosed are the use of mimecan as a marker protein in the assessment of heart failure, a marker combination comprising mimecan, and a kit for measuring mimecan.


Patent
Yeshiva University, University of Toronto and Government Of The United States | Date: 2014-05-30

The present invention addresses a need for improved treatments for filovirus infections.


Patent
Roche Holding AG and University of Toronto | Date: 2014-11-13

The invention relates to a method for assessing heart failure in vitro comprising the steps of measuring in a sample the concentration of the marker IGFBP-7, of optionally measuring in the sample the concentration of one or more other marker(s) of heart failure, and of assessing heart failure by comparing the concentration determined in for IGFBP-7 and the concentration(s) determined for the optionally one or more other marker to the concentration of this marker or these markers as established in a reference population. Also disclosed are the use of IGFBP-7 as a marker protein in the assessment of heart failure, a marker combination comprising IGFBP-7 and a kit for measuring IGFBP-7.


Patent
Roche Holding AG and University of Toronto | Date: 2016-01-27

The invention relates to a method for assessing heart failure in vitro comprising the steps of measuring in a sample the concentration of the marker CRYAB, of optionally measuring in the sample the concentration of one or more other marker(s) of heart failure selected from the group consisting of a natriuretic peptide marker, a cardiac troponin marker, and a marker of inflammation, and of assessing heart failure by comparing the concentration determined in for CRYAB and the concentration(s) determined for the optionally one or more other marker to the concentration of this marker or these markers as established in a reference population. Also disclosed are the use of CRYAB as a marker protein in the assessment of heart failure, a marker combination comprising CRYAB and a kit for measuring CRYAB.


Patent
University of Toronto and Roche Holding AG | Date: 2014-02-14

Disclosed is a method for assessing heart failure in vitro including the steps of measuring in a sample the concentration of the marker SFRP-3, of optionally measuring in the sample the concentration of one or more other marker(s) of heart failure, and of assessing heart failure by comparing the concentration determined in for SFRP-3 and the concentration(s) determined for the optionally one or more other marker to the concentration of this marker or these markers as established in a reference population. Also disclosed are the use of SFRP-3 as a marker protein in the assessment of heart failure, a marker combination comprising SFRP-3 and a kit for measuring SFRP-3.


Patent
Roche Holding AG and University of Toronto | Date: 2016-10-05

Disclosed is a method for assessing heart failure in vitro including the steps of measuring in a sample the concentration of the marker IGFBP-7, of optionally measuring in the sample the concentration of one or more other marker(s) of heart failure, and of assessing heart failure by comparing the concentration determined in for IGFBP-7 and the concentration(s) determined for the optionally one or more other marker to the concentration of this marker or these markers as established in a reference population. Also disclosed are the use of IGFBP-7 as a marker protein in the assessment of heart failure, a marker combination comprising IGFBP-7 and a kit for measuring IGFBP-7.


Grusec J.E.,University of Toronto | Davidov M.,Hebrew University of Jerusalem
Child Development | Year: 2010

There are several different theoretical and research approaches to the study of socialization, characterized by frequently competing basic tenets and apparently contradictory evidence. As a way of integrating approaches and understanding discrepancies, it is proposed that socialization processes be viewed from a domain perspective, with each domain characterized by a particular form of social interaction between the object and agent of socialization and by specific socialization mechanisms and outcomes. It is argued that this approach requires researchers to identify the domain of social interaction they are investigating, to understand that phenotypically similar behaviors may belong to different domains, and to acknowledge that caregivers who are effective in one type of interaction may not be effective in another. © 2010, Copyright the Author(s). Journal Compilation © 2010, Society for Research in Child Development, Inc.


Smith M.R.,University of Cambridge | Caron J.-B.,Royal Ontario Museum | Caron J.-B.,University of Toronto
Nature | Year: 2015

The molecularly defined clade Ecdysozoa comprises the panarthropods (Euarthropoda, Onychophora and Tardigrada) and the cycloneuralian worms (Nematoda, Nematomorpha, Priapulida, Loricifera and Kinorhyncha). These disparate phyla are united by their means of moulting, but otherwise share few morphological characters-none of which has a meaningful fossilization potential. As such, the early evolutionary history of the group as a whole is largely uncharted. Here we redescribe the 508-million-year-old stem-group onychophoran Hallucigenia sparsa from the mid-Cambrian Burgess Shale. We document an elongate head with a pair of simple eyes, a terminal buccal chamber containing a radial array of sclerotized elements, and a differentiated foregut that is lined with acicular teeth. The radial elements and pharyngeal teeth resemble the sclerotized circumoral elements and pharyngeal teeth expressed in tardigrades, stem-group euarthropods and cycloneuralian worms. Phylogenetic results indicate that equivalent structures characterized the ancestral panarthropod and, seemingly, the ancestral ecdysozoan, demonstrating the deep homology of panarthropod and cycloneuralian mouthparts, and providing an anatomical synapomorphy for the ecdysozoan supergroup. © 2015 Macmillan Publishers Limited. All rights reserved.


Chenu A.,University of Toronto | Scholes G.D.,University of Toronto | Scholes G.D.,Princeton University
Annual Review of Physical Chemistry | Year: 2015

Ultrafast energy transfer is used to transmit electronic excitation among the many molecules in photosynthetic antenna complexes. Recent experiments and theories have highlighted the role of coherent transfer in femtosecond studies of these proteins, suggesting the need for accurate dynamical models to capture the subtle characteristics of energy transfer mechanisms. Here we discuss how to think about coherence in light harvesting and electronic energy transfer. We review the various fundamental concepts of coherence, spanning from classical phenomena to the quantum superposition, and define coherence in electronic energy transfer. We describe the current status of experimental studies on light-harvesting complexes. Insights into the microscopic process are presented to highlight how and why this is a challenging problem to elucidate. We present an overview of the applicable dynamical theories to model energy transfer in the intermediate coupling regime. © 2015 by Annual Reviews. All rights reserved.


Kipps E.,Royal Marsden Hospital Medicine | Tan D.S.P.,University of Toronto | Kaye S.B.,Royal Marsden NHS Foundation Trust
Nature Reviews Cancer | Year: 2013

Malignant ascites presents a considerable clinical challenge to the management of ovarian cancer, but also provides a wealth of opportunities for translational research. The accessibility of ascitic fluid and its cellular components make it an excellent source of tumour tissue for the investigation of prognostic and predictive biomarkers, pharmacodynamic markers and for molecular profiling analysis. In this Opinion article, we discuss recent advances in our understanding of its pathophysiology, the development of new methods to characterize its molecular features and how these findings can be used to improve the treatment of malignant ascites, particularly in the context of ovarian cancer. © 2013 Macmillan Publishers Limited. All rights reserved.


Campione N.E.,University of Toronto | Evans D.C.,Royal Ontario Museum
BMC Biology | Year: 2012

Background: Body size is intimately related to the physiology and ecology of an organism. Therefore, accurate and consistent body mass estimates are essential for inferring numerous aspects of paleobiology in extinct taxa, and investigating large-scale evolutionary and ecological patterns in the history of life. Scaling relationships between skeletal measurements and body mass in birds and mammals are commonly used to predict body mass in extinct members of these crown clades, but the applicability of these models for predicting mass in more distantly related stem taxa, such as non-avian dinosaurs and non-mammalian synapsids, has been criticized on biomechanical grounds. Here we test the major criticisms of scaling methods for estimating body mass using an extensive dataset of mammalian and non-avian reptilian species derived from individual skeletons with live weights.Results: Significant differences in the limb scaling of mammals and reptiles are noted in comparisons of limb proportions and limb length to body mass. Remarkably, however, the relationship between proximal (stylopodial) limb bone circumference and body mass is highly conserved in extant terrestrial mammals and reptiles, in spite of their disparate limb postures, gaits, and phylogenetic histories. As a result, we are able to conclusively reject the main criticisms of scaling methods that question the applicability of a universal scaling equation for estimating body mass in distantly related taxa.Conclusions: The conserved nature of the relationship between stylopodial circumference and body mass suggests that the minimum diaphyseal circumference of the major weight-bearing bones is only weakly influenced by the varied forces exerted on the limbs (that is, compression or torsion) and most strongly related to the mass of the animal. Our results, therefore, provide a much-needed, robust, phylogenetically corrected framework for accurate and consistent estimation of body mass in extinct terrestrial quadrupeds, which is important for a wide range of paleobiological studies (including growth rates, metabolism, and energetics) and meta-analyses of body size evolution. © 2012 Campione and Evans; licensee BioMed Central Ltd.


Braverman M.,Princeton University | Braverman M.,University of Toronto
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2012

The primary goal of this paper is to define and study the interactive information complexity of functions. Let f(x,y) be a function, and suppose Alice is given x and Bob is given y. Informally, the interactive information complexity IC(f) of f is the least amount of information Alice and Bob need to reveal to each other to compute f. Previously, information complexity has been defined with respect to a prior distribution on the input pairs (x,y). Our first goal is to give a definition that is independent of the prior distribution. We show that several possible definitions are essentially equivalent. We establish some basic properties of the interactive information complexity IC(f). In particular, we show that IC(f) is equal to the amortized (randomized) communication complexity of f. We also show a direct sum theorem for IC(f) and give the first general connection between information complexity and (non-amortized) communication complexity. This connection implies that a non-trivial exchange of information is required when solving problems that have non-trivial communication complexity. We explore the information complexity of two specific problems - Equality and Disjointness. We show that only a constant amount of information needs to be exchanged when solving Equality with no errors, while solving Disjointness with a constant error probability requires the parties to reveal a linear amount of information to each other. © 2012 ACM.


Grant
Agency: Cordis | Branch: FP7 | Program: ERC-AG | Phase: ERC-AG-SH2 | Award Amount: 2.50M | Year: 2012

A well-functioning democracy implies that political actors are aware of the real problems in society, their potential solutions, and the associated preferences of citizens. This requires information about the real world. This project examines how individual political actors process information coming out of society. Its goal is to lay bare the patterns whereby exposure to certain types of information regarding problems lead to specific forms of attention to that information triggering particular kinds of action by political actors. For the first time, this project tackles the information-processing of political actors in a direct, encompassing and comparative manner. Drawing on previous work on agenda-setting, on bounded rationality and on representation the project first develops a theory of individual political actors dealing with information. Information-processing depends on properties of the source of information, of the message itself, and of the receiver of the information. Laying bare the information streams and information-processing of political actors is complex. The study assesses the behavior of political actors in three countries (Belgium, Canada and Israel) and across actors different institutional positions (MPs, ministers, party leaders). I expect to find differences between institutional position of actors and between nations. In fact, the countries under study have very different political systems which should lead to a different information-processing behavior of elites. The heart of the empirical part of the project is an in-depth, almost ethnographic study of the information-processing of fifty politicians in each country. These actors are observed relying on (a) time-budgeting, (b) participatory observation, and (c) interviews. Apart from this sample of fifty actors, the entire population (or a large sample) of political actors will be scrutinized using (d) surveys, (e) experiments, and (f) behavioral records.


Grant
Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2013.9.3 | Award Amount: 1.18M | Year: 2013

To pave the way towards the widespread application of on-chip mid-infrared(MIR)-pumped nonlinear supercontinuum light sources, we want to introduce a paradigm shift in integrated nonlinear optics. Rather than relying on non-standard waveguide designs, large waveguide footprints, bulky MIR pump lasers and/or limited spectral coverage in strategies that could never comply with the requirements for widespread deployment, we target a major advance based on novel material physics and device design, eliminating these issues. Our goal is to develop a near-infrared(NIR)- and MIR-emitting, ultra-compact on-chip supercontinuum light source by exploiting practically unexplored optical nonlinearities of standard silicon waveguides covered with graphene. This groundbreaking dual-band source will be realized by cascading two devices which are based on graphene-covered standard silicon waveguides, and which enable for the first time broadband self-phase modulation in the MIR and power-efficient second harmonic generation in the NIR within an ultra-compact chip footprint. To ensure that the entire supercontinuum device including the pump laser is compact, we will in addition develop a novel, small-sized, and practical modelocked MIR Tm-Ho fiber laser to pump the supercontinuum generation. These breakthroughs carry a highly novel and foundational character, and fit very well within the framework of the FET Open FP7-ICT-2013-C call. Since the partners involved in this project have both the knowledge and the equipment to model, design, fabricate and pump graphene-based nonlinear optical devices, our consortium holds all necessary skills required to successfully carry out this high-gain/high-risk project. In doing so, we will lay the foundations for graphene-on-silicon-based nonlinear photonic integrated circuits, and at the same time pave the way to the extensive use of on-chip supercontinuum light sources in real-life applications.


Feinstein A.,University of Toronto | Freeman J.,University of Plymouth | Lo A.C.,Brown University
The Lancet Neurology | Year: 2015

Disease-modifying drugs have mostly failed as treatments for progressive multiple sclerosis. Management of the disease therefore solely aims to minimise symptoms and, if possible, improve function. The degree to which this approach is based on empirical data derived from studies of progressive disease or whether treatment decisions are based on what is known about relapsing-remitting disease remains unclear. Symptoms rated as important by patients with multiple sclerosis include balance and mobility impairments, weakness, reduced cardiovascular fitness, ataxia, fatigue, bladder dysfunction, spasticity, pain, cognitive deficits, depression, and pseudobulbar affect; a comprehensive literature search shows a notable paucity of studies devoted solely to these symptoms in progressive multiple sclerosis, which translates to few proven therapeutic options in the clinic. A new strategy that can be used in future rehabilitation trials is therefore needed, with the adoption of approaches that look beyond single interventions to concurrent, potentially synergistic, treatments that maximise what remains of neural plasticity in patients with progressive multiple sclerosis. © 2015 Elsevier Ltd.


Chou L.Y.T.,Institute of Biomaterials and Biomedical Engineering | Zagorovsky K.,Institute of Biomaterials and Biomedical Engineering | Chan W.C.W.,Institute of Biomaterials and Biomedical Engineering | Chan W.C.W.,University of Toronto | Chan W.C.W.,00 College Street
Nature Nanotechnology | Year: 2014

The assembly of nanomaterials using DNA can produce complex nanostructures, but the biological applications of these structures remain unexplored. Here, we describe the use of DNA to control the biological delivery and elimination of inorganic nanoparticles by organizing them into colloidal superstructures. The individual nanoparticles serve as building blocks, whose size, surface chemistry and assembly architecture dictate the overall superstructure design. These superstructures interact with cells and tissues as a function of their design, but subsequently degrade into building blocks that can escape biological sequestration. We demonstrate that this strategy reduces nanoparticle retention by macrophages and improves their in vivo tumour accumulation and whole-body elimination. Superstructures can be further functionalized to carry and protect imaging or therapeutic agents against enzymatic degradation. These results suggest a different strategy to engineer nanostructure interactions with biological systems and highlight new directions in the design of biodegradable and multifunctional nanomedicine. © 2014 Macmillan Publishers Limited. All rights reserved.


Siu S.C.,University of Western Ontario | Siu S.C.,University of Toronto | Silversides C.K.,University of Toronto
Journal of the American College of Cardiology | Year: 2010

Bicuspid aortic valve (BAV) disease is the most common congenital cardiac defect. While the BAV can be found in isolation, it is often associated with other congenital cardiac lesions. The most frequent associated finding is dilation of the proximal ascending aorta secondary to abnormalities of the aortic media. Changes in the aortic media are present independent of whether the valve is functionally normal, stenotic, or incompetent. Although symptoms often manifest in adulthood, there is a wide spectrum of presentations ranging from severe disease detected in utero to asymptomatic disease in old age. Complications can include aortic valve stenosis or incompetence, endocarditis, aortic aneurysm formation, and aortic dissection. Despite the potential complications, 2 large contemporary series have demonstrated that life expectancy in adults with BAV disease is not shortened when compared with the general population. Because BAV is a disease of both the valve and the aorta, surgical decision making is more complicated, and many undergoing aortic valve replacement will also need aortic root surgery. With or without surgery, patients with BAV require continued surveillance. Recent studies have improved our understanding of the genetics, the pathobiology, and the clinical course of the disease, but questions are still unanswered. In the future, medical treatment strategies and timing of interventions will likely be refined. This review summarizes our current understanding of the pathology, genetics, and clinical aspects of BAV disease with a focus on BAV disease in adulthood. © 2010 American College of Cardiology Foundation.


Wallace J.L.,University of Calgary | Wallace J.L.,University of Toronto | Wang R.,Lakehead University
Nature Reviews Drug Discovery | Year: 2015

Hydrogen sulfide (H 2 S) has become recognized as an important signalling molecule throughout the body, contributing to many physiological and pathological processes. In recent years, improved methods for measuring H 2 S levels and the availability of a wider range of H 2 S donors and more selective inhibitors of H 2 S synthesis have helped to more accurately identify the many biological effects of this highly reactive gaseous mediator. Animal studies of several H 2 S-releasing drugs have demonstrated considerable promise for the safe treatment of a wide range of disorders. Several such drugs are now in clinical trials. © 2015 Macmillan Publishers Limited.


Sivak J.M.,University of Western Ontario | Sivak J.M.,University of Toronto
Investigative Ophthalmology and Visual Science | Year: 2013

Alzheimer's disease (AD) is a common, incurable, and progressive dementia, characterized by loss of learning and memory and the neuropathologic accumulation of amyloid plaques and neurofibrillary tangles in the brain. A number of similarities between AD pathology and several distinct retinal degenerations have been described, particularly with respect to either glaucoma or age-related macular degeneration (AMD), each a leading cause of vision loss and blindness worldwide. Although comparisons between these diseases may provide important new insights into their pathogenic mechanisms, glaucoma and AMD result in markedly different degenerations. Therefore, analyses of the differences and the similarities between these conditions may prove equally productive. Common mechanisms that appear to underlie all three diseases are explored here, as well as potential use of the retina as a biomarker for AD diagnosis and progression. Based on this comparison, past and current efforts to transfer therapeutic strategies between diseases are discussed. © 2013 The Association for Research in Vision and Ophthalmology, Inc.


Patent
University of Toronto and University of Western Ontario | Date: 2013-03-27

The present invention relates to variant SH2 domains for binding a phosphotyrosine (pTyr)-containing peptide. The variant SH2 domains of the present invention include a parent SH2 domain having at least one amino acid substitution in a pre-defined region of 15 amino acid positions of the parent SR2 domain, wherein said at least one amino acid substitution increases the affinity of the variant SH2 domain for the pTyr-containing peptide relative to the parent SH2 domain. The present application relates also to methods of using the variant SH2 domains in the treatment of protein kinase-associated disorders, or the diagnosis or prognosis of protein kinase-associated disorders, for isolating and measuring the concentration of pTyr-containing molecules, and as reagents in research.


Patent
University of Toronto and Frontier Inc. | Date: 2012-05-18

Means are provided of increasing the growth potential and abiotic stress resistance in plants, characterized by expression of polynucleotides stably integrated into a plant genome or stably incorporated in the plant. Further provided are isolated nucleic acids and their stable inclusion in transgenic plants. The transgenic plants have shown desirable phenotypic characteristics when compared to control plants, for example, improved drought-resistance. Also taught are plants having increased growth potential due to improved abiotic stress resistance.


Stinchcombe J.R.,University of Toronto | Kirkpatrick M.,University of Texas at Austin
Trends in Ecology and Evolution | Year: 2012

Many central questions in ecology and evolutionary biology require characterizing phenotypes that change with time and environmental conditions. Such traits are inherently functions, and new 'function-valued' methods use the order, spacing, and functional nature of the data typically ignored by traditional univariate and multivariate analyses. These rapidly developing methods account for the continuous change in traits of interest in response to other variables, and are superior to traditional summary-based analyses for growth trajectories, morphological shapes, and environmentally sensitive phenotypes. Here, we explain how function-valued methods make flexible use of data and lead to new biological insights. These approaches frequently offer enhanced statistical power, a natural basis of interpretation, and are applicable to many existing data sets. We also illustrate applications of function-valued methods to address ecological, evolutionary, and behavioral hypotheses, and highlight future directions. © 2012 Elsevier Ltd.


Althoff D.M.,Syracuse University | Segraves K.A.,Syracuse University | Johnson M.T.J.,University of Toronto
Trends in Ecology and Evolution | Year: 2014

Coevolutionary diversification is cited as a major mechanism driving the evolution of diversity, particularly in plants and insects. However, tests of coevolutionary diversification have focused on elucidating macroevolutionary patterns rather than the processes giving rise to such patterns. Hence, there is weak evidence that coevolution promotes diversification. This is in part due to a lack of understanding about the mechanisms by which coevolution can cause speciation and the difficulty of integrating results across micro- and macroevolutionary scales. In this review, we highlight potential mechanisms of coevolutionary diversification, outline approaches to examine this process across temporal scales, and propose a set of minimal requirements for demonstrating coevolutionary diversification. Our aim is to stimulate research that tests more rigorously for coevolutionary diversification. © 2013 Elsevier Ltd.


Inzlicht M.,University of Toronto | Bartholow B.D.,University of Missouri | Hirsh J.B.,University of Toronto
Trends in Cognitive Sciences | Year: 2015

Often seen as the paragon of higher cognition, here we suggest that cognitive control is dependent on emotion. Rather than asking whether control is influenced by emotion, we ask whether control itself can be understood as an emotional process. Reviewing converging evidence from cybernetics, animal research, cognitive neuroscience, and social and personality psychology, we suggest that cognitive control is initiated when goal conflicts evoke phasic changes to emotional primitives that both focus attention on the presence of goal conflicts and energize conflict resolution to support goal-directed behavior. Critically, we propose that emotion is not an inert byproduct of conflict but is instrumental in recruiting control. Appreciating the emotional foundations of control leads to testable predictions that can spur future research. © 2015 Elsevier Ltd.


Wilcox M.E.,University of Toronto | Adhikari N.K.J.,Sunnybrook Research Institute
Critical Care | Year: 2012

Introduction: Telemedicine extends intensivists' reach to critically ill patients cared for by other physicians. Our objective was to evaluate the impact of telemedicine on patients' outcomes.Methods: We searched electronic databases through April 2012, bibliographies of included trials, and indexes and conference proceedings in two journals (2001 to 2012). We selected controlled trials or observational studies of critically ill adults or children, examining the effects of telemedicine on mortality. Two authors independently selected studies and extracted data on outcomes (mortality and length of stay in the intensive care unit (ICU) and hospital) and methodologic quality. We used random-effects meta-analytic models unadjusted for case mix or cluster effects and quantified between-study heterogeneity by using I 2(the percentage of total variability across studies attributable to heterogeneity rather than to chance).Results: Of 865 citations, 11 observational studies met selection criteria. Overall quality was moderate (mean score on Newcastle-Ottawa scale, 5.1/9; range, 3 to 9). Meta-analyses showed that telemedicine, compared with standard care, is associated with lower ICU mortality (risk ratio (RR) 0.79; 95% confidence interval (CI), 0.65 to 0.96; nine studies, n = 23,526; I 2= 70%) and hospital mortality (RR, 0.83; 95% CI, 0.73 to 0.94; nine studies, n = 47,943; I 2= 72%). Interventions with continuous patient-data monitoring, with or without alerts, reduced ICU mortality (RR, 0.78; 95% CI, 0.64 to 0.95; six studies, n = 21,384; I 2= 74%) versus those with remote intensivist consultation only (RR, 0.64; 95% CI, 0.20 to 2.07; three studies, n = 2,142; I 2= 71%), but effects were statistically similar (interaction P = 0.74). Effects were also similar in higher (RR, 0.83; 95% CI, 0.68 to 1.02) versus lower (RR, 0.69; 95% CI, 0.40 to 1.19; interaction, P = 0.53) quality studies. Reductions in ICU and hospital length of stay were statistically significant (weighted mean difference (telemedicine-control), -0.62 days; 95% CI, -1.21 to -0.04 days and -1.26 days; 95% CI, -2.49 to -0.03 days, respectively; I 2> 90% for both).Conclusions: Telemedicine was associated with lower ICU and hospital mortality among critically ill patients, although effects varied among studies and may be overestimated in nonrandomized designs. The optimal telemedicine technology configuration and dose tailored to ICU organization and case mix remain unclear. © 2012 Wilcox et al.; licensee BioMed Central Ltd.


Panier S.,Sinai University | Panier S.,Cancer Research UK Research Institute | Durocher D.,Sinai University | Durocher D.,University of Toronto
Nature Reviews Molecular Cell Biology | Year: 2013

Single DNA lesions such as DNA double-strand breaks (DSBs) can cause cell death or trigger genome rearrangements that have oncogenic potential, and so the pathways that mend and signal DNA damage must be highly sensitive but, at the same time, selective and reversible. When initiated, boundaries must be set to restrict the DSB response to the site of the lesion. The integration of positive and, crucially, negative control points involving post-translational modifications such as phosphorylation, ubiquitylation and acetylation is key for building fast, effective responses to DNA damage and for mitigating the impact of DNA lesions on genome integrity. © 2013 Macmillan Publishers Limited. All rights reserved.


Etiope G.,Italian National Institute of Geophysics and Volcanology | Etiope G.,Babes - Bolyai University | Sherwood Lollar B.,University of Toronto
Reviews of Geophysics | Year: 2013

Over the last 30 years, geochemical research has demonstrated that abiotic methane (CH4), formed by chemical reactions which do not directly involve organic matter, occurs on Earth in several specific geologic environments. It can be produced by either high-temperature magmatic processes in volcanic and geothermal areas, or via low-temperature (<100°C) gas-water-rock reactions in continental settings, even at shallow depths. The isotopic composition of C and H is a first step in distinguishing abiotic from biotic (including either microbial or thermogenic) CH4. Herein we demonstrate that integrated geochemical diagnostic techniques, based on molecular composition of associated gases, noble gas isotopes, mixing models, and a detailed knowledge of the geologic and hydrogeologic context are necessary to confirm the occurrence of abiotic CH4 in natural gases, which are frequently mixtures of multiple sources. Although it has been traditionally assumed that abiotic CH4 is mainly related to mantle-derived or magmatic processes, a new generation of data is showing that low-temperature synthesis related to gas-water-rock reactions is more common than previously thought. This paper reviews the major sources of abiotic CH4 and the primary approaches for differentiating abiotic from biotic CH4, including novel potential tools such as clumped isotope geochemistry. A diagnostic approach for differentiation is proposed. Key Points Abiotic CH4 occurs in specific geologic areas under a wide range of temperature Updated global CH4 isotopic diagram is provided Integration of geochemical-geological data necessary to determine abiotic origin © 2013. American Geophysical Union. All Rights Reserved.


Gorbunov S.,University of Toronto | Vaikuntanathan V.,University of Toronto | Wee H.,George Washington University
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2013

In an attribute-based encryption (ABE) scheme, a ciphertext is associated with an ℓ-bit public index ind and a message m, and a secret key is associated with a Boolean predicate P. The secret key allows to decrypt the ciphertext and learn m iff P(ind) = 1. Moreover, the scheme should be secure against collusions of users, namely, given secret keys for polynomially many predicates, an adversary learns nothing about the message if none of the secret keys can individually decrypt the ciphertext. We present attribute-based encryption schemes for circuits of any arbitrary polynomial size, where the public parameters and the ciphertext grow linearly with the depth of the circuit. Our construction is secure under the standard learning with errors (LWE) assumption. Previous constructions of attribute-based encryption were for Boolean formulas, captured by the complexity class NC1. In the course of our construction, we present a new framework for constructing ABE schemes. As a by-product of our framework, we obtain ABE schemes for polynomialsize branching programs, corresponding to the complexity class LOGSPACE, under quantitatively better assumptions. Copyright 2013 ACM.


Khisti A.,University of Toronto | Wornell G.W.,Massachusetts Institute of Technology
IEEE Transactions on Information Theory | Year: 2010

The role of multiple antennas for secure communication is investigated within the framework of Wyner's wiretap channel. We characterize the secrecy capacity in terms of generalized eigenvalues when the sender and eavesdropper have multiple antennas, the intended receiver has a single antenna, and the channel matrices are fixed and known to all the terminals, and show that a beamforming strategy is capacity-achieving. In addition, we study a masked beamforming scheme that radiates power isotropically in all directions and show that it attains near-optimal performance in the high SNR regime. Insights into the scaling behavior of the capacity in the large antenna regime as well as extensions to ergodic fading channels are also provided. © 2006 IEEE.


Khisti A.,University of Toronto | Wornell G.W.,Massachusetts Institute of Technology
IEEE Transactions on Information Theory | Year: 2010

The capacity of the Gaussian wiretap channel model is analyzed when there are multiple antennas at the sender, intended receiver and eavesdropper. The associated channel matrices are fixed and known to all the terminals. A computable characterization of the secrecy capacity is established as the saddle point solution to a minimax problem. The converse is based on a Sato-type argument used in other broadcast settings, and the coding theorem is based on Gaussian wiretap codebooks. © 2006 IEEE.


Patent
University of Toronto and University of Central Florida | Date: 2013-11-10

The present invention provides compounds S3I-201.1066 (Formula 1) and S3I-201.2096 (Formula 2) as selective Stat3 binding agents that block Stat3 association with cognate receptor pTyr motifs, Stat3 phosphorylation and nuclear translocation, Stat3 transcriptional function, and consequently induced Stat3-specific antitumor cell effects in vitro and antitumor response in vivo.


Patent
University of Central Florida and University of Toronto | Date: 2014-08-05

In one aspect, the invention relates to substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs, derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.


Clinical trials on low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over the right dorsolateral prefrontal cortex have yielded conflicting evidence concerning its overall efficacy for treating major depression (MD). As this may have been the result of limited statistical power of individual trials, we have carried the present systematic review and meta-analysis to examine this issue. We searched the literature for English language randomized, double-blind and sham-controlled trials (RCTs) on LF-rTMS for treating MD from 1995 through July 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses, and from October 2008 until July 2012 using MEDLINE. The main outcome measures were response and remission rates as well as overall dropout rates at study end. We used a random-effects model, odds ratios (ORs) and number needed to treat (NNT). Data were obtained from eight RCTs, totaling 263 subjects with MD. After an average of 12.6±3.9 rTMS sessions, 38.2% (50/131) and 15.1% (20/132) of subjects receiving active LF-rTMS and sham rTMS were classified as responders (OR=3.35; 95% CI=1.4-8.02; p=0.007). Also, 34.6% (35/101) and 9.7% (10/103) of subjects receiving active LF-rTMS and sham rTMS were classified as remitters (OR=4.76; 95% CI=2.13-10.64; p<0.0001). The associated NNT for both response and remission rates was 5. Sensitivity analyses have shown that protocols delivering >1200 magnetic pulses in total as well as those offering rTMS as a monotherapy for MD were associated with higher rates of response to treatment. No differences on mean baseline depression scores and dropout rates for active and sham rTMS groups were found. Finally, the risk of publication bias was low. In conclusion, LF-rTMS is a promising treatment for MD, as it provides clinically meaningful benefits that are comparable to those of standard antidepressants and high-frequency rTMS. Furthermore, LF-rTMS seems to be an acceptable intervention for depressed subjects. © 2013 American College of Neuropsychopharmacology. All rights reserved.


George I.J.,University of Leeds | Abbatt J.P.D.,University of Toronto
Nature Chemistry | Year: 2010

Atmospheric aerosol particles play pivotal roles in climate and air quality. Just as chemically reduced gases experience oxidation in the atmosphere, it is now apparent that solid and liquid atmospheric particulates are also subject to similar oxidative processes. The most reactive atmospheric gas-phase radicals, in particular the hydroxyl radical, readily promote such chemistry through surficial interactions. This Review looks at progress made in this field, discussing the radical-initiated heterogeneous oxidation of organic and inorganic constituents of atmospheric aerosols. We focus on the kinetics and reaction mechanisms of such processes as well as how they can affect the physicoĝ€"chemical properties of particles, such as their composition, size, density and hygroscopicity. Potential impacts on the atmosphere include the release of chemically reactive gases such as halogens, aldehydes and organic acids, reactive loss of particle-borne molecular tracer and toxic species, and enhanced hygroscopic properties of aerosols that may improve their ability to form cloud droplets. © 2010 Macmillan Publishers Limited. All rights reserved.


Maisonneuve C.,University of Toronto | Bertholet S.,Novartis | Philpott D.J.,University of Toronto | De Gregorio E.,Novartis
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Innate immunity confers an immediate nonspecific mechanism of microbial recognition through germ line-encoded pattern recognition receptors (PRRs). Of these, Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) have shaped our current understanding of innate regulation of adaptive immunity. It is now recognized that PRRs are paramount in instructing an appropriate adaptive immune response. Their ligands have been the focus of adjuvant research with the goal of generating modern vaccine combinations tailored to specific pathogens. In this review we will highlight the recent findings in the field of adjuvant research with a particular focus on the potential of TLR and NLR ligands as adjuvants and their influence on adaptive immune responses.


Saposnik G.,University of Toronto | Levin M.,McGill University
Stroke | Year: 2011

BACKGROUND AND PURPOSE-Approximately two thirds of stroke survivors continue to experience motor deficits of the arm resulting in diminished quality of life. Conventional rehabilitation provides modest and sometimes delayed effects. Virtual reality (VR) technology is a novel adjunctive therapy that could be applied in neurorehabilitation. We performed a meta-analysis to determine the added benefit of VR technology on arm motor recovery after stroke. METHODS-We searched Medline, EMBASE, and Cochrane literature from 1966 to July 2010 with the terms "stroke," "virtual reality," and "upper arm/extremity." We evaluated the effect of VR on motor function improvement after stroke. RESULTS-From the 35 studies identified, 12 met the inclusion/exclusion criteria totaling 195 participants. Among them, there were 5 randomized clinical trials and 7 observational studies with a pre-/postintervention design. Interventions were delivered within 4 to 6 weeks in 9 of the studies and within 2 to 3 weeks in the remaining 3. Eleven of 12 studies showed a significant benefit toward VR for the selected outcomes. In the pooled analysis of all 5 randomized controlled trials, the effect of VR on motor impairment (Fugl-Meyer) was OR=4.89 (95% CI, 1.31 to 18.3). No significant difference was observed for Box and Block Test or motor function. Among observational studies, there was a 14.7% (95% CI, 8.7%-23.6%) improvement in motor impairment and a 20.1% (95% CI, 11.0%-33.8%) improvement in motor function after VR. CONCLUSIONS-VR and video game applications are novel and potentially useful technologies that can be combined with conventional rehabilitation for upper arm improvement after stroke. © 2011 American Heart Association, Inc.


Rak J.,McGill University | Guha A.,University of Toronto
BioEssays | Year: 2012

Once regarded as cellular 'debris' extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor receptor, Ras), and tumour suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers. © 2012 WILEY Periodicals, Inc.


Grant
Agency: GTR | Branch: NERC | Program: | Phase: Research Grant | Award Amount: 313.86K | Year: 2014

This project is concerned with measuring changes in global rainfall and ensuring that computer models of the climate can predict how rainfall will change in the future. As carbon dioxide and other greenhouse gases are continually added to the atmosphere, it is understood that the temperature of the surface of the earth will rise. Warmer air can hold more moisture, so as the Earth warms the rate at which the atmosphere extracts water from the surface of the earth and dumps it back as rain will also increase. Knowing precisely how much global rates of rainfall will change into the future is important to many people including farmers wanting to know which crops to plant and nations wanting to build domestic water and hydroelectric infrastructure. Measuring the total rainfall around the world is no mean feat. On land, measurements are made directly (by catching the rain) or by reliable indirect methods based on river flow and how wet the soil is. However, two-thirds of the globe is covered by ocean. It is hard to catch rain in the middle of the ocean without actually being there to do it. Although many indirect methods exist for measuring rainfall over the ocean there is great uncertainty about how much rainfall has changed over the ocean in the last 50 years or so. Thankfully there is a solution. The ocean itself acts as a giant rain catcher. Water that falls as rain is fresh water, like the water we drink. Most of the ocean however, is very salty. So the more rain that falls, the fresher the ocean water gets and the more evaporation that occurs the saltier the ocean water gets. Oceanographers can measure just how salty the water in the ocean is and have been doing so regularly for more than 50 years now. The question remains however, how do you turn measurements of the salinity of the ocean into measurement of how much rain has fallen? Well, by looking all around the globe and counting up how much more salty water there is and how much fresh water there is, researchers can estimate how much water has been evaporated in one place and fallen as rain in another. The researchers involved in this project will do this using all the observations of salinity in the ocean taken over the last 50 years. They will estimate just how much rainfall has changed. They will compare this with computer models which are commonly used to predict what will happen in the future to see how accurate they are and how they can be improved.


In spite of the fact that the diagnosis of haemophilia is essentially clinical and laboratory-based, imaging has become an important tool for the evaluation of complications, diagnostic confirmation and/or complementation and therapeutic follow-up in haemophilic arthropathy. Radiography remains the workforce horse in the diagnosis and follow-up of haemophilic arthropathy. The radiographical findings in arthropathy follow an expected sequence of events and are overall similar in different joints. Magnetic resonance imaging (MRI) has advantages over radiography based on its capability of visualizing soft tissue and cartilage changes in haemophilic joints. The recent development and standardization of MRI scoring systems for measuring soft tissue and cartilage abnormalities may enable the comparison of pathological joint findings in clinical trials conducted at different institutions across the world. The implementation of high-frequency transducers and colour/power Doppler capabilities has provided new insights for clinical applications of ultrasonography (US) in haemophilic arthropathy. In spite of the imaging modality's technical challenges such as operator-dependency, US has advantages over MRI. One of these advantages is its ability of differentiating synovium hypertrophy and hemosiderin deposition, which is not possible with MRI given the presence of susceptibility artefacts from extracellular hemosiderin on gradient-echo MR images. In addition to the aforementioned conventional imaging modalities, novel imaging techniques (blood oxygen level dependent, ultrasmall superparamagnetic iron-oxide contrast-enhanced, and T1 and T2 mapping MRI, ultrasound biomicroscopy, microbubble contrast-enhanced US and positron emission tomography, among others) hold promise for early assessment of haemophilic arthropathy in the future upon completion of their clinical validation. © 2010 The Author. Journal compilation © 2010 Blackwell Publishing Ltd.


Shephard R.J.,University of Toronto
Journal of Physical Activity and Health | Year: 2015

Background: Traditional approaches to exercise prescription have included a preliminary medical screening followed by exercise tests of varying sophistication. To maximize population involvement, qualified fitness and exercise professionals (QFEPs) have used a self-administered screening questionnaire (the Physical Activity Readiness Questionnaire, PAR-Q) and a simple measure of aerobic performance (the Canadian Aerobic Fitness Test, CAFT). However, problems have arisen in applying the original protocol to those with chronic disease. Recent developments have addressed these issues. Methods: Evolution of the PAR-Q and CAFT protocol is reviewed from their origins in 1974 to the current electronic decision tree model of exercise screening and prescription. Results: About a fifth of apparently healthy adults responded positively to the original PAR-Q instrument, thus requiring an often unwarranted referral to a physician. Minor changes of wording did not overcome this problem. However, a consensus process has now developed an electronic decision tree for stratification of exercise risk not only for healthy individuals, but also for those with various types of chronic disease. Conclusions: The new approach to clearance greatly reduces physician referrals and extends the role of QFEPs. The availability of effective screening and simple fitness testing should contribute to the goal of maximizing physical activity in the entire population. © 2015 Human Kinetics, Inc.


McKee M.D.,University of Toronto
Orthopedic Clinics of North America | Year: 2010

Clavicle fractures are common, and they comprise close to 3% of all fractures seen in fracture clinics. Midshaft fractures account for approximately 80% of all clavicle fractures and are the focus of this article. In carefully selected cases primary plate fixation of displaced midshaft clavicle fractures improves outcome, results in earlier return to function, and reduces the nonunion and symptomatic malunion rate significantly compared with nonoperative treatment. © 2010 Elsevier Inc.


Barrett J.,University of Toronto | Fleming A.S.,University of Toronto
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2011

Quality of mothering relies on the integrity of multiple physiological and behavioral systems and on two maternal factors, one proximal and one distal, that have a great impact on how a mother mothers: postpartum depression and early experiences. To mother appropriately requires the action of systems that regulate sensation, perception, affect, reward, executive function, motor output and learning. When a mother is at risk to engage in less than optimal mothering, such as when she is depressed or has experienced adversity in childhood, the function of many or all of maternal and related systems may be affected. In this paper, we will review what is currently known about the biological basis of mothering, with attention to literature on hormones but with a particular focus on recent advances in the fields of functional neuroimaging. Instead of discussing strictly 'maternal' brain imaging studies, we instead use a systems approach to survey important findings relevant to brain systems integral to and/or strongly related to the mothering experience: (a) social behavior; (b) reward and affect; (c) executive function; and (d) maternal behavior. We find that there are many commonalities in terms of the brain regions identified across these systems and, as we would expect, all are sensitive to the influence of, or function differently in the context of, depression and adverse early experience. It is likely that the similarity and cross-talk between maternal, affect and stress systems, observed behaviorally, hormonally and in the context of brain function, allows for mood disturbance and early adverse experiences to have a significant impact on the quality of mothering and the motivation to mother. © 2010 The Authors. Journal of Child Psychology and Psychiatry © 2010 Association for Child and Adolescent Mental Health. Published by Blackwell Publishing.


Review of methods. To provide a detailed description of the methods undertaken in the articles in this focus issue pertaining to cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL) and to describe the process used to develop summary statements and clinical recommendations regarding factors associated with the mechanisms, diagnosis, progression, and treatment of CSM and OPLL. We present methods used in conducting the systematic, evidence-based reviews and development of expert panel summary statements and clinical recommendations of the mechanisms, diagnosis, progression, and treatment of CSM and OPLL. Our intent is that clinicians will combine the information from these systematic reviews, narrative reviews, and primary research studies with an understanding of their own capacities and experience to better manage patients with CSM or OPLL and consider future research for the diagnosis and treatment of these diseases. For the systematic reviews, which make up the bulk of the studies in this focus issue, a systematic search and critical review of the English language literature was undertaken for articles published on the mechanisms, diagnosis, progression, and treatment of CSM and OPLL. Articles were screened for relevance using a priori criteria and relevant articles were critically reviewed. Whether an article was included for review depended on whether the study question was descriptive, one of therapy, or one of prognosis. The strength of evidence for the overall body of literature in each topic area was determined by 2 independent reviewers considering risk of bias, consistency, directness, and precision of results using a modification of the Grading of Recommendation Assessment, Development and Evaluation criteria. Disagreements were resolved by consensus. Findings from articles meeting inclusion criteria were summarized. From these summaries, summary statements or clinical recommendations were formulated among subject experts through a modified Delphi process using the Grading of Recommendation Assessment, Development and Evaluation approach. Methods for the 2 primary research studies and the narrative reviews are also reviewed. Because of the nature of questions that needed to be addressed, not all studies in this focus issue were amenable to systematic review. As a result, this focus issue consists of several different article types, including 1 research protocol, 2 primary research studies, 2 narrative literature reviews, 7 systematic reviews, and 3 articles that combine a systematic review component with either a narrative section (n = 2) or a provider survey (n = 1). In general, the strength of evidence ratings ranged from insufficient to moderate. Summary statements or clinical recommendations were made according to available evidence and study type: 16 summary statements were made across 8 articles, and 17 clinical recommendations were made across 9 articles. Three articles had both summary statements and clinical recommendations, 5 had summary statements only, 6 had clinical recommendations only, and 1 (the research protocol) was not amenable to either. Systematic reviews, narrative reviews, and primary research studies were undertaken to understand the mechanisms, diagnosis, progression, and treatment of CSM and OPLL and to provide summary statements and clinical recommendations. This article reports the methods used in the studies in this focus issue. SUMMARY STATEMENTS: The objectives of this focus issue were met using a variety of article and study designs, each of which has some unique methodological aspects associated with it. The reader should refer to the full article in this issue for additional details specific to that topic. The methods for systematic review follow accepted standards for rigor and, together with the application of Grading of Recommendation Assessment, Development and Evaluation, are intended to allow for transparency in the process for creating the clinical recommendation.


This life cycle assessment (LCA) examines the claim that lightweight and refillable packaging alternatives to conventional single use glass bottles for wines and spirits reduce environmental impacts. Using LCA input data from laboratory and field research, as well as questionnaires to industry, the potential life cycle impacts of five types of 1 l wine packages and four types of 750 ml spirit packages are compared. In addition, detailed wine and spirit volume sales data are used to undertake an LCA comparison of packaging consumption at a municipal scale. Impacts associated with the wine and spirit packaging supplied in the City of Toronto, Canada in 2008 are compared with a plausible alternative comprising only lightweight and refillable containers which reduces the mass of waste by approximately half. Four alternative means of packaging, including the container, closures, capsules and labels, are evaluated: lightweight single use glass bottles; refillable glass bottles; polyethylene terephthalate bottles; and aseptic cartons. LCA results estimated using the ReCiPe impact assessment method address both the relative impact differences between the packaging systems, as well as the cumulative impacts from the consumption of packages of multiple sizes and types within a municipality. Out of the five types of packages evaluated, the refillable glass bottle and aseptic carton prove to have the lowest net endpoint level environmental impacts, with impact reductions, relative to the conventional single use glass container, reaching as high as 87%. At the municipal scale, the alternative packaging scenario is responsible for endpoint level impact reductions of between 40% and 42%. © 2013 Elsevier Ltd. All rights reserved.


Wright J.G.,University of Toronto
Clinical Orthopaedics and Related Research | Year: 2011

Background: Although many children with spina bifida and associated scoliosis or dislocated hips undergo spine or hip surgery, the benefits are uncertain. Questions/purposes: The purpose was to perform an evidence-based review on the benefits and risks of surgery for dislocated hips and scoliosis in spina bifida. Methods: I performed a Medline® and Embase® search from 1950 to 2009 for Level I to Level III studies investigating the benefits and risks of surgery for scoliosis and hip dislocation in patients with spina bifida. When available, I extracted types of surgery, complication rates, functional outcomes of seating, walking, and overall physical function. All treatment recommendations received a Grade of Recommendation: Grade A (consistent Level I studies); Grade B (consistent Level II and III studies); Grade C (consistent level IV and V studies); or Grade I (insufficient or contradictory studies). Results: Combined anterior and posterior surgery had lower rates of nonunion for scoliosis. Although there may be some benefit in seating, overall physical function measured in a different and nonstandardized fashion was not much changed and major complication rates, including nonunion and infections for scoliosis surgery, exceed 50% in several studies. For dislocated hips, the impact on walking ability appears related to contracture (not dislocation). Surgery for hip dislocation did not improve walking ability. The literature provides no guidance on the best treatment for unilateral dislocation. Conclusions: The benefits of scoliosis surgery are uncertain (Grade I). Spine surgery, if performed, should be anterior and posterior (Grade B). An all-pedicle approach for scoliosis surgery may be effective (Level I). Hip reduction surgery did not improve walking (Grade B) but may be appropriate in low-level unilateral dislocation (Level I). © 2011 The Association of Bone and Joint Surgeons®.


Mcnaughton N.,University of Toronto
Medical Education | Year: 2013

Context Emotion in medical education rests between the idealised and the invisible, sitting uneasily at the intersection between objective fact and subjective values. Examining the different ways in which emotion is theorised within medical education is important for a number of reasons. Most significant is the possibility that ideas about emotion can inform a broader understanding of issues related to competency and professionalism. Objectives The current paper provides an overview of three prevailing discourses of emotion in medical education and the ways in which they activate particular professional expectations about emotion in practice. Methods A Foucauldian critical discourse analysis of the medical education literature was carried out. Keywords, phrases and metaphors related to emotion were examined for their effects in shaping medical socialisation processes. Discussion Despite the increasing recognition over the last two decades of emotion as 'socially constructed', the view of emotion as individualised is deeply embedded in our language and conceptual frameworks. The discourses that inform our emotion talk and practice as teachers and health care professionals are important to consider for the effects they have on competence and professional identity, as well as on practitioner and patient well-being. Expanded knowledge of how emotion is 'put to work' within medical education can make visible the invisible and unexamined emotion schemas that serve to reproduce problematic professional behaviours. For this discussion, three main discourses of emotion will be identified: a physiological discourse in which emotion is described as located inside the individual as bodily states which are universally experienced; emotion as a form of competence related to skills and abilities, and a socio-cultural discourse which calls on conceptions from the humanities and social sciences and directs our attention to emotion's function in social exchanges and its role as a social, political and cultural mediator. © 2013 Blackwell Publishing Ltd.


Chan A.W.,University of Toronto
BMJ (Clinical research ed.) | Year: 2013

High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.


Schafer M.H.,University of Toronto
Journals of Gerontology - Series B Psychological Sciences and Social Sciences | Year: 2011

Background.The overlap between social networks and health represents a key area of research in social gerontology. Set in a continuing care retirement community, this research focuses on how health is related to outgoing and incoming reports of social interaction among residents. Method.Study participants (n = 123) were given the RAND 36-item Health Survey and asked about their social interaction with other people living at the retirement community. Negative binomial and linear regression analysis was used to assess associations between measures of network centrality and health. Results.Retirement community residents in better health received more nominations from their peers about general socializing, net of how many ties they themselves reported. The ties received by healthier people, moreover, tended to come from others who were central in the network. Conversely, those in better health reported fewer close ties with their coresidents, net of the alter reports. Discussion.Results are interpreted in light of status processes, which emerge in bounded social settings. © The Author 2011.


Liscidini M.,University of Pavia | Sipe J.E.,University of Toronto
Physical Review Letters | Year: 2013

We identify a relation between the number of photon pairs generated by parametric fluorescence, through either spontaneous parametric down-conversion (SPDC) or spontaneous four-wave mixing, and the number generated by the corresponding stimulated process, respectively, either difference-frequency generation or stimulated four-wave mixing. On the basis of this very general result, we show that the characterization of SPDC sources of two-photon states in a given system can be performed solely by studying stimulated emission. We call this technique stimulated emission tomography (SET). We show that the number of photons detected in SET can be 9 orders of magnitude larger than the average number of coincidence counts in two-photon quantum state tomography. These results open the way to the study of sources of quantum-correlated photon pairs with unprecedented precision and unparalleled resolution. © 2013 American Physical Society.


Mitchell R.H.B.,University of Toronto | Goldstein B.I.,University of Toronto
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2014

Objective There has been rapid growth in research regarding inflammation in neuropsychiatric disorders as it relates to youth. We therefore set out to systematically review the literature on inflammation and neuropsychiatric disorders in children and adolescents. Method A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were included if proinflammatory markers (PIMs) in children and/or adolescents with neuropsychiatric disorders were measured. Results Sixty-seven studies were included, involving 3,952 youth. Evidence for a proinflammatory state is strongest for autism spectrum disorders (ASD). PIMs are elevated in children and adolescents with major depressive disorder (MDD), bipolar disorder (BD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), Tourette's disorder (TD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SZ). However, the data are inconsistent. Evidence for specific PIMs is equivocal at this stage, although the findings in youth with MDD, BD, and PTSD converge with the extant adult literature in these areas. Definitive conclusions are limited by methodologic factors including cross-sectional and retrospective study design, between-study differences in specific markers and methods of analysis, small sample size, and other sources of heterogeneity. Conclusion The literature regarding inflammation among children and adolescents with neuropsychiatric disorders represents nearly 4,000 youth. There is preliminary evidence for elevated markers of inflammation in this population. Larger, prospective studies are needed to realize the goal of inflammatory markers informing clinical practice. In the interim, present findings suggest that further examination of this topic is warranted.


DeVeale B.,University of Toronto | van der Kooy D.,University of Toronto | Babak T.,Stanford University
PLoS Genetics | Year: 2012

In contrast to existing estimates of approximately 200 murine imprinted genes, recent work based on transcriptome sequencing uncovered parent-of-origin allelic effects at more than 1,300 loci in the developing brain and two adult brain regions, including hundreds present in only males or females. Our independent replication of the embryonic brain stage, where the majority of novel imprinted genes were discovered and the majority of previously known imprinted genes confirmed, resulted in only 12.9% concordance among the novel imprinted loci. Further analysis and pyrosequencing-based validation revealed that the vast majority of the novel reported imprinted loci are false-positives explained by technical and biological variation of the experimental approach. We show that allele-specific expression (ASE) measured with RNA-Seq is not accurately modeled with statistical methods that assume random independent sampling and that systematic error must be accounted for to enable accurate identification of imprinted expression. Application of a robust approach that accounts for these effects revealed 50 candidate genes where allelic bias was predicted to be parent-of-origin-dependent. However, 11 independent validation attempts through a range of allelic expression biases confirmed only 6 of these novel cases. The results emphasize the importance of independent validation and suggest that the number of imprinted genes is much closer to the initial estimates. © 2012 DeVeale et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Pereira M.P.,University of Toronto | Kelley S.O.,University of Toronto
Journal of the American Chemical Society | Year: 2011

The number of antimicrobial agents available for use in humans is limited by the difficulty of discovering chemical agents with selective toxicity to bacterial targets. Numerous small molecule inhibitors have potential as antimicrobial agents, yet their use has been prevented by high levels of toxic cross-reactivity in human cells. For example, methotrexate (Mtx) is an effective antimetabolite that exerts its effects by inhibiting DHFR. It is a potent antibacterial when accumulated intracellularly, but toxicity in human cells limits clinical utility in infectious disease treatment. Here, we describe peptide conjugates of Mtx that are sequestered into the mitochondria of human cells (mt-Mtx). This alteration in localization of Mtx, which directs it away from its enzyme target, decreases its toxicity in human cells by a factor of 103. Mt-Mtx, however, maintains activity against a variety of pathogenic Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). The results from this proof-of-principle study describe a novel methodology for augmenting the antibacterial efficacy of drugs amenable to peptide conjugation while simultaneously decreasing their toxicity to the host organism. © 2011 American Chemical Society.


Marchildon G.P.,University of Toronto
Healthcare Papers | Year: 2016

Regionalization is arguably the most significant health reform in Canada since medicare. Although a majority of provinces continue to have regionalized systems in Canada, the policy is more contested today than it was a decade ago. Since Ontario's implementation of local health integration networks (LHINs) in 2006 and Alberta's elimination of regional health authorities (RHAs) in favour of Alberta Health Services in 2008, Canada has had differing approaches to regionalization. However, due to the centralization of physician budgets in provincial health ministries, primary care has not been integrated into any regionalization model in Canada. This factor has severely constrained the performance of RHAs and their ability to meet their respective legislative mandates. Moreover, the lack of research on regionalization has meant that provincial governments are working from an extremely limited evidence base on which to make critical decisions on the structuring of health systems in Canada.


Diamond M.,University of Toronto | Schuster P.,Perimeter Institute for Theoretical Physics
Physical Review Letters | Year: 2013

New sub-GeV gauge forces ("dark photons") that kinetically mix with the photon provide a promising scenario for MeV-GeV dark matter and are the subject of a program of searches at fixed-target and collider facilities around the world. In such models, dark photons produced in collisions may decay invisibly into dark-matter states, thereby evading current searches. We reexamine results of the SLAC mQ electron beam dump experiment designed to search for millicharged particles and find that it was strongly sensitive to any secondary beam of dark matter produced by electron-nucleus collisions in the target. The constraints are competitive for dark photon masses in the ∼1-30 MeV range, covering part of the parameter space that can reconcile the apparent (g-2)μ anomaly. Simple adjustments to the original SLAC search for millicharges may extend sensitivity to cover a sizable portion of the remaining (g-2)μ anomaly-motivated region. The mQ sensitivity is therefore complementary to ongoing searches for visible decays of dark photons. Compared to existing direct-detection searches, mQ sensitivity to electron-dark-matter scattering cross sections is more than an order of magnitude better for a significant range of masses and couplings in simple models. © 2013 American Physical Society.


Ryabinkin I.G.,University of Toronto | Izmaylov A.F.,University of Toronto
Physical Review Letters | Year: 2013

We show that finite systems with conical intersections can exhibit spontaneous symmetry breaking which manifests itself in spatial localization of eigenstates. This localization has a geometric phase origin and is robust against variation of model parameters. The transition between localized and delocalized eigenstate regimes resembles a continuous phase transition. The localization slows down the low-energy quantum nuclear dynamics at low temperatures. © 2013 American Physical Society.


Intensified relations between biodiversity conservation organizations and private-sector actors are analyzed through a historical perspective that positions biodiversity conservation as an organized political project. Within this view the organizational dimensions of conservation exist as coordinated agreement and action among a variety of actors that take shape within radically asymmetrical power relations. This paper traces the privileged position of " business" in aligning concepts of sustainable development and ecological modernization within the emerging institutional context of the Convention on Biological Diversity and the Global Environment Facility in ways that help to secure continued access to "nature as capital", and create the institutional conditions to shape the work of conservation organizations. The contemporary emergence of business as a major actor in shaping contemporary biodiversity conservation is explained in part by the organizational characteristics of modernist conservation that subordinates it to larger societal and political projects such as neoliberal capitalism. © 2010 The Author Journal compilation © 2010 Editorial Board of Antipode.


Alam M.Z.,University of Toronto | Aitchison J.S.,University of Toronto | Mojahedi M.,University of Toronto
Laser and Photonics Reviews | Year: 2014

Plasmonics has attracted a lot of interest in the past few years because of its unique features, especially for its ability to confine light in extremely small volumes. However, application of plasmonics is restricted by the large propagation loss associated with plasmonic waveguides. On the other hand, dielectric waveguides enjoy low loss, although the mode confinement is relatively weaker. Hybrid plasmonic waveguides (HPWGs), which combine these two guiding mechanisms, allow one to utilize the benefits of both technologies. Over the past few years there have been intense research activities around the world on this new guiding scheme. In this work the operating principle of HPWGs, various HPWG structures proposed by different research groups, and their potentail applications are reviewed. Plasmonics has the ability to confine light in extremely small volumes. However, application of plasmonics is restricted by the large propagation loss associated with plasmonic waveguides. Dielectric waveguides enjoy low loss, although the mode confinement is relatively weaker. Hybrid plasmonic waveguides (HPWGs), which combine these two guiding mechanisms, allow one to utilize the benefits of both technologies. In this work the operating principle of HPWGs, various HPWG structures proposed by different research groups, and their potentail applications are reviewed. © 2014 by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Partitioning of Se and Te has been measured between coexisting sulfide liquid, monosulfide solid solution (MSS) and silicate melt at 0.9-1.5 GPa, 1200-1300 °C, fO2 controlled near the fayalite-magnetite-quartz buffer (FMQ-1.2 to -1.6) and 3-22 wt% FeO in the silicate melt. Both elements are highly compatible in the sulfide phase relative to silicate liquid (Dsulfide phase/silicate liquid > 600), with the identity of the sulfide dictating the sense of Se-Te fractionation. Whereas the measured DTe/DSe is ~5-9 for sulfide liquid/silicate liquid partitioning, MSS/silicate melt partitioning fractionates Te from Se in the opposite sense, with DTe/DSe of ~0.5-0.8. At fixed fO2, DSulLiq/SilLiq values for both Se and Te decrease ~8-fold over the range in silicate melt FeO content investigated. The relative values of DSulLiq/SilLiq for Cu to Se increase with increasing FeO in the silicate melt, such that DCu exceeds DSe only for melts with >11 wt% FeO. Hence the standard belief that DCu>DSe as indicative of sulfide removal should be carefully assessed in the context of the FeO content of the magmas involved.Assuming a chondritic mantle Se/Te, predicted MSS and sulfide liquid compositions are generally in accord with natural mantle sulfides, in terms of their designation as MSS or sulfide liquid, based on independent criteria. However, additional variability is likely due to Te redistribution in accessory platinum group minerals (PGM), or that some sulfides are metasomatic. Calculations show that the Se/Te ratio of silicate melt derived from a sulfide liquid-saturated mantle is significantly higher, and more variable, than for silicate melt in equilibrium with residual MSS; modest sulfide liquid removal at low pressure, however, likely obscures the Se/Te fractionation imposed by the source sulfide phase. Models indicate that the composition of MORB is consistent with melts produced from sulfide-bearing sources with chondritic Se/Te, and source sulfur contents higher than estimates for depleted mantle. The calculated composition of sulfide-saturated melting residues show relatively little deviation in Se/Te if MSS is residual, but a sharp drop in this ratio for sulfide liquid control. Although the data are scattered, a portion of the peridotite array near the primitive mantle composition is consistent with model trends, and suggests control by residual MSS. © 2015 Elsevier B.V.


Rucinski S.M.,University of Toronto
Astronomical Journal | Year: 2015

High-resolution spectroscopic observations of AW UMa, obtained on three consecutive nights with a median time resolution of 2.1 minutes, have been analyzed using the broadening function method in the spectral window of 22.75 nm around the 518 nm Mg I triplet region. Doppler images of the system reveal the presence of vigorous mass motions within the binary system; their presence puts into question the solid-body rotation assumption of the contact binary model. AW UMa appears to be a very tight, semi-detached binary; the mass transfer takes place from the more massive to the less massive component. The primary, a fast-rotating star with V sin i = 181.4 ± 2.5 km s-1, is covered with inhomogeneities: very slowly drifting spots and a dense network of ripples more closely participating in its rotation. The spectral lines of the primary show an additional broadening component (called the " pedestal") that originates either in the equatorial regions, which rotate faster than the rest of the star by about 50 km s-1, or in an external disk-like structure. The secondary component appears to be smaller than predicted by the contact model. The radial velocity field around the secondary is dominated by accretion of matter transferred from (and possibly partly returned to) the primary component. The parameters of the binary are A sin i = 2.73 ± 0.11 R⊙ and M1 sin3 e i = 1.29 ± 0.15 M⊙, M2 sin3 i = 0.128 ± 0.016 M⊙. The mass ratio, qsp = M2/M1 = 0.099 ± 0.003, while still the most uncertain among the spectroscopic elements, is substantially different from the previous numerous and mutually consistent photometric investigations which were based on the contact model. It should be studied why photometry and spectroscopy give such discrepant results and whether AW UMa is an unusual object or if only very high-quality spectroscopy can reveal the true nature of W UMa-type binaries. © 2015. The American Astronomical Society. All rights reserved.


Yeomans J.S.,University of Toronto
Handbook of Experimental Pharmacology | Year: 2012

All five muscarinic receptor subtypes and mRNAs are found widely in the brain stem, with M 2 muscarinic receptors most concentrated in the hindbrain. Three cholinergic cell groups, Ch5: pedunculopontine (PPT); Ch6: laterodorsal tegmental (LDT); Ch8: parabigeminal (PBG), are found in the tegmentum. Ch5,6 neurons are activated by arousing and reward-activating stimuli, and inhibited via M 2-like autoreceptors. Ch5,6 ascending projections activate many forebrain regions, including thalamus, basal forebrain, and orexin/hypocretin neurons (via M 3 receptors) for waking arousal and attention. Ch5,6 activation of dopamine neurons of the ventral tegmental area and substantia nigra (via M 5 receptors) increases reward-seeking and energizes motor functions. M 5 receptors on dopamine neurons facilitate brain-stimulation reward, opiate rewards and locomotion, and male ultrasonic vocalizations during mating in rodents. Ch5 cholinergic activation of superior colliculus intermediate layers facilitates fast saccades and approach turns, accompanied by nicotinic and muscarinic inhibition of the startle reflex in pons. Ch8 PBG neurons project to the outer layers of the superior colliculus only, where M 2 receptors are associated with retinotectal terminals. Ch5,6 descending projections to dorsal pontine reticular formation contribute to M 2-dependent REM sleep. © 2012 Springer-Verlag Berlin Heidelberg.


Chew C.,University of Toronto | Eysenbach G.,University of Toronto
PLoS ONE | Year: 2010

Background: Surveys are popular methods to measure public perceptions in emergencies but can be costly and time consuming. We suggest and evaluate a complementary "infoveillance" approach using Twitter during the 2009 H1N1 pandemic. Our study aimed to: 1) monitor the use of the terms "H1N1" versus "swine flu" over time; 2) conduct a content analysis of "tweets"; and 3) validate Twitter as a real-time content, sentiment, and public attention trend-tracking tool. Methodology/Principal Findings: Between May 1 and December 31, 2009, we archived over 2 million Twitter posts containing keywords "swine flu," "swineflu," and/or "H1N1." using Infovigil, an infoveillance system. Tweets using "H1N1" increased from 8.8% to 40.5% (R2 =.788; p<.001), indicating a gradual adoption of World Health Organizationrecommended terminology. 5,395 tweets were randomly selected from 9 days, 4 weeks apart and coded using a tri-axial coding scheme. To track tweet content and to test the feasibility of automated coding, we created database queries for keywords and correlated these results with manual coding. Content analysis indicated resource-related posts were most commonly shared (52.6%). 4.5% of cases were identified as misinformation. News websites were the most popular sources (23.2%), while government and health agencies were linked only 1.5% of the time. 7/10 automated queries correlated with manual coding. Several Twitter activity peaks coincided with major news stories. Our results correlated well with H1N1 incidence data. Conclusions: This study illustrates the potential of using social media to conduct "infodemiology" studies for public health. 2009 H1N1-related tweets were primarily used to disseminate information from credible sources, but were also a source of opinions and experiences. Tweets can be used for real-time content analysis and knowledge translation research, allowing health authorities to respond to public concerns. © 2010 Chew et al.


Swillam M.A.,University of Toronto
Optics express | Year: 2010

Plasmonic modes in rectangular metallic waveguides are analyzed in depth and are demonstrated to possess attractive properties for different applications. Their dispersion characteristics allow for wide range of applications including slow and fast light, metamaterial, low loss energy transmission, and opportunities for sensing devices. The sensitivity of this waveguide configuration is higher than its counterparts and can reach four times the sensitivity of the MIM structures. The characteristics of the TM(10) mode are demonstrated. Its applications for sensing, low propagation loss with relaxed practical dimension are also highlighted. A high effective index of more than 30 is also obtainable for the TE(01) mode for slow light operation. A non resonant negative index material with isotropic polarization in the visible region is also proposed using this waveguide structure.


Xu H.,University of Toronto | Li B.,University of Toronto
Proceedings - IEEE INFOCOM | Year: 2013

Many cloud services are running on geographically distributed datacenters for better reliability and performance. We consider the emerging problem of joint request mapping and response routing with distributed datacenters in this paper. We formulate the problem as a general workload management optimization. A utility function is used to capture various performance goals, and the location diversity of electricity and bandwidth costs are realistically modeled. To solve the large-scale optimization, we develop a distributed algorithm based on the alternating direction method of multipliers (ADMM). Following a decomposition-coordination approach, our algorithm allows for a parallel implementation in a datacenter where each server solves a small sub-problem. The solutions are coordinated to find an optimal solution to the global problem. Our algorithm converges to near optimum within tens of iterations, and is insensitive to step sizes. We empirically evaluate our algorithm based on real-world workload traces and latency measurements, and demonstrate its effectiveness compared to conventional methods. © 2013 IEEE.


Chitambar E.,University of Toronto
Physical Review Letters | Year: 2011

In this Letter, we investigate the number of measurement and communication rounds needed to implement certain tasks by local quantum operations and classical communication (LOCC), a relatively unexplored topic. To demonstrate the possible strong dependence on the round number, we consider the problem of converting three-qubit entanglement into two-qubit form, specifically in the random distillation setting of. We find that the number of LOCC rounds needed for a transformation can depend on the amount of entanglement distilled. In fact, for a wide range of transformations, the required number of rounds is infinite (unbounded). This represents the first concrete example of a task needing an infinite number of rounds to implement. © 2011 American Physical Society.


Tabatabaei N.,University of Toronto | Mandelis A.,University of Toronto
Physical Review Letters | Year: 2011

Energy transport in diffusion-wave fields is gradient-driven and therefore diffuse, yielding depth-integrated responses with poor axial resolution. Using matched-filter principles, we propose a methodology enabling these parabolic diffusion-wave energy fields to exhibit energy localization akin to propagating hyperbolic wave fields. This not only improves axial resolution but also allows for deconvolution of individual responses of superposed axially discrete sources, opening a new field of depth-resolved subsurface thermal coherence tomography using diffusion waves. © 2011 American Physical Society.


Kluger R.,University of Toronto
Current Opinion in Chemical Biology | Year: 2010

Red cells are the oxygen-carrying components of blood. In modern medical practice, transfusions are given as suspensions of type-matched red cells in saline to replace lost blood, preventing organ damage and allowing for recovery. Since red cells cannot be stored for more than about 40 days and because they can transmit infections, alternative materials for transfusions were developed to replace the oxygenation function of the red cells. One approach involves chemically stabilizing hemoglobin, the oxygen-carrying protein of the red cell, while also adjusting its oxygenation properties to replicate that of the red cell. Evaluation of clinical trials of all products led to the conclusion that none that were tested would be suitable for clinical use [Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM: Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. J Am Med Assoc 2008, 299:2304-2312]. Most notably, the materials increased blood pressure and some were associated with increased risk of heart attacks. More recently, it was found that materials from covalent addition of polyethylene glycol polymers (PEG) to hemoglobin do not elicit the undesired effects on blood pressure [Vandegriff K, Bellelli A, Samaja M, Malavalli A, Brunori M, Winslow RM: Rates of NO binding to MP4, a non-hypertensive polyethylene glycol-conjugated hemoglobin. FASEB J 2003, 17:A183; Vandegriff KD, Malavalli A, Wooldridge J, Lohman J, Winslow RM: MP4: a new nonvasoactive PEG-Hb conjugate. Transfusion 2003, 43:509-516]. Also, materials with higher oxygen affinity than red cells are able to provide oxygenation at the sites in capillaries that have the most critical need for oxygen [Villela NR, Cabrales P, Tsai AG, Intaglietta M: Microcirculatory effects of changing blood hemoglobin oxygen affinity during hemorrhagic shock resuscitation in an experimental model. Shock 2009, 31:645-652]. It had been considered that the origin of the negative effects of the tested hemoglobin derivatives was because of their scavenging of endogenous nitric oxide (NO), the signal for vasodilation. It has been observed that an increase in the concentration of nitrite in circulation leads to an increase in NO concentration. This is consistent with the well-known reaction of hemoglobin with nitrite that produces NO and oxidized hemoglobin [Cannon RO 3rd, Schechter AN, Panza JA, Ognibene FP, Pease-Fye ME, Waclawiw MA, Shelhamer JH, Gladwin MT: Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest 2001, 108:279-287; Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, et al.: Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003, 9:1498-1505]. The PEG-hemoglobin and nitrite results are especially interesting as the hemoglobin to which PEG has been conjugated produces NO from nitrite at an enhanced rate [Lui FE, Dong P, Kluger R: Polyethylene glycol conjugation enhances the nitrite reductase activity of native and cross-linked hemoglobin. Biochemistry 2008, 47:10773-10780; Lui FE, Kluger R: Enhancing nitrite reductase activity of modified hemoglobin: bis-tetramers and their PEGylated derivatives. Biochemistry 2009, 48:11912-11919]. © 2010 Elsevier Ltd.


Brock K.K.,University of Toronto
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: To assess the accuracy, reproducibility, and computational performance of deformable image registration algorithms under development at multiple institutions on common datasets. Methods and Materials: Datasets from a lung patient (four-dimensional computed tomography [4D-CT]), a liver patient (4D-CT and magnetic resonance imaging [MRI] at exhale), and a prostate patient (repeat MRI) were obtained. Radiation oncologists localized anatomic structures for accuracy assessment. Algorithm accuracy was determined by comparing the computer-predicted displacement at each bifurcation point with the displacement computed from the oncologists' annotations. Thirty-seven academic institutions and medical device manufacturers with published evidence of active deformable image registration capabilities were invited to participate. Results: Twenty-seven groups agreed to participate; 6 did not return results. Sixteen completed the liver 4D-CT, 12 the lung 4D-CT, 3 the prostate MRI, and 3 the liver MRI-CT. The range of average absolute error for the lung 4D-CT was 0.6-1.2 mm (left-right [LR]), 0.5-1.8 mm (anterior-posterior [AP]), and 0.7-2.0 mm (superior-inferior [SI]); the liver 4D-CT was 0.8-1.5 mm (LR), 1.0-5.2 mm (AP), and 1.0-5.9 mm (SI); the liver MRI-CT was 1.1-2.6 mm (LR), 2.0-5.0 mm (AP), and 2.2-2.6 mm (SI); and the repeat prostate MRI prostate datasets was 0.5-6.2 mm (LR), 3.1-3.7 mm (AP), and 0.4-2.0 mm (SI). Conclusions: An infrastructure was developed to assess multi-institution deformable registration accuracy. The results indicate large discrepancies in reported shifts, although the majority of deformable registration algorithms performed at an accuracy equivalent to the voxel size, promising to improve treatment planning, delivery, and assessment. © 2010 Elsevier Inc. All rights reserved.


Perrault S.D.,University of Toronto | Chan W.C.W.,University of Toronto
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Many small molecular anticancer agents are often ineffective at detecting or treating cancer due to their poor pharmacokinetics. Using nanoparticles as carriers can improve this because their large size reduces clearance and improves retention within tumors, but it also slows their rate of transfer from circulation into the tumor interstitium. Here, we demonstrate an alternative strategy whereby a molecular contrast agent and engineered nanoparticle undergo in vivo molecular assembly within tumors, combining the rapid influx of the smaller and high retention of the larger component. This strategy provided rapid tumor accumulation of a fluorescent contrast agent, 16- and 8-fold faster than fluorescently labeled macromolecule or nanoparticle controls achieved. Diagnostic sensitivity was 3.0 times that of a passively targeting nanoparticle, and this improvement was achieved 3 h after injection. The advantage of the in vivo assembly approach for targeting is rapid accumulation of small molecular agents in tumors, shorter circulation time requirements, possible systemic clearance while maintaining imaging sensitivity in the tumor, and nanoparticle anchors in tumors can be utilized to alter the pharmacokinetics of contrast agents, therapeutics, and other nanoparticles. This study demonstrates molecular assembly of nanoparticles within tumors, and provides a new basis for the future design of nanomaterials for medical applications.


Jebrail M.J.,University of Toronto | Wheeler A.R.,University of Toronto
Current Opinion in Chemical Biology | Year: 2010

Digital microfluidics (DMF) has recently emerged as a popular technology for a wide range of applications in chemical biology. In DMF, nL-mL droplets containing samples and reagents are controlled (i.e., moved, merged, mixed, and dispensed from reservoirs) by applying a series of electrical potentials to an array of electrodes coated with a hydrophobic insulator. DMF is distinct from microchannel-based fluidics as it allows for precise control over multiple reagent phases (liquid and solid) in heterogeneous systems with no need for complex networks of microvalves. Here, we review the state-of-the-art in DMF as applied to a wide range of applications in chemical biology, including proteomics, enzyme assays and immunoassays, applications involving DNA, cell-based assays, and clinical applications. © 2010 Elsevier Ltd.


Sessle B.J.,University of Toronto
International Review of Neurobiology | Year: 2011

Many orofacial pain conditions involve inflammation of orofacial tissues and they range from acute pulpitis (toothache) and mucositis to chronic arthritic conditions affecting the temporomandibular joint (TMJ). This article reviews the peripheral and central neural mechanisms involved in orofacial inflammatory pain states, including the integral role that peripheral and central sensitization play in the pain features that characterize these states. It also outlines the recent evidence for the contribution of non-neural processes, especially those involving glial cells. © 2011 Elsevier Inc.


O'Brien K.,University of Toronto
AIDS and behavior | Year: 2010

The purpose of this project was to identify key research priorities related to HIV and rehabilitation. We conducted a scoping study which included a literature review of published and grey literature, followed by focus group and interview consultations with 28 participants including people living with HIV, researchers, educators, clinicians, and policy makers with expertise in HIV and rehabilitation. Qualitative content analysis was used to identify emergent themes related to research priorities in HIV and rehabilitation. The resulting Framework of HIV and Rehabilitation Research provided an outline for approaching research in the field. The framework included three overlapping research priorities: (a) living with HIV across the lifespan, (b) disability, and (c) rehabilitation that should be viewed through environmental and/or personal contextual lenses, using different methodological approaches. Six key research priorities from this framework were identified through additional consultation with new and returning participants including: (1) disability and episodic disability, (2) concurrent health conditions aging with HIV, (3) HIV and the brain, (4) labour force and income support, (5) access to and effectiveness of rehabilitation, and (6) development and evaluation of outcome measurement tools. These priorities inform a future plan for HIV and rehabilitation research that will increase our knowledge to enhance practice, programming and policy for people living with HIV.


Wong A.M.F.,University of Toronto
Canadian Journal of Ophthalmology | Year: 2012

Amblyopia is a visual impairment secondary to abnormal visual experience (e.g., strabismus, anisometropia, form deprivation) during early childhood that cannot be corrected immediately by glasses alone. It is the most common cause of monocular blindness globally. Patching remains the mainstay of treatment, but it is not always successful and there are also compliance and recurrence issues. Because amblyopia is a neural disorder that results from abnormal stimulation of the brain during the critical periods of visual development, it is essential to understand the neural mechanisms of amblyopia in order to devise better treatment strategies. In this review, I examine our current understanding of the neural mechanisms that underlie the characteristic deficits associated with amblyopia. I then examine modern neuroimaging findings that show how amblyopia affects various brain regions and how it disrupts the interactions among these brain regions. Following this, I review current concepts of brain plasticity and their implications for novel therapeutic strategies, including perceptual learning and binocular therapy, that may be beneficial for both children and adults with amblyopia. © 2012 Canadian Ophthalmological Society.


Whitehead C.,University of Toronto
Medical Education | Year: 2013

Context: The dominance of biomedical science in medical education has been contested throughout the past century, with recurring calls for more social science and humanities content. The centrality of biomedicine is frequently traced back to Abraham Flexner's 1910 report, 'Medical Education in the United States and Canada'. However, Flexner advocated for a scientist-doctor, rather than a curriculum filled with science content. Examination of the discourses of science since Flexner allows us to explore the place of various knowledge forms in medical education. Methods: A Foucauldian critical discourse analysis was performed, examining the discourses of scientific medicine in Flexner's works and North American medical education articles in subsequent decades. Foucault's methodological principles were used to identify statements, keywords and metaphors that emerged in the development of the discourses of scientific medicine, with particular attention to recurring arguments and shifts in the meaning and use of terms. Results: Flexner's scientist-doctor was an incisive thinker who drew upon multiple forms of knowledge. In the post-Flexner medical education reforms, the perception of science as a discursive object embedded in the curriculum became predominant over that of the scientist as the discursive subject who uses science. Science was then considered core curricular content and was discursively framed as impossibly vast. A parallel discourse, one of the insufficiency of biomedical science for the proper training of doctors, has existed over the past century, even as the humanities and social sciences have remained on the margins in medical school curricula. Conclusions: That discourses of scientific medicine have reinforced the centrality of biomedicine in medical education helps to explain the persistent marginalisation of other important knowledge domains. Medical educators need to be aware of the effects of these discourses on understandings of medical knowledge, particularly when contemplating curricular reform. © 2013 Blackwell Publishing Ltd.


Murphy M.,University of Toronto
Social Studies of Science | Year: 2015

Responding to the call by Maria Puig de la Bellacasa for Science and Technology Studies to take up ‘matters of care’, this article cautions against equating care with positive feelings and, in contrast, argues for the importance of grappling with the non-innocent histories in which the politics of care already circulates, particularly in transnational couplings of feminism and health. The article highlights these histories by tracing multiple versions of the politics of care in a select set of feminist engagements with the pap smear and cervical cancer. Drawing on postcolonial and indigenous feminist commitments, as well as amplifying Donna Haraway’s call to ‘stay with the trouble’, the article seeks to disturb hegemonic histories and arrangements of race, colonialism, and political economy, while simultaneously valuing divergent multi-local itineraries as relevant to technoscientific matters of care. This call for a politics of ‘unsettling’ care strives to stir up and put into motion what is sedimented, while embracing the generativity of discomfort, critique, and non-innocence. © 2015, © The Author(s) 2015.


Eder L.,University of Toronto
Arthritis care & research | Year: 2011

Epidemiologic studies about the incidence of psoriatic arthritis (PsA) are limited to a few population-based studies. There are limited data regarding the incidence of PsA in patients with psoriasis. We aimed to determine the incidence of PsA among a prospective cohort of psoriasis patients. The setting is a prospective longitudinal cohort study of psoriasis patients without arthritis. The patients are assessed annually by a rheumatologist in order to detect the onset of arthritis. We summarize the results of 4 years of followup and report the cumulative incidence of PsA from the time of entry to the study that was estimated using an event per person-years analysis and a nonparametric analysis. Three hundred thirteen psoriasis patients that had at least 1 year of followup were included in the analysis. The annual incidence rate was found to be 1.87 (95% confidence interval 0.71-3.03) PsA cases per 100 psoriasis patients. The incidence rate of PsA in patients with psoriasis may be higher than previously reported, particularly among patients with moderate to severe psoriasis. Copyright © 2011 by the American College of Rheumatology.


Citations in peer-reviewed articles and the impact factor are generally accepted measures of scientific impact. Web 2.0 tools such as Twitter, blogs or social bookmarking tools provide the possibility to construct innovative article-level or journal-level metrics to gauge impact and influence. However, the relationship of the these new metrics to traditional metrics such as citations is not known. (1) To explore the feasibility of measuring social impact of and public attention to scholarly articles by analyzing buzz in social media, (2) to explore the dynamics, content, and timing of tweets relative to the publication of a scholarly article, and (3) to explore whether these metrics are sensitive and specific enough to predict highly cited articles. Between July 2008 and November 2011, all tweets containing links to articles in the Journal of Medical Internet Research (JMIR) were mined. For a subset of 1573 tweets about 55 articles published between issues 3/2009 and 2/2010, different metrics of social media impact were calculated and compared against subsequent citation data from Scopus and Google Scholar 17 to 29 months later. A heuristic to predict the top-cited articles in each issue through tweet metrics was validated. A total of 4208 tweets cited 286 distinct JMIR articles. The distribution of tweets over the first 30 days after article publication followed a power law (Zipf, Bradford, or Pareto distribution), with most tweets sent on the day when an article was published (1458/3318, 43.94% of all tweets in a 60-day period) or on the following day (528/3318, 15.9%), followed by a rapid decay. The Pearson correlations between tweetations and citations were moderate and statistically significant, with correlation coefficients ranging from .42 to .72 for the log-transformed Google Scholar citations, but were less clear for Scopus citations and rank correlations. A linear multivariate model with time and tweets as significant predictors (P < .001) could explain 27% of the variation of citations. Highly tweeted articles were 11 times more likely to be highly cited than less-tweeted articles (9/12 or 75% of highly tweeted article were highly cited, while only 3/43 or 7% of less-tweeted articles were highly cited; rate ratio 0.75/0.07 = 10.75, 95% confidence interval, 3.4-33.6). Top-cited articles can be predicted from top-tweeted articles with 93% specificity and 75% sensitivity. Tweets can predict highly cited articles within the first 3 days of article publication. Social media activity either increases citations or reflects the underlying qualities of the article that also predict citations, but the true use of these metrics is to measure the distinct concept of social impact. Social impact measures based on tweets are proposed to complement traditional citation metrics. The proposed twimpact factor may be a useful and timely metric to measure uptake of research findings and to filter research findings resonating with the public in real time.


Irrazabal T.,University of Toronto | Belcheva A.,University of Toronto | Girardin S.E.,University of Toronto | Martin A.,University of Toronto | Philpott D.J.,University of Toronto
Molecular Cell | Year: 2014

In recent years, our understanding of the mechanisms underlying colorectal carcinogenesis has vastly expanded. Underlying inflammation within the intestine, diet, and most recently, the gut microbiota, have been demonstrated to influence the development of colorectal cancer. However, since cancer is ultimately a genetic disease, these factors are thought to create genotoxic stress within the intestinal environment topromote genetic and epigenetic alterations leading to cancer. In this review, we will focus on how gutmicrobes intersect with inflammation, diet, and host genetics to influence the development of colon cancer. © 2014 Elsevier Inc.


Robinson C.M.,University of Toronto | Ohh M.,University of Toronto
FEBS Letters | Year: 2014

Loss of von Hippel-Lindau protein (pVHL) is known to contribute to the initiation and progression of tumours associated with VHL disease as well as certain sporadic tumours including clear cell renal cell carcinoma (ccRCC). The VHL gene was first identified and cloned over 20 years ago and our understanding of its functions and effects has significantly increased since then. The best-known function of pVHL is its role in promoting the degradation of hypoxia-inducible factor α subunit (HIFα) as part of an E3 ubiquitin ligase complex. HIF stabilisation and transcriptional activation are also associated with various epigenetic alterations, indicating a potential role for VHL loss with changes in the epigenome. This review will highlight current knowledge regarding pVHL as well as discuss potentially novel roles of pVHL and how these may impact on cancer progression. © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Marshall J.C.,St Michaels Hospital | Marshall J.C.,University of Toronto
Trends in Molecular Medicine | Year: 2014

The systemic inflammatory response is biologically complex, redundant, and activated by both infectious and noninfectious triggers. Its manipulation can cause both benefit and harm. More than 100 randomized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival. With one short-lived exception, none of these has resulted in new treatments. The current challenge for sepsis research lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate large studies of clinical and biochemical epidemiology to understand the course of illness, better integration of basic and clinical science, and the creation of stratification systems to target treatment towards those who are most likely to benefit. © 2014 Elsevier Ltd.


Gaisano H.Y.,University of Toronto
Trends in Endocrinology and Metabolism | Year: 2014

Exocytosis in pancreatic β-cells employs Munc18/soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes that mediate the priming and docking onto the plasma membrane (PM) of insulin granules, called predocked granules, that sit on the PM until Ca2+ influx evokes fusion. This accounts for most of the initial peak secretory response. However, the subsequent sustained phase of glucose-stimulated insulin secretion arises from newcomer granules that have a minimal residence time at the PM before fusion. In this Opinion I discuss recent work that has begun to decipher the components of the exocytotic machinery of newcomer granules, including a Munc18/SNARE complex that is different from that mediating the fusion of predocked granules and which can potentially rescue defective insulin secretion in diabetes. These insights are applicable to other neuroendocrine cells that exhibit sustained secretion. © 2014 Elsevier Ltd.


Mulvihill E.E.,University of Toronto | Drucker D.J.,University of Toronto
Endocrine Reviews | Year: 2014

Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology ofDPP4with a focus on: 1) identification of pharmacological vs physiologicalDPP4substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4. © 2014 by the Endocrine Society.


Ching A.T.,University of Toronto
International Journal of Industrial Organization | Year: 2010

This paper introduces an empirical demand model with aggregate learning and consumer heterogeneity in price sensitivity. The model is applied to the prescription drug market after patent expiration during the 80s, when the diffusion of generic drugs is fairly slow and consumer price sensitivity is known to be heterogeneous. I also introduce a new estimation approach to take the price endogeneity problem into account for this class of models. My approach is to estimate the demand model jointly with a pseudo-pricing policy function, which is a reduced-form function of observed and unobserved state variables. My estimation and counterfactual exercises demonstrate the value of estimating such a structural demand model, e.g., it allows one to learn whether consumers have optimistic or pessimistic prior, how aggregate learning affects the product diffusion rates in different latent segments of the population, and quantify the role of learning in explaining new product diffusion. I also find evidence that the brand-name price elasticities of demand (evaluated at the observed prices) are often less than one and increase over time, suggesting that brand-name firms might set their prices lower than what they would do if they were myopic, in order to slow down the learning process for generic qualities. But such an incentive might diminish over time as the uncertainty slowly resolves. © 2010 Elsevier B.V.


Gareau M.G.,University of Toronto
Nature reviews. Gastroenterology & hepatology | Year: 2010

The use of probiotics is increasing in popularity for both the prevention and treatment of a variety of diseases. While a growing number of well-conducted, prospective, randomized, controlled, clinical trials are emerging and investigations of underlying mechanisms of action are being undertaken, questions remain with respect to the specific immune and physiological effects of probiotics in health and disease. This Review considers recent advances in clinical trials of probiotics for intestinal disorders in both adult and pediatric populations. An overview of recent in vitro and in vivo research related to potential mechanisms of action of various probiotic formulations is also considered.


MacEachen E.,University of Toronto
Journal of occupational rehabilitation | Year: 2010

INTRODUCTION: Small businesses (SBs) play an important role in global economies, employ half of all workers, and pose distinct workplace health problems. This systematic review of qualitative peer-reviewed literature was carried out to identify and synthesize research findings about how SB workplace parties understand and enact processes related to occupational health and safety (OHS). METHODS: The review was conducted as part of a larger mixed-method review and in consultation with stakeholders. A comprehensive literature search identified 5067 studies. After screening for relevance, 20 qualitative articles were identified. Quality assessment led to 14 articles of sufficient quality to be included in the meta-ethnographic findings synthesis. RESULTS: This review finds that SBs have distinctive social relations of work, apprehensions of workplace risk, and legislative requirements. Eight themes were identified that consolidate knowledge on how SB workplace parties understand OHS hazards, how they manage risk and health problems, and how broader structures, policies and systems shape the practice of workplace health in SBs. The themes contribute to 'layers of evidence' that address SB work and health phenomena at the micro (e.g. employer or worker behavior), meso (e.g. organizational dynamics) and macro (e.g. state policy) levels. CONCLUSIONS: This synthesis details the unique qualities and conditions of SBs that merit particular attention from planners and occupational health policy makers. In particular, the informal workplace social relations can limit workers' and employers' apprehension of risk, and policy and complex contractual conditions in which SBs are often engaged (such as chains of subcontracting) can complicate occupational health responsibilities. This review questions the utility of SB exemptions from OHS regulations and suggests a legislative focus on the particular needs of SBs. It considers ways that workers might activate their own workplace health concerns, and suggests that more qualitative research on OHS solutions is needed. It suggests that answers to the SB OHS problems identified in this review might lie in third party interventions and improved worker representation.


Zadeh G.,University of Toronto | Aldape K.,University of Texas M. D. Anderson Cancer Center
Nature Genetics | Year: 2014

Pediatric diffuse gliomas are rare but aggressive brain tumors for which effective therapies are unavailable. New studies identify recurrent mutations of the ACVR1 gene in these tumors, identify molecular subtypes and highlight differences between gliomas affecting children and adults. © 2014 Nature America, Inc. All rights reserved.


Huse J.T.,Sloan Kettering Cancer Center | Aldape K.D.,University of Toronto
Clinical Cancer Research | Year: 2014

While the classification of diffuse gliomas has relied on the examination of morphologic features supplemented with techniques such as immunohistochemistry, there is an increasing recognition of substantial biologic diversity within morphologically defined entities. High-throughput technologies, in particular studies that integrate genome-wide data from diverse molecular platforms, increasingly identify the existence of robust and distinct glioma subtypes. While treatment advances and improvement of outcomes for patients with diffuse glioma have been modest, there may be benefit to integrate findings from biologic studies into clinical practice to enhance the precision of treatment for these diseases. Recent examples such as the identification of mutations in IDH1 and IDH2 as an early genetic event that is predominantly in lower-grade gliomas (grades 2 and 3) underscore the importance of molecular discovery leading to the ability to develop subclassifications with prognostic and potentially therapeutic implications. In contrast, glioblastoma (grade 4), the most common and aggressive glioma, typically arises without IDH mutation, supporting the need for different therapeutic approaches. Additional genomic and epigenomic signatures are generally nonoverlapping between IDH-mutant and IDH wild-type diffuse glioma, and despite comparable histopathology, IDH-mutant gliomas can be considered as biologically distinct from IDH wild-type gliomas. In this CCR Focus article, we highlight and summarize the current understanding of recent molecular findings and the relationships of these findings to clinical trials and clinical management. © 2014 AACR.


Seeman P.,University of Toronto
ACS Chemical Neuroscience | Year: 2014

Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the human striatum, in contrast to haloperidol and chlorpromazine, which have a prolonged occupation of D2 receptors. The chemical structure of clozapine facilitates a relatively rapid dissociation from D2 receptors. After short-term occupation of D2 receptors, peak neural activity raises synaptic dopamine, which then displaces clozapine. While clozapine also occupies other types of receptors, they may not have a significant role in preventing parkinsonism. Clozapine's transient occupation of D2 receptors permits patients to move easily and comfortably. © 2013 American Chemical Society.


Aquino C.C.,University of Toronto | Fox S.H.,University of Toronto
Movement Disorders | Year: 2015

The first years of Parkinson disease (PD) treatment are marked by good and sustained responses to dopaminergic therapy. With disease progression and longer exposure to levodopa (l-dopa), patients develop a range of l-dopa-induced complications that include motor and non-motor symptoms. Motor complications include motor fluctuations, characterized by periods of reduced benefit from the medication, and l-dopa-induced dyskinesia, characterized by emergence of hyperkinetic involuntary movements. Dyskinesia can occur at peak effect of l-dopa, at the beginning and end of dose, or between doses. These motor complications are often associated with fluctuations in non-motor symptoms, particularly fluctuations in neuropsychiatric, autonomic, and sensory symptoms. Recognizing such complications and understanding their relationship with the timing of l-dopa doses is essential for adequate diagnosis and management. © 2014 International Parkinson and Movement Disorder Society.


Gong S.-G.,University of Toronto
Journal of Cellular Physiology | Year: 2014

The breadth and scope of Fibroblast Growth Factor signaling is immense, with documentation of its role in almost every organism and system studied so far. FGF ligands signal through a family of four distinct tyrosine kinase receptors, the FGF receptors (FGFRs). One contribution to the diversity of function and signaling of FGFs and their receptors arises from the numerous alternative splicing variants that have been documented in the FGFR literature. The present review discusses the types and roles of alternatively spliced variants of the FGFR family members and the significant impact of alternative splicing on the physiological functions of five broad classes of FGFR isoforms. Some characterized known regulatory mechanisms of alternative splicing and future directions in studies of FGFR alternative splicing are also discussed. Presence, absence, and/or the combination of specific exons within each FGFR protein impart upon each individual isoform its unique function and expression pattern during normal function and in diseased states (e.g., in cancers and birth defects). A better understanding of the diversity of FGF signaling in different developmental contexts and diseased states can be achieved through increased knowledge of the presence of specific FGFR isoforms and their impact on downstream signaling and functions. Modern high-throughput techniques afford an opportunity to explore the distribution and function of isoforms of FGFR during development and in diseases. © 2014 Wiley Periodicals, Inc.


Kalia L.V.,University of Toronto | Lang A.E.,University of Toronto
The Lancet | Year: 2015

Parkinson's disease is a neurological disorder with evolving layers of complexity. It has long been characterised by the classical motor features of parkinsonism associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra. However, the symptomatology of Parkinson's disease is now recognised as heterogeneous, with clinically significant non-motor features. Similarly, its pathology involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates other than just Lewy bodies. The cause of Parkinson's disease remains unknown, but risk of developing Parkinson's disease is no longer viewed as primarily due to environmental factors. Instead, Parkinson's disease seems to result from a complicated interplay of genetic and environmental factors affecting numerous fundamental cellular processes. The complexity of Parkinson's disease is accompanied by clinical challenges, including an inability to make a definitive diagnosis at the earliest stages of the disease and difficulties in the management of symptoms at later stages. Furthermore, there are no treatments that slow the neurodegenerative process. In this Seminar, we review these complexities and challenges of Parkinson's disease. © 2015 Elsevier Ltd.


Eysenbach G.,University of Toronto
Journal of Medical Internet Research | Year: 2014

In 2012, the Internet Corporation for Assigned Names and Numbers (ICANN) opened a new round of applications for generic top-level domain (gTLD) names, receiving 1930 applications, of which at least 18 were related to health (eg, ".doctor", ".health", ".med"). The entry of new, commercial players applying to create health-related names reopens the debate on the role of international organizations, governments, non-governmental organizations, and other stakeholders regarding the safeguards and policies needed to protect consumers. © Holly O Witteman.


Pearson C.E.,The Hospital for Sick Children | Pearson C.E.,University of Toronto
PLoS Genetics | Year: 2011

Diseases associated with unstable repetitive elements in the DNA, RNA, and amino acids have consistently revealed scientific surprises. Most diseases are caused by expansions of trinucleotide repeats, which ultimately lead to diseases like Huntington's disease, myotonic dystrophy, fragile X syndrome, and a series of spinocerebellar ataxias. These repeat mutations are dynamic, changing through generations and within an individual, and the repeats can be bi-directionally transcribed. Unsuspected modes of pathogenesis involve aberrant loss of protein expression; aberrant over-expression of non-mutant proteins; toxic-gain-of-protein function through expanded polyglutamine tracts that are encoded by expanded CAG tracts; and RNA-toxic-gain-of-function caused by transcripts harboring expanded CUG, CAG, or CGG tracts. A recent advance reveals that RNA transcripts with expanded CAG repeats can be translated in the complete absence of a starting ATG, and this Repeat Associated Non-ATG translation (RAN-translation) occurs across expanded CAG repeats in all reading frames (CAG, AGC, and GCA) to produce homopolymeric proteins of long polyglutamine, polyserine, and polyalanine tracts. Expanded CTG tracts expressing CUG transcripts also show RAN-translation occurring in all three frames (CUG, UGC, and GCU), to produce polyleucine, polycysteine, and polyalanine. These RAN-translation products can be toxic. Thus, one unstable (CAG)•(CTG) DNA can produce two expanded repeat transcripts and homopolymeric proteins with reading frames (the AUG-directed polyGln and six RAN-translation proteins), yielding a total of potentially nine toxic entities. The occurrence of RAN-translation in patient tissues expands our horizons of modes of disease pathogenesis. Moreover, since RAN-translation counters the canonical requirements of translation initiation, many new questions are now posed that must be addressed. This review covers RAN-translation and some of the pertinent questions. © 2011 Christopher E. Pearson.


Deber R.B.,University of Toronto
Healthcare Policy | Year: 2014

Accountability is a key component of healthcare reforms, in Canada and internationally, but there is increasing recognition that one size does not fit all. A more nuanced understanding begins with clarifying what is meant by accountability, including specifying for what, by whom, to whom and how. These papers arise from a Partnership for Health System Improvement (PHSI), funded by the Canadian Institutes of Health Research (CIHR), on approaches to accountability that examined accountability across multiple healthcare subsectors in Ontario. The partnership features collaboration among an interdisciplinary team, working with senior policy makers, to clarify what is known about best practices to achieve accountability under various circumstances. This paper presents our conceptual framework. It examines potential approaches (policy instruments) and postulates that their outcomes may vary by subsector depending upon (a) the policy goals being pursued, (b) governance/ownership structures and relationships and (c) the types of goods and services being delivered, and their production characteristics (e.g., contestability, measurability and complexity).


Qin S.,University of Toronto | Min J.,University of Toronto
Trends in Biochemical Sciences | Year: 2014

PWWP domain-containing proteins are often involved in chromatin-associated biological processes, such as transcriptional regulation and DNA repair, and recent studies have shown that the PWWP domain specifies chromatin localization. Mutations in the PWWP domain, a 100-150 amino acid motif, have been linked to various human diseases, emphasizing its importance. Structural studies reveal that PWWP domains possess a conserved aromatic cage for histone methyl-lysine recognition, and synergistically bind both histone and DNA, which contributes to their nucleosome-binding ability and chromatin localization. Furthermore, the PWWP domain often cooperates with other histone and DNA 'reader' or 'modifier' domains to evoke crosstalk between various epigenetic marks. Here, we discuss these recent advances in understanding the structure and function of the PWWP domain. © 2014 Elsevier Ltd.


Brierley J.D.,University of Toronto
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Surgery is the mainstay of treatment for thyroid cancer. The role for external beam radiotherapy (EBRT) as an adjuvant to surgery or as the primary therapy is established in anaplastic thyroid cancer but is controversial in differentiated thyroid cancer and uncertain in medullary thyroid cancer. This update reviews the recent reported success of combining EBRT with taxanes in anaplastic thyroid cancer. Also discussed are the recent reports from large single institutions that support the recommendations of the American and British Thyroid Associations on the use of EBRT in high-risk differentiated thyroid cancer. Further evidence on the role of EBRT in MTC is discussed. The important advances in the delivery of EBRT using intensity-modulated radiation and image-guided radiation that result in more accurate and potentially more effective radiation therapy with less toxicity are also discussed. Copyright © 2011 by The Endocrine Society.


Duffin J.,University of Toronto
Respiratory Physiology and Neurobiology | Year: 2011

Breathing responds to changes in CO2 and O2 detected by respiratory chemoreceptors. In this paper I examine the methodologies for a quantitative assessment of the respiratory chemoreflex characteristics in humans. My intention is to provide the investigator unfamiliar with these methods an overview and introduction that allows them to choose the methodology that answers their needs. Included are brief background histories of such testing techniques and the way in which they have been refined and improved over time, a description of current techniques and tips for their implementation, and a comparative assessment of their relative strengths and weaknesses. I begin with a statement of the problem that provides a brief review of the chemoreflex control of breathing, and difficulties in measuring the chemoreflex characteristics. Then each of the two major methodologies, steady-state and rebreathing techniques are described in detail. Lastly, I compare and contrast these two methodologies. © 2011 Elsevier B.V.


Mitochondria are key organelles in eukaryotic cells principally responsible for multiple cellular functions. In addition to a plethora of somatic mutations as well as polymorphic sequence variations in mitochondrial DNA (mtDNA), the identification of increased or reduced mtDNA copy number has been increasingly reported in a broad range of primary human cancers, underscoring that accumulation of mtDNA content alterations may be a pivotal factor in eliciting persistent mitochondrial deficient activities and eventually contributing to cancer pathogenesis and progression. However, the detailed roles of altered mtDNA amount in driving the tumorigenic process remain largely unknown. This review outlines mtDNA content changes present in various types of common human malignancies and briefly describes the possible causes and their potential connections to the carcinogenic process. The present state of our knowledge regarding how altered mtDNA quantitative levels could be utilized as a diagnostic biomarker for identifying genetically predisposed population that should undergo intensive screening and early surveillance program is also discussed. Taken together, these findings strongly indicate that mtDNA copy number alterations may exert a crucial role in the pathogenic mechanisms of tumor development. Continued insights into the functional significance of altered mtDNA quantities in the etiology of human cancers will hopefully help in establishing novel potential targets for anti-tumor drugs and intervention therapies. © 2011 Elsevier Inc. All Rights Reserved.


Archer M.C.,University of Toronto
Genes and Cancer | Year: 2011

Cancer cells exhibit altered metabolism characterized by the generation of adenosine triphosphate by glycolysis and generation of fatty acids by de novo synthesis. The majority of genes involved in these pathways have binding sites for specificity protein (Sp) transcription factors in their promoters. Studies showing that Sp transcription factors, particularly Sp1, are involved in the regulation in cancer cells of hexokinase, pyruvate kinase, lactate dehydrogenase, fatty acid synthase, and hypoxia-inducible factor-1α are reviewed. Glycolysis and lipogenesis in cancers are also known to be stimulated by the constitutive activation of the PI3K/Akt signaling pathway. Evidence is presented for the notion that Sp transcription factors may act in concert with Akt to regulate the abnormal metabolism of cancer cells. © The Author(s) 2011.


Laprise P.,Laval University | Tepass U.,University of Toronto
Trends in Cell Biology | Year: 2011

Apical-basal polarity is a basic organizing principle of epithelial cells. Consequently, defects in polarity are associated with numerous human pathologies, including many forms of cancer. Recent work in Drosophila has identified novel roles for, or has greatly enhanced our understanding of, functional modules within the epithelial polarity network. A series of recent papers have highlighted the key function of the scaffolding protein Bazooka/Par3 as an early polarity landmark, and its crucial role in dynamic segregation of the apical membrane from the adherens junction. Moreover, novel polarity modules have recently been discovered; the Yurt/Coracle group supports the basolateral membrane during a defined time window of development, while a second module, including the kinases LKB1 and AMP-activated protein kinase, is required for polarity when epithelial cells experience metabolic stress. These new findings emphasize unforeseen complexities in the regulation of epithelial polarity, and raise new questions about the mechanisms of epithelial tissue organization and function. © 2011 Elsevier Ltd.


Malkin D.,University of Toronto
Genes and Cancer | Year: 2011

Li-Fraumeni syndrome (LFS) is a classic cancer predisposition disorder that is commonly associated with germline mutations of the p53 tumor suppressor gene. Examination of the wide spectrum of adult-onset and childhood cancers and the distribution of p53 mutations has led to a greater understanding of cancer genotype-phenotype correlations. However, the complex LFS phenotype is not readily explained by the simple identification of germline p53 mutations in affected individuals. Recent work has identified genetic events that modify the LFS phenotype. These include intragenic polymorphisms, mutations/polymorphisms of genes in the p53 regulatory pathway, as well as more global events such as aberrant copy number variation and telomere attrition. These genetic events may, in part, explain the breadth of tumor histiotypes within and across LFS families, the apparent accelerated age of onset within families, and the range of clinical outcomes among affected family members. This review will examine the clinical and genetic definitions of LFS and offer insight into how lessons learned from the study of this rare disorder may inform similar questions in other familial cancer syndromes. © The Author(s) 2011.


Frappier L.,University of Toronto | Verrijzer C.P.,Erasmus Medical Center
Current Opinion in Genetics and Development | Year: 2011

Protein ubiquitylation is involved in the regulation of virtually all aspects of eukaryotic cell biology, including gene expression. The central function of E3 ubiquitin ligases in target selection is well established. More recently, it has become appreciated that deubiquitylating enzymes (DUBs) are crucial components of ubiquitin-regulated cellular switches. Here, we discuss advances in our understanding of how DUBs regulate chromatin dynamics and gene expression. DUBs are integral components of the transcription machinery, involved in both gene activation and repression. They modulate the ubiquitylation status of histones H2A and H2B, which play pivotal roles in a cascade of molecular events that determine chromatin status. A DUB module in the SAGA coactivator complex is required for gene activation, whereas other DUBs are part of the Polycomb gene-silencing machinery. DUBs also control the level or subcellular compartmentalization of selective transcription factors, including the tumour suppressor p53. Typically, DUB specificity and activity are defined by its partner proteins, enabling remarkably versatile and sophisticated regulation. Recent findings not only underscore the pervasive and pivotal role of DUBs in gene expression control, but also raise paradoxical questions concerning the molecular mechanisms involved. © 2011 Elsevier Ltd.


Rutkevich L.A.,University of Toronto | Williams D.B.,University of Toronto
Current Opinion in Cell Biology | Year: 2011

Protein folding within the endoplasmic reticulum occurs in conjunction with a complex array of molecular chaperones and folding catalysts that assist the folding process as well as function in quality control processes to monitor the outcome. In this review, we summarize recent advances in the calnexin/calreticulin chaperone system that is directed primarily toward Asn-linked glycoproteins, as well as the protein disulfide isomerase family of enzymes that catalyze disulfide formation, reduction, and isomerization. We highlight issues related to function and substrate specificity as well as the functional interplay between the two systems. © 2010 Elsevier Ltd.


Hirschfield G.M.,University of Toronto | Invernizzi P.,IRCCS Instituto Clinico Humanitas
Seminars in Liver Disease | Year: 2011

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that has a prevalence of 1 in 1000 women over the age of 40. Treatment is presently limited to ursodeoxycholic acid, a hydrophilic bile acid that has nonspecific, choleretic, effects in cholestatic liver disease. PBC has strong autoimmune features, including highly specific loss of tolerance to a ubiquitous mitochondrial antigen. Both environmental and genetic factors are considered important in the pathogenesis of disease. Prior to the advent of genome-wide association studies, only class II human leucocyte antigen (HLA) loci (HLA-DRB1*08,*11, and*13) had been reproducibly shown to associate with disease. Non-HLA loci were suggested for several genes (e.g., CTLA-4, MDR3), but often inconclusively replicated. With the application of genome-wide technology, HLA was confirmed as the strongest association and many other risk loci have been identified, with equivalent effect size to HLA, including IL12A, IL12RB2, STAT4, IRF5-TNPO3, 17q12.21, MMEL1, SPIB, and CTLA-4. These collectively support an important role for innate and adaptive immunity in development of disease. Further insights are predicted as studies with larger cohorts are assembled, and different approaches are taken to further discover common and uncommon gene variants associated with disease. Disease subphenotypes such as response to therapy, clinical progression, and symptoms remain additional areas for further dedicated studies, and in which different genetic risk factors may be relevant. Identification of risk loci associated with disease has the potential to aid development of rational, disease-specific, therapies in the future. © 2011 by Thieme Medical Publishers, Inc.


Klotz L.,University of Toronto | Emberton M.,University College London
Nature Reviews Clinical Oncology | Year: 2014

Low-risk prostate cancer, defined as Gleason Score 6 or less with PSA <10 ng/ml, is diagnosed in about half of men undergoing screening. Approximately 30% of men diagnosed with low-risk disease harbour high-grade cancer that is unrepresented on the biopsy. Moreover, a small percentage of low-grade cancers have molecular alterations that result in progression to aggressive disease. Favourable-risk prostate cancer should be managed with close follow up. Active surveillance is appropriate for most patients with low-risk disease, and radical treatment should be reserved for cases in which higher-risk disease is identified. In turn, focal therapy aims to preserve tissue and function in men who have been diagnosed with localized disease, and should be offered to men with higher risk disease at baseline, as an alternative to whole-gland radiation or surgery, or when the patient transitions from low-risk to higher-risk disease. The two strategies should be viewed as complementary elements of care that can be applied in a risk-stratified manner. In this Review, we discuss the rationale and current status of active surveillance-which constitutes a standard of care in most evidence-based guidelines-and comment on whether and when focal therapy should complement it in those men wishing to continue a tissue-preserving strategy. © 2014 Macmillan Publishers Limited. All rights reserved. © 2014 Macmillan Publishers Limited. All rights reserved.


Hanley W.B.,University of Toronto
Molecular Genetics and Metabolism | Year: 2011

Recent reviews have suggested that some patients with "non-PKU mild hyperphenylalaninemia" (MHP) might display neuropsychological executive function deficits and should be considered for treatment with tetrahydrobipterin (BH4) and/or phenylalanine (Phe) restricted diet.Patients with phenylketonuria (PKU) - Classical and Mild/Atypical variants - appear to need "mean lifetime phenylalanine (Phe) levels" of 120-360 μmol/L for optimal results. MHP patients, on the other hand, have natural Phe levels of 200-600 μmol/L. Until recently this was thought to be a benign condition.The available literature has been reviewed in detail and no good evidence, to date, has been uncovered to support treatment of MHP. It is suggested that more MHP subjects be tested to confirm this.A plea is made to formulate a consistent world-wide classification of the PKU phenotypes. © 2011 Elsevier Inc.


Jaumouille V.,University of Toronto | Grinstein S.,University of Toronto
Current Opinion in Cell Biology | Year: 2011

Particle engulfment during phagocytosis has long been appreciated to be an active, actin-driven process. By contrast, the preceding stage - securing the target to the surface of the phagocyte - was thought to result from the passive diffusion of receptors along the membrane towards their ligands on the particle surface. Recent evidence, however, challenges this notion, demonstrating that receptors do not diffuse freely along the phagocyte surface and that actin polymerization and tyrosine phosphorylation are required for optimal particle binding. The interpretation and significance of these observations are the subject of this opinion piece. © 2010 Elsevier Ltd.


Tran B.,University of Toronto | Bedard P.L.,University of Toronto
Breast Cancer Research | Year: 2011

Gene expression profiling has led to a new molecular classification of breast cancer characterized by four intrinsic subtypes: basal-like, HER2-positive, luminal A, and luminal B. Despite expressing estrogen receptor, the luminal-B subtype confers increased risk of early relapse with endocrine therapy compared with the luminal-A subtype. Although luminal-B definitions vary, the hallmark appears to be increased expression of proliferation-related genes. Several biological pathways are identified as possible contributors to the poor outcomes, and novel agents targeting these pathways are being developed with aims to improve survival. We review the definition of luminal-B breast cancer, its pathological and clinical features, and potential targets for treatment. © 2011 BioMed Central Ltd.


Schapira M.,University of Toronto
Current Chemical Genomics | Year: 2011

There are about fifty SET domain protein methyltransferases (PMTs) in the human genome, that transfer a methyl group from S-adenosyl-L-methionine (SAM) to substrate lysines on histone tails or other peptides. A number of structures in complex with cofactor, substrate, or inhibitors revealed the mechanisms of substrate recognition, methylation state specificity, and chemical inhibition. Based on these structures, we review the structural chemistry of SET domain PMTs, and propose general concepts towards the development of selective inhibitors. © Matthieu Schapira.


Kushwah R.,University of Toronto | Hu J.,University of Toronto
Cell and Bioscience | Year: 2011

Dendritic cells (DCs) play a key role in initiating immune responses and maintaining immune tolerance. In addition to playing a role in thymic selection, DCs play an active role in tolerance under steady state conditions through several mechanisms which are dependent on IL-10, TGF-β, retinoic acid, indoleamine-2,3,-dioxygenase along with vitamin D. Several of these mechanisms are employed by DCs in induction of regulatory T cells which are comprised of Tr1 regulatory T cells, natural and inducible foxp3 +regulatory T cells, Th3 regulatory T cells and double negative regulatory T cells. It appears that certain DC subsets are highly specialized in inducing regulatory T cell differentiation and in some tissues the local microenvironment plays a role in driving DCs towards a tolerogenic response. In this review we discuss the recent advances in our understanding of the mechanisms underlying DC driven regulatory T cell induction. © 2011 Kushwah and Hu; licensee BioMed Central Ltd.


Billeter J.C.,University of Toronto
Proceedings. Biological sciences / The Royal Society | Year: 2012

In Drosophila melanogaster, biological rhythms, aggression and mating are modulated by group size and composition. However, the fitness significance of this group effect is unknown. By varying the composition of groups of males and females, we show that social context affects reproductive behaviour and offspring genetic diversity. Firstly, females mating with males from the same strain in the presence of males from a different strain are infecund, analogous to the Bruce effect in rodents, suggesting a social context-dependent inbreeding avoidance mechanism. Secondly, females mate more frequently in groups composed of males from more than one strain; this mitigates last male sperm precedence and increases offspring genetic diversity. However, smell-impaired Orco mutant females do not increase mating frequency according to group composition; this indicates that social context-dependent changes in reproductive behaviour depend on female olfaction, rather than direct male-male interactions. Further, variation in mating frequency in wild-type strains depends on females and not males. The data show that group composition can affect variance in the reproductive success of its members, and that females play a central role in this process. Social environment can thus influence the evolutionary process.


Yaffe M.J.,University of Toronto | Mainprize J.G.,University of Toronto
Radiology | Year: 2010

Purpose: To assess a schema for estimating the risk of radiationinduced breast cancer following exposure of the breast to ionizing radiation as would occur with mammography and to provide data that can be used to estimate the potential number of breast cancers, cancer deaths, and womanyears of life lost attributable to radiation exposure delivered according to a variety of screening scenarios. Materials and Methods: An excess absolute risk model was used to predict the number of radiation-induced breast cancers attributable to the radiation dose received for a single typical digital mammography examination. The algorithm was then extended to consider the consequences of various scenarios for routine screening beginning and ending at different ages, with examinations taking place at 1-or 2-year intervals. A life-table correction was applied to consider reductions of the cohort size over time owing to nonradiationrelated causes of death. Finally, the numbers of breast cancer deaths and woman-years of life lost that might be attributable to the radiation exposure were calculated. Cancer incidence and cancer deaths were estimated for individual attained ages following the onset of screening, and lifetime risks were also calculated. Results: For a cohort of 100000 women each receiving a dose of 3.7 mGy to both breasts and who were screened annually from age 40 to 55 years and biennially thereafter to age 74 years, it is predicted that there will be 86 cancers induced and 11 deaths due to radiation-induced breast cancer. Conclusion: For the mammographic screening regimens considered that begin at age 40 years, this risk is small compared with the expected mortality reduction achievable through screening. The risk of radiation-induced breast cancer should not be a deterrent from mammographic screening of women over the age of 40 years. © RSNA, 2010.


Olaya-Castro A.,University College London | Scholes G.D.,University of Toronto
International Reviews in Physical Chemistry | Year: 2011

Electronic excitation energy transfer is ubiquitous in a variety of multi- chromophoric systems and has been a subject of numerous investigations in the last century. Recently, sophisticated experimental and theoretical studies of excited state dynamics have been developed with the purpose of attaining a more detailed picture of the coherent and incoherent quantum dynamics relevant to energy transfer processes in a variety of molecular aggregates. In particular, great efforts have been made towards finding experimental signatures of coherent superpositions of electronic states in some light-harvesting antenna complexes and to understand their practical implications. This review intends to provide some foundations, and perhaps inspirations, of new directions of research. In particular, we emphasise current opinions of several effects that go beyond normal Förster theory and highlight open problems in the description of energy transfer beyond standard approximations as well as the need of new approaches to characterise the 'quantumness' of excited states and energy transfer dynamics in multichromophoric systems. © 2011 Taylor & Francis.


This section of the cervical spondylotic myelopathy Spine focus issue collates the existing evidence related to natural history and nonoperative management. In the case of patients with symptomatic cervical spondylotic myelopathy treated nonoperatively, while 20% to 62% will deteriorate at 3 to 6 years of follow-up, no specific patient or disease characteristics have been shown to predict this change reliably. For patients without myelopathy with spondylotic cord compression, the rate of myelopathy development is approximately 8% at 1 year and approximately 23% at 4 years of follow-up. Clinical and/or electrophysiological evidence of cervical radiculopathy has been shown to predict such progression and should prompt strong consideration of surgical decompression. With respect to nonoperative care, in the case of mild myelopathy, there is low evidence that such treatment may have a role; for moderate and severe myelopathy, this treatment results in outcomes inferior to those of surgery and is not recommended. Given the unpredictably progressive nature of cervical myelopathy, the indications for nonoperative management are ostensibly limited. Finally, the preclinical rationale and clinical translation of a putative neuroprotective drug, which may one day serve to augment the effects of surgery in the treatment of cervical spondylotic myelopathy, is presented and discussed.


Weatheritt R.J.,University of Toronto | Gibson T.J.,Structural and Computational Biology Unit | Babu M.M.,University of Cambridge
Nature Structural and Molecular Biology | Year: 2014

Although many proteins are localized after translation, asymmetric protein distribution is also achieved by translation after mRNA localization. Why are certain mRNA transported to a distal location and translated on-site? Here we undertake a systematic, genome-scale study of asymmetrically distributed protein and mRNA in mammalian cells. Our findings suggest that asymmetric protein distribution by mRNA localization enhances interaction fidelity and signaling sensitivity. Proteins synthesized at distal locations frequently contain intrinsically disordered segments. These regions are generally rich in assembly-promoting modules and are often regulated by post-translational modifications. Such proteins are tightly regulated but display distinct temporal dynamics upon stimulation with growth factors. Thus, proteins synthesized on-site may rapidly alter proteome composition and act as dynamically regulated scaffolds to promote the formation of reversible cellular assemblies. Our observations are consistent across multiple mammalian species, cell types and developmental stages, suggesting that localized translation is a recurring feature of cell signaling and regulation.


Chen T.,University of Toronto | Song J.,University of Toronto | Chan H.S.,University of Toronto
Current Opinion in Structural Biology | Year: 2015

The diverse biological functions of intrinsically disordered proteins (IDPs) have markedly raised our appreciation of protein conformational versatility, whereas the existence of energetically favorable yet functional detrimental nonnative interactions underscores the physical limitations of evolutionary optimization. Here we survey recent advances in using biophysical modeling to gain insight into experimentally observed nonnative behaviors and IDP properties. Simulations of IDP interactions to date focus mostly on coupled folding-binding, which follows essentially the same organizing principle as the local-nonlocal coupling mechanism in cooperative folding of monomeric globular proteins. By contrast, more innovative theories of electrostatic and aromatic interactions are needed for the conceptually novel but less-explored 'fuzzy' complexes in which the functionally bound IDPs remain largely disordered. © 2014 Elsevier Ltd.


Beale T.M.,University of Toronto | Chudzinski M.G.,University of Toronto | Sarwar M.G.,University of Toronto | Taylor M.S.,University of Toronto
Chemical Society Reviews | Year: 2013

Halogen bonds are noncovalent interactions in which covalently bound halogens act as electrophilic species. The utility of halogen bonding for controlling self-assembly in the solid state is evident from a broad spectrum of applications in crystal engineering and materials science. Until recently, it has been less clear whether, and to what extent, halogen bonding could be employed to influence conformation, binding or reactivity in the solution phase. This tutorial review summarizes and interprets solution-phase thermodynamic data for halogen bonding interactions obtained over the past six decades and highlights emerging applications in molecular recognition, medicinal chemistry and catalysis. © 2013 The Royal Society of Chemistry.


Richardson D.B.,University of Toronto
Renewable and Sustainable Energy Reviews | Year: 2013

Electric vehicles (EVs) and renewable energy sources offer the potential to substantially decrease carbon emissions from both the transportation and power generation sectors of the economy. Mass adoption of EVs will have a number of impacts and benefits, including the ability to assist in the integration of renewable energy into existing electric grids. This paper reviews the current literature on EVs, the electric grid, and renewable energy integration. Key methods and assumptions of the literature are discussed. The economic, environmental and grid impacts of EVs are reviewed. Numerous studies assessing the ability of EVs to integrate renewable energy sources are assessed; the literature indicates that EVs can significantly reduce the amount of excess renewable energy produced in an electric system. Studies on wind-EV interaction are much more detailed than those on solar photovoltaics (PV) and EVs. The paper concludes with recommendations for future research. © 2012 Elsevier Ltd.


Morris R.H.,University of Toronto
Journal of the American Chemical Society | Year: 2014

A simple equation (pKa THF = ΣAL + Ccharge + Cnd + Cd6) can be used to obtain an estimate of the pKa of diamagnetic transition metal hydride and dihydrogen complexes in tetrahydrofuran, and, by use of conversion equations, in other solvents. It involves adding acidity constants AL for each of the ligands in the 5-, 6-, 7-, or 8-coordinate conjugate base complex of the hydride or dihydrogen complex along with a correction for the charge (C charge = -15, 0 or 30 for x = +1, 0 or -1 charge, respectively) and the periodic row of the transition metal (Cnd = 0 for 3d or 4d metal, 2 for 5d metal) as well as a correction for d6 octahedral acids (Cd6 = 6 for d6 metal ion in the acid, 0 for others) that are not dihydrogen complexes. Constants AL are provided for 13 commonly occurring ligand types; of these, nine neutral ligands are correlated with Lever's electrochemical ligand parameters EL. This method gives good estimates of the over 170 literature pKa values that range from less than zero to 50 with a standard deviation of 3 pKa units for complexes of the metals chromium to nickel, molybdenum, ruthenium to palladium, and tungsten to platinum in the periodic table. This approach allows a quick assessment of the acidity of hydride complexes found in nature (e.g., hydrogenases) and in industry (e.g., catalysis and hydrogen energy applications). The pKa values calculated for acids that have bulky or large bite angle chelating ligands deviate the most from this correlation. The method also provides an estimate of the base strength of the deprotonated form of the complex. © 2014 American Chemical Society.


Isakson S.R.,University of Toronto
Journal of Agrarian Change | Year: 2015

While agricultural production has always been a risky endeavour, it has become even more so in the current context of climatic change and increasing market uncertainty. Meanwhile, the rollback of state protections has rendered small-scale farmers, especially marginalized peasant producers in the Global South, particularly vulnerable to these contemporary stressors. This essay critically evaluates the contemporary roll-out of financial derivatives that purportedly aim to mitigate smallholder vulnerability. It gives particular attention to a novel type of derivative known as index-based agricultural insurance (IBAI) that plays an increasingly prominent role in initiatives to 'climate proof' agriculture. The creation of IBAI markets has required significant work, including (1) technical interventions to debundle environmental risk from agricultural production and rebundle it in novel ways that support private financial capital and agricultural input suppliers, (2) extensive state support in the creation of risk markets, and (3) the construction of an accommodating 'insurance culture' among small-scale producers. In addition to mitigating weather-based risk, a primary objective of IBAI is to spur agricultural modernization. In promoting this agenda, IBAI initiatives may have the paradoxical effect of exposing smallholders to new risks while expanding their overall vulnerability to environmental and economic stressors. © 2015 John Wiley & Sons Ltd.


Vallurupalli P.,University of Toronto | Bouvignies G.,University of Toronto | Kay L.E.,University of Toronto
Journal of the American Chemical Society | Year: 2012

Ever since its initial development, solution NMR spectroscopy has been used as a tool to study conformational exchange. Although many systems are amenable to relaxation dispersion approaches, cases involving highly skewed populations in slow chemical exchange have, in general, remained recalcitrant to study. Here an experiment to detect and characterize "invisible" excited protein states in slow exchange with a visible ground-state conformation (excited-state lifetimes ranging from ∼5 to 50 ms) is presented. This method, which is an adaptation of the chemical exchange saturation transfer (CEST) magnetic resonance imaging experiment, involves irradiating various regions of the spectrum with a weak B 1 field while monitoring the effect on the visible major-state peaks. The variation in major-state peak intensities as a function of frequency offset and B 1 field strength is quantified to obtain the minor-state population, its lifetime, and excited-state chemical shifts and line widths. The methodology was validated with 15N CEST experiments recorded on an SH3 domain-ligand exchanging system and subsequently used to study the folding transition of the A39G FF domain, where the invisible unfolded state has a lifetime of ∼20 ms. Far more accurate exchange parameters and chemical shifts were obtained than via analysis of Carr-Purcell-Meiboom-Gill relaxation dispersion data. © 2012 American Chemical Society.


Barrett S.C.H.,University of Toronto
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Flowering plants possess an unrivaled diversity of mechanisms for achieving sexual and asexual reproduction, often simultaneously. The commonest type of asexual reproduction is clonal growth (vegetative propagation) in which parental genotypes (genets) produce vegetative modules (ramets) that are capable of independent growth, reproduction, and often dispersal. Clonal growth leads to an expansion in the size of genets and increased fitness because large floral displays increase fertility and opportunities for outcrossing. Moreover, the clonal dispersal of vegetative propagules can assist "mate finding," particularly in aquatic plants. However, there are ecological circumstances in which functional antagonism between sexual and asexual reproductive modes can negatively affect the fitness of clonal plants. Populations of heterostylous and dioecious species have a small number of mating groups (two or three), which should occur at equal frequency in equilibrium populations. Extensive clonal growth and vegetative dispersal can disrupt the functioning of these sexual polymorphisms, resulting in biased morph ratios and populations with a single mating group, with consequences for fertility and mating. In populations in which clonal propagation predominates, mutations reducing fertility may lead to sexual dysfunction and even the loss of sex. Recent evidence suggests that somatic mutations can play a significant role in influencing fitness in clonal plants and may also help explain the occurrence of genetic diversity in sterile clonal populations. Highly polymorphic genetic markers offer outstanding opportunities for gaining novel insights into functional interactions between sexual and clonal reproduction in flowering plants. © 2015, National Academy of Sciences. All rights reserved.


Robinson G.E.,University of Toronto
Journal of Nervous and Mental Disease | Year: 2015

There is controversy about the use of antidepressant medication during pregnancy. Decisions about their use are affected by understanding the risks of these medications causing pregnancy loss, congenitalmalformations, neonatal adaptation syndrome, persistent pulmonary hypertension of the newborn, autism spectrum disorder, or long-term neurocognitive deficits. Although some research has raised concerns about antidepressants causing harm to the fetus and neonate, other studies have disputed these findings or noted that any risks found do not exceed the risk of congenital problems found in 1%to 3% of neonates in the general population. Untreated depression during pregnancy can also cause harm from poor diet, substance abuse, suicidal behavior, or prematurity. Decisions about the use of antidepressants during pregnancy must be based on a risk-benefit analysis based on the best evidence of the risks of treating or not treatingmaternal depression. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Ohlsson A.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer side effects. To determine the efficacy and safety of ibuprofen for closing a PDA in preterm and/or low birth weight infants. Seperate comparisons are presented for 1. ibuprofen (iv) compared with placebo; 2. ibuprofen (oral) compared with placebo; 3. ibuprofen (oral or iv) compared with other cyclo-oxygenase inhibitors (given iv or orally); 4. ibuprofen (oral) versus indomethacin (given iv or orally); 5. ibuprofen (oral) versus iv ibuprofen; 6. high dose versus standard dose of iv ibuprofen; 7. early versus expectant administration of iv ibuprofen. We searched The Cochrane Library, MEDLINE, EMBASE, Clincialtrials.gov, Controlled-trials.com, www.abstracts2view.com/pas, and personal files in July 2012. Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in newborn infants. Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. Twenty-seven studies are included in this review. One study (n = 136) compared iv ibuprofen versus placebo. Ibuprofen reduced the composite outcome of infant deaths, infants who dropped out or required rescue treatment; risk ratio (RR) 0.58 (95% confidence interval (CI) 0.38 to 0.89); risk difference (RD) -0.22 (95% CI -0.38 to -06); number needed to benefit (NNTB) 5 (95% CI 3 to 17). One study (n = 64) compared oral ibuprofen with placebo. There was a significant reduction in the failure rate to close a PDA; RR 0.26 (95% CI 0.11 to 0.62); RD -0.44 (95% CI -0.65 to -0.23); NNTB 2 (95% CI 2 to 4). Failure rates for PDA closure with ibuprofen (oral or iv) compared with indomethacin (oral or iv) was reported in 20 studies (n = 1019 infants). There was no significant difference between the groups; typical RR 0.98 (95% CI 0.80 to 1.20) I(2) = 0%; typical RD -0.01 (95% CI -0.06 to 0.05); I(2) = 0%. The risk of developing necrotising enterocolitis (NEC) was reduced for ibuprofen (15 studies (n = 865); typical RR 0.68 (95% CI 0.47 to 0.99); typical RD -0.04 (95% CI -0.08 to -0.00; (P = 0.04); NNTB 25 (95% CI 13, infinity); I(2) = 0%). The duration of ventilatory support was reduced with ibuprofen (oral or iv) compared with iv or oral indomethacin (six studies, n = 471) mean difference (MD) -2.35 days (95% CI -3.71 to -0.99); I(2) = 19%. Failure rates for PDA closure with oral ibuprofen compared with indomethacin (oral or iv) were reported in seven studies (n = 189 infants). There was no significant difference between the groups; typical RR 0.82 (95% CI 0.52 to 1.29); typical RD -0.06 (95% CI -0.18 to 0.06). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (oral or iv) six studies (n = 166); typical RR 0.44 (95% CI 0.23 to 0.82); RD -0.15 (95% CI -0.25 to -0.04); NNTB 7 (95% CI 4 to 25). There was no heterogeneity for this outcome. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with iv ibuprofen, three studies (n = 236) typical RR 0.37 (95% CI 0.23 to 0.61); typical RD -0.24 (95% CI -0.35 to -0.13); NNTB 4 (95% CI 3 to 8). There was less evidence of transient renal insufficiency in infants who received ibuprofen compared with indomethacin. High dose versus standard dose of iv ibuprofen and early versus expectant administration of iv ibuprofen have only been studied in two trials. Ibuprofen is as effective as indomethacin in closing a PDA and reduces the risk of NEC and transient renal insufficiency. Given the reduction in NEC ibuprofen currently appears to be the drug of choice. Oro-gastric administration of ibuprofen appears at least as effective as iv administration. Too few patients have been enrolled in studies assessing the effectiveness of a high dose of ibuprofen versus the standard dose and early versus expectant administration of ibuprofen to make recommendations. Studies are needed to evaluate the effect of ibuprofen compared with indomethacin treatment on longer-term outcomes in infants with PDA.


Dennis C.L.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

A meta-analysis of 21 studies suggests the mean prevalence rate for depression across the antenatal period is 10.7%, ranging from 7.4% in the first trimester to a high of 12.8% in the second trimester. Due to maternal treatment preferences and potential concerns about fetal and infant health outcomes, diverse non-pharmacological treatment options are needed. To assess the effect of interventions other than pharmacological, psychosocial, or psychological interventions compared with usual antepartum care in the treatment of antenatal depression. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013), scanned secondary references and contacted experts in the field to identify other published or unpublished trials. All published and unpublished randomised controlled trials of acceptable quality evaluating non-pharmacological/psychosocial/psychological interventions to treat antenatal depression. Both review authors participated in the evaluation of methodological quality and data extraction. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for continuous data. Six trials were included involving 402 women from the United States, Switzerland, and Taiwan. For most comparisons a single trial contributed data and there were few statistically significant differences between control and intervention groups.In a trial with 38 women maternal massage compared with non-specific acupuncture (control group) did not significantly decrease the number of women with clinical depression or depressive symptomatology immediately post-treatment (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.25 to 2.53; mean difference (MD) -2.30, 95% CI -6.51 to 1.91 respectively). In another trial with 88 women there was no difference in treatment response or depression remission rates in women receiving maternal massage compared with those receiving non-specific acupuncture (RR 1.33, 95% CI 0.82 to 2.18; RR 1.14, 95% CI 0.59 to 2.19 respectively).In a trial with 35 women acupuncture specifically treating symptoms of depression, compared with non-specific acupuncture, did not significantly decrease the number of women with clinical depression or depressive symptomatology immediately post-treatment (RR 0.47, 95% CI 0.11 to 2.13; MD -3.00, 95% CI -8.10 to 2.10). However, women who received depression-specific acupuncture were more likely to respond to treatment compared with those receiving non-specific acupuncture (RR 1.68, 95% CI 1.06 to 2.66).In a trial with 149 women, maternal massage by a woman's significant other, compared with standard care, significantly decreased the number of women with depressive symptomatology immediately post-treatment (MD -6.70, 95% CI -9.77 to -3.63). Further, women receiving bright light therapy had a significantly greater change in their mean depression scores over the five weeks of treatment than those receiving a dim light placebo (one trial, n = 27; MD -4.80, 95% CI -8.39 to -1.21). However, they were not more likely to have a treatment response or experience a higher remission rate (RR 1.79, 95% CI 0.90 to 3.56; RR 1.89, 95% CI 0.81 to 4.42).Lastly, two trials examined the treatment effect of omega-3 oils. Women receiving omega-3 had a significantly lower mean depression score following eight weeks of treatment than those receiving a placebo (one trial, n = 33; MD -4.70, 95% CI -7.82 to -1.58). Conversely, in a smaller trial (21 women) there was no significant difference in the change in mean depression scores for women receiving omega-3 and those receiving a placebo (MD 0.36, 95% CI -0.17 to 0.89), and women who received omega-3 were no more likely to respond to treatment (RR 2.26, 95% CI 0.78 to 6.49) or have higher remission rates (RR 2.12, 95% CI 0.51 to 8.84). Women in the placebo group were just as likely to report a side effect as those in the omega-3 group (RR 1.12, 95% CI 0.56 to 2.27). The evidence is inconclusive to allow us to make any recommendations for depression-specific acupuncture, maternal massage, bright light therapy, and omega-3 fatty acids for the treatment of antenatal depression. The included trials were too small with non-generalisable samples, to make any recommendations.


Ohlsson A.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Nosocomial infections continue to be a significant cause of morbidity and mortality among preterm and/or low birth weight (LBW) infants. Preterm infants are deficient in immunoglobulin G (IgG); therefore, administration of intravenous immunoglobulin (IVIG) may have the potential of preventing or altering the course of nosocomial infections. To use systematic review/meta-analytical techniques to determine whether IVIG administration (compared with placebo or no intervention) to preterm (< 37 weeks' postmenstrual age (PMA) at birth) or LBW (< 2500 g birth weight) infants or both is effective/safe in preventing nosocomial infection. For this update, MEDLINE, EMBASE, CINAHL, The Cochrane Library, Controlled Trials, ClinicalTrials.gov and PAS Abstracts2view were searched in May 2013. We selected randomised controlled trials (RCTs) in which a group of participants to whom IVIG was given was compared with a control group that received a placebo or no intervention for preterm (< 37 weeks' gestational age) and/or LBW (< 2500 g) infants. Studies that were primarily designed to assess the effect of IVIG on humoral immune markers were excluded, as were studies in which the follow-up period was one week or less. Data collection and analysis was performed in accordance with the methods of the Cochrane Neonatal Review Group. Nineteen studies enrolling approximately 5000 preterm and/or LBW infants met inclusion criteria. No new trials were identified in May 2013.When all studies were combined, a significant reduction in sepsis was noted (typical risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74 to 0.98; typical risk difference (RD) -0.03, 95% CI 0.00 to -0.05; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 20 to infinity), and moderate between-study heterogeneity was reported (I(2) 54% for RR, 55% for RD). A significant reduction of one or more episodes was found for any serious infection when all studies were combined (typical RR 0.82, 95% CI 0.74 to 0.92; typical RD -0.04, 95% CI -0.02 to -0.06; NNTB 25, 95% CI 17 to 50), and moderate between-study heterogeneity was observed (I(2) 50% for RR, 62% for RD). No statistically significant differences in mortality from all causes were noted (typical RR 0.89, 95% CI 0.75 to 1.05; typical RD -0.01, 95% CI -0.03 to 0.01), and no heterogeneity for RR (I(2) = 21%) or low heterogeneity for RD was documented (I(2) = 28%). No statistically significant difference was seen in mortality from infection; in incidence of necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) or intraventricular haemorrhage (IVH) or in length of hospital stay. No major adverse effects of IVIG were reported in any of these studies. IVIG administration results in a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection but is not associated with reductions in other clinically important outcomes, including mortality. Prophylactic use of IVIG is not associated with any short-term serious side effects.The decision to use prophylactic IVIG will depend on the costs and the values assigned to the clinical outcomes. There is no justification for conducting additional RCTs to test the efficacy of previously studied IVIG preparations in reducing nosocomial infections in preterm and/or LBW infants.


Ohlsson A.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Neonates are at higher risk of infection due to immuno-incompetence. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks' gestation, and endogenous synthesis begins several months after birth. Administration of intravenous immunoglobulin (IVIG) provides immunoglobulin G (IgG) that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody-dependent cytotoxicity and improve neutrophilic chemo-luminescence. Theoretically, infectious morbidity and mortality could be reduced by the administration of IVIG. To assess the effects of IVIG on mortality/morbidity caused by suspected or proven infection at study entry in neonates. To assess in a subgroup analysis the effects of IgM-enriched IVIG on mortality from suspected infection. For this update, MEDLINE, EMBASE, The Cochrane Library, CINAHL, trial registries, Web of Science, reference lists of identified studies, meta-analyses and personal files were searched in 2013. No language restrictions were applied. Randomised or quasi-randomised controlled trials; newborn infants (< 28 days old); IVIG for treatment of suspected or proven bacterial/fungal infection compared with placebo or no intervention; one of the following outcomes was reported: mortality, length of hospital stay or psychomotor development at follow-up. Statistical analyses included typical risk ratio (RR), risk difference (RD), weighted mean difference (WMD), number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) (all with 95% confidence intervals (CIs) and the I-squared (I(2)) statistic to examine for statistical heterogeneity). The updated search identified one published study and one ongoing study. A total of eight studies evaluating 3871 infants are included in this review.Mortality during hospital stay in infants with clinically suspected infection at trial entry was not significantly different after IVIG treatment (8 studies (n = 2425); typical RR 0.94, 95% CI 0.80 to 1.12; typical RD -0.01, 95% CI - 0.04 to 0.02 I(2) = 28% for RR and 32% for RD). Death or major disability at 2 years corrected age was not significantly different in infants with suspected infection after IVIG treatment (one study (n = 1985); RR 0.98, 95% CI 0.88 to 1.09 RD -0.01, 95% CI -0.05 to 0.03). Mortality during hospital stay was not significantly different after IVIG treatment in infants with proven infection at trial entry (RR 0.95, 95% CI 0.74 to 1.21 RD -0.01, 95% CI -0.04 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with proven infection at trial entry (RR 1.03, 95% CI 0.91 to 1.18; RD 0.01, 95% CI -0.04 to 0.06). Mortality during hospital stay in infants with clinically suspected or proven infection at trial entry was not significantly different after IVIG treatment (1 study (n = 3493); RR 1.00, 95% CI 0.86 to 1.16; RD 0.00, 95% CI - 0.02 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with suspected or proven infection at trial entry (1 study (n = 3493); RR 1.00, 95% CI 0.92 to 1.09; RD -0.00, 95% CI -0.03 to 0.03). Length of hospital stay was not reduced for infants with suspected/proven infection at trial entry (1 study (n = 3493); mean difference (MD) 0.00 days, 95% CI -0.61 to 0.61). No significant difference in mortality during hospital stay after IgM-enriched IVIG treatment for suspected infection was reported at trial entry (3 studies (n = 164); typical RR 0.57, 95% CI 0.31 to 1.04; RD -0.12, 95% CI -0.24 to 0.00 ; P = 0.06); I(2) = 2% for RR and 0% for RD). In previous reviews, we encouraged researchers to undertake well-designed trials to confirm or refute the effectiveness of IVIG in reducing adverse outcomes in neonates with suspected infection. Such a trial has been undertaken. Results of the INIS trial, which enrolled 3493 infants, carry a heavy weight in the current update of this review, and the undisputed results show no reduction in death or major disability at 2 years of age. Routine administration of IVIG to prevent mortality in infants with suspected or proven neonatal infection is not recommended.


Dennis C.L.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2013

Epidemiological studies and meta-analyses of predictive studies have consistently demonstrated the importance of psychosocial and psychological variables as postpartum depression risk factors. While interventions based on these variables may be effective treatment strategies, theoretically they may also be used in pregnancy and the early postpartum period to prevent postpartum depression. Primary: to assess the effect of diverse psychosocial and psychological interventions compared with usual antepartum, intrapartum, or postpartum care to reduce the risk of developing postpartum depression. Secondary: to examine (1) the effectiveness of specific types of psychosocial and psychological interventions, (2) the effectiveness of professionally-based versus lay-based interventions, (3) the effectiveness of individually-based versus group-based interventions, (4) the effects of intervention onset and duration, and (5) whether interventions are more effective in women selected with specific risk factors. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2011), scanned secondary references and contacted experts in the field. We updated the search on 31 December 2012 and added the results to the awaiting classification section of the review for assessment at the next update. All published and unpublished randomised controlled trials of acceptable quality comparing a psychosocial or psychological intervention with usual antenatal, intrapartum, or postpartum care. Review authors and a research co-ordinator with Cochrane review experience participated in the evaluation of methodological quality and data extraction. Additional information was sought from several trial researchers. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for continuous data. Twenty-eight trials, involving almost 17,000 women, contributed data to the review. Overall, women who received a psychosocial or psychological intervention were significantly less likely to develop postpartum depression compared with those receiving standard care (average RR 0.78, 95% confidence interval (CI) 0.66 to 0.93; 20 trials, 14,727 women). Several promising interventions include: (1) the provision of intensive, individualised postpartum home visits provided by public health nurses or midwives (RR 0.56, 95% CI 0.43 to 0.73; two trials, 1262 women); (2) lay (peer)-based telephone support (RR 0.54, 95% CI 0.38 to 0.77; one trial, 612 women); and (3) interpersonal psychotherapy (standardised mean difference -0.27, 95% CI -0.52 to -0.01; five trials, 366 women). Professional- and lay-based interventions were both effective in reducing the risk to develop depressive symptomatology. Individually-based interventions reduced depressive symptomatology at final assessment (RR 0.75, 95% CI 0.61 to 0.92; 14 trials, 12,914 women) as did multiple-contact interventions (RR 0.78, 95% CI 0.66 to 0.93; 16 trials, 11,850 women). Interventions that were initiated in the postpartum period also significantly reduced the risk to develop depressive symptomatology (RR 0.73, 95% CI 0.59 to 0.90; 12 trials, 12,786 women). Identifying mothers 'at-risk' assisted the prevention of postpartum depression (RR 0.66, 95% CI 0.50 to 0.88; eight trials, 1853 women). Overall, psychosocial and psychological interventions significantly reduce the number of women who develop postpartum depression. Promising interventions include the provision of intensive, professionally-based postpartum home visits, telephone-based peer support, and interpersonal psychotherapy.


Sud S.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2013

High frequency oscillation is an alternative to conventional mechanical ventilation that is sometimes used to treat patients with acute respiratory distress syndrome, but effects on oxygenation, mortality and adverse clinical outcomes are uncertain. This review was originally published in 2004 and was updated in 2011. To determine clinical and physiological effects of high frequency oscillation (HFO) in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) compared to conventional ventilation. We electronically searched CENTRAL (Ovid), MEDLINE (Ovid), EMBASE (Ovid), and ISI (from inception to March 2011). The original search was performed in 2002. We manually searched reference lists from included studies and review articles; searched conference proceedings of the American Thoracic Society (1994 to 2010), Society of Critical Care Medicine (1994 to 2010), European Society of Intensive Care Medicine (1994 to 2010), and American College of Chest Physicians (1994 to 2010); contacted clinical experts in the field; and searched for unpublished and ongoing trials in clinicaltrials.gov and controlled-trials.com. Randomized controlled clinical trials comparing treatment using HFO with conventional mechanical ventilation for children and adults diagnosed with ALI or ARDS. Three authors independently extracted data on clinical, physiological, and safety outcomes according to a predefined protocol. We contacted investigators of all included studies to clarify methods and obtain additional data. We used random-effects models in the analyses. Eight RCTs (n = 419) were included; almost all patients had ARDS. The risk of bias was low in six studies and unclear in two studies. The quality of evidence for hospital and six-month mortality was moderate and low, respectively. The ratio of partial pressure of oxygen to inspired fraction of oxygen at 24, 48, and 72 hours was 16% to 24% higher in patients receiving HFO. There were no significant differences in oxygenation index because mean airway pressure rose by 22% to 33% in patients receiving HFO (P < 0.01).  In patients randomized to HFO, mortality was significantly reduced (RR 0.77, 95% CI 0.61 to 0.98; P = 0.03; 6 trials, 365 patients, 160 deaths) and treatment failure (refractory hypoxaemia, hypercapnoea, hypotension, or barotrauma) was less likely (RR 0.67, 95% CI 0.46 to 0.99; P = 0.04; 5 trials, 337 patients, 73 events). Other risks, including adverse events, were similar. We found substantial between-trial statistical heterogeneity for physiological (I = 21% to 95%) but not clinical (I = 0%) outcomes.  Pooled results were based on few events for most clinical outcomes. The findings of this systematic review suggest that HFO was a promising treatment for ALI and ARDS prior to the uptake of current lung protective ventilation strategies. These findings may not be applicable with current conventional care, pending the results of large multi-centre trials currently underway.


Rose L.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Automated closed loop systems may improve adaptation of the mechanical support to a patient's ventilatory needs and facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of ventilation. To compare the duration of weaning from mechanical ventilation for critically ill ventilated adults and children when managed with automated closed loop systems versus non-automated strategies. Secondary objectives were to determine differences in duration of ventilation, intensive care unit (ICU) and hospital length of stay (LOS), mortality, and adverse events. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2); MEDLINE (OvidSP) (1948 to August 2011); EMBASE (OvidSP) (1980 to August 2011); CINAHL (EBSCOhost) (1982 to August 2011); and the Latin American and Caribbean Health Sciences Literature (LILACS). In addition we received and reviewed auto-alerts for our search strategy in MEDLINE, EMBASE, and CINAHL up to August 2012. Relevant published reviews were sought using the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA Database). We also searched the Web of Science Proceedings; conference proceedings; trial registration websites; and reference lists of relevant articles. We included randomized controlled trials comparing automated closed loop ventilator applications to non-automated weaning strategies including non-protocolized usual care and protocolized weaning in patients over four weeks of age receiving invasive mechanical ventilation in an intensive care unit (ICU). Two authors independently extracted study data and assessed risk of bias. We combined data into forest plots using random-effects modelling. Subgroup and sensitivity analyses were conducted according to a priori criteria. Pooled data from 15 eligible trials (14 adult, one paediatric) totalling 1173 participants (1143 adults, 30 children) indicated that automated closed loop systems reduced the geometric mean duration of weaning by 32% (95% CI 19% to 46%, P = 0.002), however heterogeneity was substantial (I(2) = 89%, P < 0.00001). Reduced weaning duration was found with mixed or medical ICU populations (43%, 95% CI 8% to 65%, P = 0.02) and Smartcare/PS™ (31%, 95% CI 7% to 49%, P = 0.02) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (17%, 95% CI 8% to 26%) and ICU length of stay (LOS) (11%, 95% CI 0% to 21%). There was no difference in mortality rates or hospital LOS. Overall the quality of evidence was high with the majority of trials rated as low risk. Automated closed loop systems may result in reduced duration of weaning, ventilation, and ICU stay. Reductions are more likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PS™ and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population.


Dawson L.A.,University of Toronto
Seminars in Radiation Oncology | Year: 2011

Experience with radiation therapy for the treatment of hepatocellular carcinoma (HCC) and liver metastases has increased rapidly in the past decade. This is principally because of advances in imaging and radiation techniques that can conform high doses to focal cancers and to a better understanding of how to avoid radiation-induced liver toxicity. Guidelines on how to use radiation therapy safely are becoming more clearly established, and reports of tumor control at 2 to 5 years show the potential for cure after radiation therapy for early-stage HCC and liver metastases. For both HCC and liver metastases, the best outcomes after radiation therapy are found in patients with fewer than 3 lesions that are <6 cm in size, with intact liver function and no extrahepatic metastases. There is a strong rationale for using radiation therapy in patients unsuitable for or with expected poor outcomes after standard local-regional therapies. These patients tend to have advanced tumors (large, multifocal, or invading vessels) and/or impaired liver function, reducing the chance of cure and increasing the chance of toxicity. In these patients, the benefits of radiation therapy over systemic therapy or best supportive therapy should be established in randomized trials. © 2011 Elsevier Inc.


Sorbara M.T.,University of Toronto | Philpott D.J.,University of Toronto
Immunological Reviews | Year: 2011

Peptidoglycan is a conserved structural component of the bacterial cell wall with molecular motifs unique to bacteria. The mammalian immune system takes advantage of these properties and has evolved to recognize this microbial associated molecular pattern. Mammals have four secreted peptidoglycan recognition proteins, PGLYRP-1-4, as well as two intracellular sensors of peptidoglycan, Nod1 and Nod2. Recognition of peptidoglycan is important in initiating and shaping the immune response under both homeostatic and infection conditions. During infection, peptidoglycan recognition drives both cell-autonomous and whole-organism defense responses. Here, we examine recent advances in the understanding of how peptidoglycan recognition shapes mammalian immune responses in these diverse contexts. © 2011 John Wiley & Sons A/S.


Brock K.K.,University of Toronto
Seminars in Radiation Oncology | Year: 2011

Imaging for radiation therapy treatment planning and delivery is a critical component of the radiation planning process for liver cancer. Because of the lack of inherent contrast between liver tumors and the surrounding liver, intravenous contrast is required for accurate target delineation on the planning computed tomography scan. The appropriate phase of contrast is tumor specific, with arterial phase imaging usually used to define hepatocellular carcinoma and venous phase imaging for vascular thrombosis related to hepatocellular carcinoma and most types of liver metastases. Breathing motion and changes in the liver position day to day may be substantial and need to be considered at the time of radiation planning and treatment. Many types of integrated imaging-radiation treatment systems and image-guidance strategies are available to produce volumetric and/or planar imaging at the time of treatment delivery to reduce the negative impact of geometric changes that may occur. Image-guided radiation therapy facilitates reduced PTV margins and dose escalation and improves the precision of radiation therapy, so the prescribed doses are more likely to represent those actually delivered. © 2011 Elsevier Inc.


Adeli K.,University of Toronto
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

Regulated cell metabolism involves acute and chronic regulation of gene expression by various nutritional and endocrine stimuli. To respond effectively to endogenous and exogenous signals, cells require rapid response mechanisms to modulate transcript expression and protein synthesis and cannot, in most cases, rely on control of transcriptional initiation that requires hours to take effect. Thus, co-and posttranslational mechanisms have been increasingly recognized as key modulators of metabolic function. This review highlights the critical role of mRNA translational control in modulation of global protein synthesis as well as specific protein factors that regulate metabolic function. First, the complex lifecycle of eukaryotic mRNAs will be reviewed, including our current understanding of translational control mechanisms, regulation by RNA binding proteins and microRNAs, and the role of RNA granules, including processing bodies and stress granules. Second, the current evidence linking regulation of mRNA translation with normal physiological and metabolic pathways and the associated disease states are reviewed. A growing body of evidence supports a key role of translational control in metabolic regulation and implicates translational mechanisms in the pathogenesis of metabolic disorders such as type 2 diabetes. The review also highlights translational control of apolipoprotein B (apoB) mRNA by insulin as a clear example of endocrine modulation of mRNA translation to bring about changes in specific metabolic pathways. Recent findings made on the role of 5′-untranslated regions (5′-UTR), 3′-UTR, RNA binding proteins, and RNA granules in mediating insulin regulation of apoB mRNA translation, apoB protein synthesis, and hepatic lipoprotein production are discussed. © 2011 the American Physiological Society.


Anagnostou E.,Bloorview Research Institute | Taylor M.J.,University of Toronto
Molecular Autism | Year: 2011

Autism spectrum disorder (ASD) refers to a syndrome of social communication deficits and repetitive behaviors or restrictive interests. It remains a behaviorally defined syndrome with no reliable biological markers. The goal of this review is to summarize the available neuroimaging data and examine their implication for our understanding of the neurobiology of ASD. Although there is variability in the literature on structural magnetic resonance literature (MRI), there is evidence of volume abnormalities in both grey and white matter, with a suggestion of some region-specific differences. Early brain overgrowth is probably the most replicated finding in a subgroup of people with ASD, and new techniques, such as cortical-thickness measurements and surface morphometry have begun to elucidate in more detail the patterns of abnormalities as they evolve with age, and are implicating specific neuroanatomical or neurodevelopmental processes. Functional MRI and diffusion tensor imaging techniques suggest that such volume abnormalities are associated with atypical functional and structural connectivity in the brain, and researchers have begun to use magnetic resonance spectroscopy (MRS) techniques to explore the neurochemical substrate of such abnormalities. The data from multiple imaging methods suggests that ASD is associated with an atypically connected brain. We now need to further clarify such atypicalities, and start interpreting them in the context of what we already know about typical neurodevelopmental processes including migration and organization of the cortex. Such an approach will allow us to relate imaging findings not only to behavior, but also to genes and their expression, which may be related to such processes, and to further our understanding of the nature of neurobiologic abnormalities in ASD. © 2011 Anagnostou and Taylor; licensee BioMed Central Ltd.


Salter M.W.,University of Toronto | Beggs S.,University of Toronto
Cell | Year: 2014

Recent findings challenge the concept that microglia solely function in disease states in the central nervous system (CNS). Rather than simply reacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculpt the structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity. These physiological functions of microglia in the normal CNS begin during development and persist into maturity. Here, we develop a conceptual framework for functions of microglia beyond neuroinflammation and discuss the rich repertoire of signaling and communication motifs in microglia that are critical both in pathology and for the normal physiology of the CNS. © 2014 Elsevier Inc.


Ussher J.R.,University of Toronto | Drucker D.J.,University of Toronto
Circulation Research | Year: 2014

Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment of type 2 diabetes mellitus. Activation of GLP-1R signaling or inhibition of DPP-4 activity produces a broad range of overlapping and unique cardiovascular actions. Native GLP-1 regulates cardiovascular biology via activation of the classical GLP-1R, or through GLP-1(9-36), a cardioactive metabolite generated by DPP-4-mediated cleavage. In contrast, clinically approved GLP-1R agonists are not cleaved to GLP-1(9-36) and produce the majority of their actions through the classical GLP-1R. The cardiovascular mechanisms engaged by DPP-4 inhibition are more complex, encompassing increased levels of intact GLP-1, reduced levels of GLP-1(9-36), and changes in levels of numerous cardioactive peptides. Herein we review recent experimental and clinical advances that reveal how GLP-1R agonists and DPP-4 inhibitors affect the normal and diabetic heart and coronary vasculature, often independent of changes in blood glucose. Improved understanding of the complex science of incretin-based therapies is required to optimize the selection of these therapeutic agents for the treatment of diabetic patients with cardiovascular disease. © 2014 American Heart Association, Inc.


Rubenfeld G.D.,University of Toronto
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Acute respiratory distress syndrome (ARDS) is a common, lethal, and morbid respiratory complication primarily seen in the setting of major trauma and infection. Despite advances in mechanical ventilation for ARDS, many interventions have not been successful in reducing mortality. Recent grant announcements and ongoing clinical trials indicate an interest in preventing ARDS. This Perspective challenges some of the basic assumptions of ARDS prevention and preventive care in the intensive care unit. ARDS is an organ function surrogate outcome. Studies of surrogate outcomes in medicine have repeatedly failed to show an association with patient-centered outcomes that might include mortality, quality of life, patient satisfaction, and cost. Organ failure surrogate outcomes in critical care, including oxygenation, cardiac output, and blood pressure, have similarly failed to show a consistent association with patient-centered benefit. Trials designed to demonstrate an effect on surrogate outcomes will rarely be able to demonstrate small, but important, harms so that the net benefit of prevention can be calculated. This will leave clinicians with insufficient information to balance the unknown benefits of ARDS prevention with imprecisely estimated costs or risks of prevention. Because ARDS diagnosis relies on oxygenation and the chest radiograph that might be directly influenced by the prophylactic intervention, studies must be designed to insure that the prevention is not merely cosmetic. Strategies that prevent ARDS need to be tested in trials sufficiently powered to demonstrate their patient-centered costs, benefits and harms before widespread adoption. Copyright © 2015 by the American Thoracic Society.


Adams J.J.,University of Toronto | Sidhu S.S.,University of Toronto
Current Opinion in Structural Biology | Year: 2014

Synthetic antibody technologies enable the rapid production of affinity reagents through in vitro selections. The production of synthetic antibodies relies on sophisticated design strategies to produce combinatorial diversity libraries that encode antibody populations optimized for molecular recognition. The technology takes advantage of display technologies that enable amplification, selection and manipulation of antibodies in vitro. The rapid yet highly controlled nature of these methods has opened new avenues in basic and clinical research. Here we review recent advances in structural biology facilitated by synthetic antibodies, as well as advances in library designs and selection methods. © 2013 Elsevier Ltd.


Fogel N.,University of Toronto
Tuberculosis | Year: 2015

Summary Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (MTB) that usually affects the lungs leading to severe coughing, fever, and chest pains. Although current research in the past four years has provided valuable insight into TB transmission, diagnosis, and treatment, much remains to be discovered to effectively decrease the incidence of and eventually eradicate TB. The disease still puts a strain on public health, being only second to HIV/AIDS in causing high mortality rates. This review will highlight the history of TB as well as provide an overview of the current literature on epidemiology, pathogenesis and the immune response, treatment, and control of TB. In this race to combat a disease that knows no boundaries, it is necessary to have a conceptual and clear understanding of TB overall with the hope of providing better treatment through novel and collaborative research and public health efforts. © 2015 The Author.


Perry J.R.,University of Toronto
Current Opinion in Neurology | Year: 2010

Purpose of review: Venous thromboembolism (VTE) is common in patients with brain tumors. Anticoagulant therapy is feared due to the risk of bleeding, especially intracranial hemorrhage. Emerging treatment approaches targeting angiogenesis, may increase the risk of both thrombosis and bleeding. Recent advances in the cause, prevention, and treatment of VTE in brain tumor patients in the era of antiangiogenic therapy are reviewed. Recent findings: About 20-30% of malignant glioma patients develop clinically significant thromboembolism; however, a recent randomized trial suggested increased intracranial bleeding with the use of prophylactic anticoagulation. Antiangiogenic therapies, especially those targeting vascular endothelial growth factor or its receptor, may increase the risk of thrombosis. New data regarding the safety of anticoagulation concurrent with bevacizumab have emerged. Summary: VTE is common perioperatively and throughout the course of brain tumor therapy. Therapeutic anticoagulation followed by secondary anticoagulant thromboprophylaxis is indicated in most patients with DVT or pulmonary embolism, including patients receiving antiangiogenic agents. The role of primary antithrombotic prophylaxis remains unclear. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Lapinsky S.E.,University of Toronto
Current Opinion in Infectious Diseases | Year: 2010

Purpose of Review: Two recent viral epidemics producing pneumonitis (severe acute respiratory syndrome and pandemic influenza A H1N1) have highlighted the potential for viral infections to cause respiratory failure with a significant risk of mortality. This review describes these epidemics and other causes of epidemic viral pneumonia. Recent Findings: The recent literature highlights the rapidity with which these emerging viral infections can be characterized and how management strategies, including supportive care, antiviral therapy and infection control precautions, can be rapidly shared and implemented. Summary: The severe acute respiratory syndrome outbreak was too short to allow management protocols to be tested in a research environment. The current 2009 influenza A (H1N1) pandemic is fortunately not associated with as high a mortality rate as the avian influenza A (H5N1), another potential pandemic candidate virus. Prior pandemic planning as well as research planning has allowed a rapid response to this outbreak, with a significant amount of literature generated in a few months. Other common seasonal viruses, such as respiratory syncytial virus and parainfluenza, as well as previously poorly recognized viruses such as hantavirus, have the ability to cause significant respiratory morbidity and mortality. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Holthausen M.H.,University of Toronto | Weigand J.J.,TU Dresden
Chemical Society Reviews | Year: 2014

The aim of this review is to provide a comprehensive view of the chemistry of cationic polyphosphorus cages. The synthetic protocols established for their preparation, which are all based on the functionalization of P4, and their intriguing follow-up chemistry are highlighted. In addition, this review intends to foster the interest of the inorganic, organic, catalytic and material oriented chemical communities in the versatile field of polyphosphorus cage compounds. In the long term, this is envisioned to contribute to the development of new synthetic procedures for the functionalization of P4 and its transformation into (organo-)phosphorus compounds and materials of added value. © 2014 the Partner Organisations.


Sgro M.J.,University of Toronto | Stephan D.W.,University of Toronto
Chemical Communications | Year: 2013

Hf-phosphinoamide cation complexes behave as metal-based frustrated Lewis pairs and bind one or two equivalent of CO2 and in as well can activate CO2 in a bimetallic fashion to give a pseudo-tetrahedral P2CO2 fragment linking two Hf centres.© The Royal Society of Chemistry 2013.


Field R.D.,University of Toronto
Journal of Geophysical Research: Atmospheres | Year: 2010

Stable isotopes of oxygen and hydrogen are important paleoclimate indicators and can be obtained from many different natural archives in Europe such as tree rings and speleothems. In this study, a comparison was made of controls on European precipitation δ18 O between observations from the Global Network of Isotopes in Precipitation and from the NASA Goddard Institute for Space Studies ModelE general circulation model. In both observations and the general circulation model, the local temperature effect was identified and extended outside of Europe. This temperature control, in turn, was related to a North Atlantic Oscillation-like dipóle but with centers of action different than standard NAO definitions. An examination of midtropospheric circulation controls showed that European δ18O in fact reflects the hemisphere-wide teleconnections associated with the Northern Annular Mode. Seasonal differences were found in the strength of all controls on δ18O, with the annual controls being the combination of strong winter and weak summer controls. The weaker temperature effect in summer is well-known and has been universally attributed to the effects of continental moisture recycling, but the results of this study show that an additional factor is the reduced variability in summertime atmospheric circulation. The strong agreement between observed and modeled controls can help to improve interpretations of paleoclimatic archives of δ18O, particularly in terms of shifts in atmospheric circulation. Copyright 2010 by the American Geophysical Union.


Chin K.J.,University of Toronto
The Cochrane database of systematic reviews | Year: 2013

Several approaches exist to produce local anaesthetic blockade of the brachial plexus. It is not clear which is the technique of choice for providing surgical anaesthesia of the lower arm, although infraclavicular blockade (ICB) has several purported advantages. We therefore performed a systematic review of ICB compared to the other brachial plexus blocks (BPBs). This review was originally published in 2010 and was updated in 2013. The objective of this review was to evaluate the efficacy and safety of infraclavicular block (ICB) compared to other approaches to the brachial plexus in providing regional anaesthesia for surgery on the lower arm. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5); MEDLINE (1966 to June 2013) via OvidSP; and EMBASE (1980 to June 2013) via OvidSP. We also searched conference proceedings (from 2004 to 2012) and the www.clinicaltrials.gov trials registry. The searches for the original review were performed in September 2008. We included any randomized controlled trials (RCTs) that compared ICB with other BPBs as the sole anaesthetic technique for surgery on the lower arm. The primary outcome was adequate surgical anaesthesia within 30 minutes of block completion. Secondary outcomes included sensory block of individual nerves, tourniquet pain, onset time of sensory blockade, block performance time, block-associated pain and complications related to the block. In our original review we included 15 studies with 1020 participants and excluded two. In this updated review we included seven new studies and excluded six, bringing the total number of included studies to 22 and involving 1732 participants. The control group intervention was the axillary block in 14 studies, supraclavicular block in six studies, mid-humeral block in two studies, and parascalene block in one study. One study compared ICB to both axillary and supraclavicular blocks. Nine studies employed ultrasound-guided ICB. The risk of failed surgical anaesthesia 30 minutes after block completion was similar for ICB and all other BPBs (11.4% versus 12.9%, risk ratio (RR) 0.88, 95% CI 0.51 to 1.52, P = 0.64), but tourniquet pain was less likely with ICB (11.9% versus 18.0%; RR of experiencing tourniquet pain 0.66, 95% CI 0.47 to 0.92, P = 0.02). Subgroup analysis by method of nerve localization, and by control group intervention, did not show any statistically significant differences in the risk of failed surgical anaesthesia. However when compared to a single-injection axillary block, ICB was better at providing complete sensory block of the musculocutaneous nerve (RR for failure 0.46, 95% CI 0.27 to 0.60, P < 0.0001). ICB had a slightly longer sensory block onset time (mean difference (MD) 1.9 min, 95% CI 0.2 to 3.6, P = 0.03) but was faster to perform than multiple-injection axillary (MD -2.7 min, 95% CI -3.4 to -2.0, P < 0.00001) or mid-humeral (MD -4.8 min, 95% CI -6.0 to -3.6, P < 0.00001) blocks. ICB is as safe and effective as any other BPBs, regardless of whether ultrasound or neurostimulation guidance is used. The advantages of ICB include a lower likelihood of tourniquet pain during surgery, more reliable blockade of the musculocutaneous nerve when compared to a single-injection axillary block, and a significantly shorter block performance time compared to multi-injection axillary and mid-humeral blocks.


Stephan D.W.,University of Toronto | Erker G.,University of Munster
Chemical Science | Year: 2014

Frustrated Lewis pairs have been used to activate a variety of small molecules. In this review we focus on the recent chemistry of FLPs with CO 2, CO, N2O, NO and SO2. While FLP capture of these small molecule is achieved in all of these cases, subsequent applications of the products include stoichiometric and catalytic reductions of CO 2, C-O bond scission of CO and use of FLP-NO radicals in polymerization. © 2014 the Partner Organisations.


Rotstein B.H.,University of Toronto | Rotstein B.H.,Harvard University | Zaretsky S.,University of Toronto | Rai V.,University of Toronto | And 2 more authors.
Chemical Reviews | Year: 2014

The progress made in multicomponent reactions (MCRs) that either produce small heterocycles or employ them as starting materials are investigated. Driven by strain release, multicomponent reactions employing small ring heterocycles offer opportunities for atom-economical synthesis of organic molecules. Isocyanide-based MCRs are made possible by the 1,1-amphoteric nature of the isocyanide functional group. Passerini and Ugi reactions are the two most well-known isocyanide-based MCRs. One strategy to extend MCR reactivity is to substitute one component of a known MCR with a small heterocycle. A second strategy for MCRs that employ epoxides for attack on bromonium ions is the introduction of an additional nucleophile to conduct the terminal ring opening, rather than bromide formed in situ. It is noteworthy that alternate factors can also provide the driving force, leading to opportunities to retain the core structures of small heterocycles in products. In some cases, small ring heterocycles can even be built during multicomponent synthesis.


Stanley S.,University of Toronto
Geophysical Research Letters | Year: 2010

Magnetic field measurements demonstrate that Saturn's internally generated magnetic field has an extremely small dipole tilt. The nearly-perfect axisymmetry of Saturn's dipole is troubling because of Cowling's theorem which states that an axisymmetric magnetic field cannot be maintained by a dynamo. A possible mechanism to axisymmetrize the observed field involves differential rotation in a stably-stratified electrically conducting layer surrounding the dynamo. Here we use numerical dynamo models to study the axisymmetrizing effects of stably stratified layers surrounding the dynamo. We find that a thin stably-stratified layer which undergoes differential rotation due to thermal winds as a result of pole to equator temperature differences can produce a more axisymmetrized field. Surprisingly, we find that the direction of the zonal flows and their equatorial symmetry is a crucial factor for magnetic field axisymmetry since some zonal flows act to destabilize the dynamo producing non-axisymmetric fields. Copyright © 2010 by the American Geophysical Union.


Lisjak A.,University of Toronto | Grasselli G.,University of Toronto
Journal of Rock Mechanics and Geotechnical Engineering | Year: 2014

The goal of this review paper is to provide a summary of selected discrete element and hybrid finite-discrete element modeling techniques that have emerged in the field of rock mechanics as simulation tools for fracturing processes in rocks and rock masses. The fundamental principles of each computer code are illustrated with particular emphasis on the approach specifically adopted to simulate fracture nucleation and propagation and to account for the presence of rock mass discontinuities. This description is accompanied by a brief review of application studies focusing on laboratory-scale models of rock failure processes and on the simulation of damage development around underground excavations. © 2014 Institute of Rock and Soil Mechanics, Chinese Academy of Sciences.


Zhu L.,University of Toronto
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2016

Existing n-process randomized wait-free (and obstructionfree) consensus protocols from registers all use at least n registers. In 1992, it was proved that such protocols must use Ω(√n) registers. Recently, this was improved to Ω(n) registers in the anonymous setting, where processes do not have identifiers. Closing the gap in the general case, however, remained an open problem. We resolve this problem by proving that every randomized wait-free (or obstructionfree) consensus protocol for n processes must use at least n - 1 registers. © 2016 ACM.


Dopamine D3 receptors are implicated in cue-induced relapse to drug seeking. We have previously shown that systemic administration of a selective D3 antagonist reduces cue-induced reinstatement of nicotine seeking in rats. The current study sought to investigate potential neural substrates mediating this effect. The D3 antagonist SB-277011-A (0.01-1 μg/0.5 μl/side) infused into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens, significantly attenuated cue-induced reinstatement of nicotine seeking. Moreover, infusion of SB-277011-A (1 μg/0.5 μl/side) into the basolateral amygdala or lateral habenula had no effect on food self-administration. Together with the finding that systemic SB-277011-A had no effect on extinction responding, this suggests that the effects observed here were on reinstatement and cue seeking, and not due to nonspecific motor activation or contextual-modified residual responding. The further finding of binding of [125I]7-OH-PIPAT to D3 receptors in the lateral habenula and in the basolateral amygdala is consistent with an important role of D3 receptors in these areas in nicotine seeking. It was also found that systemic administration of the selective D2 antagonist L741626 decreased cue-induced reinstatement, consistent with a role of D2 and D3 receptors in modulating this behavior. The current study supports an important role for D3 receptors in the basolateral amygdala and lateral habenula in cue-induced reinstatement.Neuropsychopharmacology advance online publication, 6 August 2014; doi:10.1038/npp.2014.158.


Gholizadeh S.,University of Toronto
Neuropsychopharmacology | Year: 2014

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in the FMR1 gene that codes for fragile X mental retardation protein (FMRP). To determine if FMRP expression in the central nervous system could reverse phenotypic deficits in the Fmr1 knockout (KO) mouse model of FXS, we used a single-stranded adeno-associated viral (AAV) vector with viral capsids from serotype 9 that contained a major isoform of FMRP. FMRP transgene expression was driven by the neuron-selective synapsin-1 promoter. The vector was delivered to the brain via a single bilateral intracerebroventricular injection into neonatal Fmr1 KO mice and transgene expression and behavioral assessments were conducted 22-26 or 50-56 days post injection. Western blotting and immunocytochemical analyses of AAV-FMRP-injected mice revealed FMRP expression in the striatum, hippocampus, retrosplenial cortex, and cingulate cortex. Cellular expression was selective for neurons and reached ∼50% of wild-type levels in the hippocampus and cortex at 56 days post injection. The pathologically elevated repetitive behavior and the deficit in social dominance behavior seen in phosphate-buffered saline-injected Fmr1 KO mice were reversed in AAV-FMRP-injected mice. These results provide the first proof of principle that gene therapy can correct specific behavioral abnormalities in the mouse model of FXS.Neuropsychopharmacology advance online publication, 6 August 2014; doi:10.1038/npp.2014.167.


Cvetkovska M.,University of Toronto | Vanlerberghe G.C.,University of Toronto
New Phytologist | Year: 2012

The nonenergy-conserving alternative oxidase (AOX) has been hypothesized to modulate the amount of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in plant mitochondria but there is sparse direct in planta evidence to support this. • Laser scanning fluorescent confocal microscopy and biochemical methods were used to directly estimate in planta leaf concentrations of superoxide, nitric oxide (NO), peroxynitrite (ONOO -) and hydrogen peroxide (H 2O 2) in wildtype (Wt) tobacco (Nicotiana tabacum) and transgenic tobacco with altered amounts of AOX. • We found that plants lacking AOX have increased concentrations of leaf mitochondrial-localized and leaf NO in comparison to the Wt, while leaf concentrations of H 2O 2 were similar or lower in the AOX-suppressed plants. • Based on our results, we suggest that AOX respiration acts to reduce the generation of ROS and RNS in plant mitochondria by dampening the leak of single electrons from the electron transport chain to O 2 or nitrite. This may represent a universal role for AOX in plants. More work is now needed to establish the functional implications of this role, such as during abiotic and biotic stress. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.


Previous studies have demonstrated that lower local anaesthetic (LA) volumes can be used for ultrasound (US)-guided interscalene brachial plexus block (ISB). However, no study has examined whether US can reduce the volume required when compared with nerve stimulation (NS) for ISB. Our aim was to do this by comparing the minimum effective analgesic volumes (MEAVs). After ethics approval and informed consent, patients undergoing shoulder surgery were recruited to this randomized, double-blind, up-down sequential allocation study. The volume used for both US and NS was dependent upon the success or failure of the previous block. Success was defined as a verbal rating score of 0/10, 30 min after surgery. Ten needle passes were allowed before defaulting to the opposite group. Patients received general anaesthesia. Pain scores and analgesic consumption were assessed by a blinded observer. Statistical comparisons of continuous variables were performed using Student's t-test and Mann-Whitney U-test as appropriate. Categorical variables were analysed using χ 2 test. MEAV values were estimated using log-transformed up-down independent pairs analysis and probit regression. Significance was assumed at P<0.05 (two-sided). The MEAV required to provide effective analgesia was significantly (P=0.034) reduced to 0.9 ml [95% confidence interval (CI) 0.3-2.8] in the US group from 5.4 ml (95% CI 3.4-8.6) in the NS group. Fewer needle passes were needed to identify the brachial plexus with US (1 vs 3; P<0.0001) and patients had less pain at 30 min after surgery (P=0.03). US reduces the number of attempts, LA volume, and postoperative pain when compared with NS for ISB.


Cowen D.,University of Toronto
Annals of the Association of American Geographers | Year: 2010

In recent years, U.S. military and civilian agencies have been rethinking security in the context of globalized production and trade. No longer lodged in a conflict between territorial borders and global flows, national security is increasingly a project of securing supranational systems. The maritime border has been a critical site for experimentation, and a spate of new policy is blurring "inside" and "outside" national space, reconfiguring border security, and reorganizing citizenship and labor rights. These programs seek to govern integrated economic space while they resurrect borders and sanction new forms of containment. Forces that disrupt commodity flows are cast as security threats with labor actions a key target of policy. Direct connections result between market rule created to secure logistic space and the broader project of neoliberalism. Even as neoliberalism is credited with expanding capitalist markets and market logics, it is logistics that have put the cold calculation of cost at the center of the production of space. Since World War II, logistics experts have conceptualized economy anew by spatializing cost-benefit analysis and applying systems analysis to distribution networks. The "revolution in logistics" has changed how space is conceived and represented, and transformed the practical management of supply chains. Historically a military technology of war and colonialism abroad, today logistics lead rather than support the strategies of firms and the security of nations across transnational space. These shifts have implications for the geopolitics of borders and security but also for social and political forms premised on the territory and ontology of national space. © 2010 by Association of American Geographers.


Boone M.P.,University of Toronto | Stephan D.W.,University of Toronto
Journal of the American Chemical Society | Year: 2013

The PBP ligand (Ph2PC6H4)2BPh was used to prepare ((Ph2PC6H4) 2B(Cl)(η6-Ph)RuCl (1) and subsequently [((Ph 2PC6H4)2B(η6-Ph)) RuCl][B(C6F5)4] (2). The latter species exhibited Lewis acidity on the η6-Ph ring, as reaction with Cy3P gave the donor-acceptor adduct [(Ph2PC 6H4)2B(η5-C6H 5-o-PCy3)RuCl][B(C6F5)4] (3). Steric frustration of this binding was seen with Mes3P, and yet the combination of 2 and Mes3P reacted with H2 to give a 2:1 mixture of 5-o and 5-p, two isomers of [(Ph2PC6H 4)2B(η5-C6H6)RuCl] (5), along with [Mes3PH][HB(C6F5)3]. Compound 2 behaves as C-based Lewis acid and thus can also be used for catalytic hydrogenation of aldimines at room temperature via a frustrated Lewis pair mechanism. © 2013 American Chemical Society.


Mahdi T.,University of Toronto | Stephan D.W.,University of Toronto | Stephan D.W.,King Abdulaziz University
Journal of the American Chemical Society | Year: 2014

Hydrogenation of alkyl and aryl ketones using H2 is catalytically achieved in 18 examples using 5 mol % B(C6F5)3 in an ethereal solvent. In these cases the borane and ether behave as a frustrated Lewis pair to activate H2 and effect the reduction. © 2014 American Chemical Society.


Dimitrijevic E.,University of Toronto | Taylor M.S.,University of Toronto
ACS Catalysis | Year: 2013

An overview of the applications of boronic and borinic acids in catalysis is presented. Taking advantage of the Lewis acidity of trivalent boron and the reversible covalent interactions of organoboron acids with OH groups, diverse modes of catalytic reactivity have been achieved. Interactions with carbonyl compounds enable acceleration of addition and cycloaddition processes, whereas binding of their enol tautomers can lead to organoboron-catalyzed aldol and related reactions. Binding of organoboron acids to hydroxyl and carboxyl OH groups has been employed as a mode of electrophilic activation for catalysis of substitution, cycloaddition, rearrangement, and elimination reactions. By altering the nature of the interaction with the organoboron acid catalyst, activation of OH groups as pronucleophiles is also possible, resulting in catalyst-controlled methods for regioselective functionalization of diols and carbohydrate derivatives. Applications of organoboron acids in bifunctional and assisted catalysis are also discussed. © 2013 American Chemical Society.


Moore G.W.K.,University of Toronto
Geophysical Research Letters | Year: 2012

The Beaufort Sea High (BSH), an anti-cyclone over the Beaufort Sea, is an important feature of the summer atmospheric circulation over the Arctic Ocean. For example, years characterized by low Arctic sea ice extent are typically associated with the presence of a stronger BSH; with the opposite occurring during years with high sea ice extent. In this paper, we show that there exists variability on the decadal time scale in the intensity and location of the summer BSH. We also show that there has been a trend towards a stronger summer BSH that began in the late 1990s. This trend is shown to be coincident with a tendency towards a reduction in cyclogenesis during the summer over the Beaufort Sea. We argue that that these trends are the result of a warming of the troposphere in the western Arctic and the concomitant reduction in baroclincity. © Copyright 2012 by the American Geophysical Union.


Chiu L.L.Y.,University of Toronto | Radisic M.,University of Toronto
Biomaterials | Year: 2010

The aim of this study was to engineer a biomaterial capable of supporting vascularization in vitro and in vivo. We covalently immobilized vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang1) onto three-dimensional porous collagen scaffolds using 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC) chemistry. Over both 3 and 7 days in vitro, seeded endothelial cells (ECs) had increased proliferation on scaffolds with immobilized VEGF and/or Ang1 compared to unmodified scaffolds and soluble growth factor controls. Notably, the group with co-immobilized VEGF and Ang1 showed significantly higher cell number (P = 0.0079), higher overall lactate production rate (P = 0.0044) and higher overall glucose consumption rate (P = 0.0034) at Day 3, compared to its corresponding soluble control for which growth factors were added to culture medium. By Day 7, hematoxylin and eosin, live/dead, CD31, and von Willebrand factor staining all showed improved tube formation by ECs when cultivated on scaffolds with co-immobilized growth factors. Interestingly, scaffolds with co-immobilized VEGF and Ang1 showed increased EC infiltration in the chorioallantoic membrane (CAM) assay, compared to scaffolds with independently immobilized VEGF/Ang1. This study presents an alternative method for promoting the formation of vascular structures, via covalent immobilization of angiogenic growth factors that are more stable than soluble ones and have a localized effect. © 2009 Elsevier Ltd. All rights reserved.


Zywiel M.G.,University of Toronto
The bone & joint journal | Year: 2013

Down's syndrome is associated with a number of musculoskeletal abnormalities, some of which predispose patients to early symptomatic arthritis of the hip. The purpose of the present study was to review the general and hip-specific factors potentially compromising total hip replacement (THR) in patients with Down's syndrome, as well as to summarise both the surgical techniques that may anticipate the potential adverse impact of these factors and the clinical results reported to date. A search of the literature was performed, and the findings further informed by the authors' clinical experience, as well as that of the hip replacement in Down Syndrome study group. The general factors identified include a high incidence of ligamentous laxity, as well as associated muscle hypotonia and gait abnormalities. Hip-specific factors include: a high incidence of hip dysplasia, as well as a number of other acetabular, femoral and combined femoroacetabular anatomical variations. Four studies encompassing 42 hips, which reported the clinical outcomes of THR in patients with Down's syndrome, were identified. All patients were successfully treated with standard acetabular and femoral components. The use of supplementary acetabular screw fixation to enhance component stability was frequently reported. The use of constrained liners to treat intra-operative instability occurred in eight hips. Survival rates of between 81% and 100% at a mean follow-up of 105 months (6 to 292) are encouraging. Overall, while THR in patients with Down's syndrome does present some unique challenges, the overall clinical results are good, providing these patients with reliable pain relief and good function.


Klinkova A.,University of Toronto | Choueiri R.M.,University of Toronto | Kumacheva E.,University of Toronto
Chemical Society Reviews | Year: 2014

Self-assembly of plasmonic nanoparticles offers a labour- and cost-efficient strategy for the expansion of the library of plasmonic nanostructures with highly tunable, coupled optical properties. This review covers recent advances in solution-based self-assembly of plasmonic nanoparticles, modelling of the self-assembly process and of the optical properties of the resulting nanostructures, and potential applications of self-assembled plasmonic nanostructures. © 2014 the Partner Organisations.


Juurlink D.N.,University of Toronto
British Journal of Clinical Pharmacology | Year: 2016

Sometimes mistakenly characterized as a 'universal antidote,' activated charcoal (AC) is the most frequently employed method of gastrointestinal decontamination in the developed world. Typically administered as a single dose (SDAC), its tremendous surface area permits the binding of many drugs and toxins in the gastrointestinal lumen, reducing their systemic absorption. Like other decontamination procedures, the utility of SDAC attenuates with time, and, although generally safe, it is not free of risk. A large body of evidence demonstrates that SDAC can reduce the absorption of drugs and xenobiotics but most such studies involve volunteers and have little generalizability to clinical practice. Few rigorous clinical trials of SDAC have been conducted, and none validate or refute its utility in those patients who are intuitively most likely to benefit. Over the past decade, a growing body of observational data have demonstrated that SDAC can elicit substantial reductions in drug absorption in acutely poisoned patients. The challenge for clinicians rests in differentiating those patients most likely to benefit from SDAC from those in whom meaningful improvement is doubtful. This is often a difficult determination not well suited to an algorithmic approach. The present narrative review summarizes the data supporting the benefits and harms of SDAC, and offers pragmatic suggestions for clinical practice. © 2015 The British Pharmacological Society.


Walks A.,University of Toronto
Urban Studies | Year: 2013

Much attention has been given to increasing dominance of the post-war suburbs, and the concomitant rise of 'suburbanism' in ways of life in the 'post-metropolis'. However, the meaning of suburbanism is rarely specified and there have been insufficient attempts to theorise its relationship to the urban. Drawing on the dialectical analyses of Henri Lefebvre, this article presents a theory of suburbanism as a subset of urbanism, with which it is in constant productive tension. Six distinct dimensions of the urbanism-suburbanism dialectic are identified, derived from extrapolating Lefebvre's urban theory into second- and third-order analyses. These aspects of suburbanism are conceptualised not as static characteristics but as qualities that dynamically flow through, rather than define, particular places. Suburbanism is thus conceptualised separately from those places often termed suburbs, opening up the potential for interaction between these dimensions and the lived realities of everyday urban life and politics. © 2012 Urban Studies Journal Limited.


Sinha S.S.,University of Toronto
Sleep Medicine Reviews | Year: 2016

Traumatic events have been increasingly recognized as important precipitants of clinically significant insomnia. Trauma is an extreme form of stressful life event that generates a sustained neurobiological response triggering the onset and maintenance of insomnia. Trauma may disrupt the normal sleep-wake regulatory mechanism by sensitizing the central nervous system's arousal centers, leading to pronounced central and physiological hyperarousal. The central concept of hyperarousal has been linked to both the pathogenesis of insomnia and to the neurobiological changes in the aftermath of traumatic events, and may be a neurobiological commonality underlying trauma and insomnia. This paper presents evidence for trauma-induced insomnia and advances a model of it as an important nosological and neurobiological entity. Trauma-induced insomnia may occur in the absence of full-blown posttraumatic stress disorder (PTSD), and may also be a precursor of subsequent PTSD development. Converging lines of evidence from the neuroscience of insomnia with the neurobiology and psychophysiology of stress, fear, trauma and PTSD will be integrated to advance understanding of the condition. Preclinical and clinical stress and fear paradigms have informed the neurobiological pathways mediating the production of insomnia by trauma. Elucidating the underlying neurobiological substrates can establish novel biological markers to identify persons at risk for the condition, and help optimize treatment of the trauma-insomnia interface. Early identification and treatment of trauma-induced insomnia may prevent the development of PTSD, as well as other important sequelae such as depression, substance dependence, and other medical conditions. © 2015 Elsevier Ltd.


Adams-Cioaba M.A.,University of Toronto
Nature communications | Year: 2011

Proteolysis of eukaryotic histone tails has emerged as an important factor in the modulation of cell-cycle progression and cellular differentiation. The recruitment of lysosomal cathepsin L to the nucleus where it mediates proteolysis of the mouse histone H3 tail has been described recently. Here, we report the three-dimensional crystal structures of a mature, inactive mutant of human cathepsin L alone and in complex with a peptide derived from histone H3. Canonical substrate-cathepsin L interactions are observed in the complex between the protease and the histone H3 peptide. Systematic analysis of the impact of posttranslational modifications at histone H3 on substrate selectivity suggests cathepsin L to be highly accommodating of all modified peptides. This is the first report of cathepsin L-histone H3 interaction and the first structural description of cathepsin L in complex with a substrate.


Bruix J.,University of Barcelona | Reig M.,University of Barcelona | Sherman M.,University of Toronto
Gastroenterology | Year: 2016

Evidence-based management of patients with hepatocellular carcinoma (HCC) is key to their optimal care. For individuals at risk for HCC, surveillance usually involves ultrasonography (there is controversy over use of biomarkers). A diagnosis of HCC is made based on findings from biopsy or imaging analyses. Molecular markers are not used in diagnosis or determination of prognosis and treatment for patients. The Barcelona Clinic Liver Cancer algorithm is the most widely used staging system. Patients with single liver tumors or as many as 3 nodules ≤3 cm are classified as having very early or early-stage cancer and benefit from resection, transplantation, or ablation. Those with a greater tumor burden, confined to the liver, and who are free of symptoms are considered to have intermediate-stage cancer and can benefit from chemoembolization if they still have preserved liver function. Those with symptoms of HCC and/or vascular invasion and/or extrahepatic cancer are considered to have advanced-stage cancer and could benefit from treatment with the kinase inhibitor sorafenib. Patients with end-stage HCC have advanced liver disease that is not suitable for transplantation and/or have intense symptoms. Studies now aim to identify molecular markers and imaging techniques that can detect patients with HCC at earlier stages and better predict their survival time and response to treatment. © 2016 AGA Institute.


Zuberi K.,University of Toronto
Nucleic acids research | Year: 2013

GeneMANIA (http://www.genemania.org) is a flexible user-friendly web interface for generating hypotheses about gene function, analyzing gene lists and prioritizing genes for functional assays. Given a query gene list, GeneMANIA extends the list with functionally similar genes that it identifies using available genomics and proteomics data. GeneMANIA also reports weights that indicate the predictive value of each selected data set for the query. GeneMANIA can also be used in a function prediction setting: given a query gene, GeneMANIA finds a small set of genes that are most likely to share function with that gene based on their interactions with it. Enriched Gene Ontology categories among this set can sometimes point to the function of the gene. Seven organisms are currently supported (Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Homo sapiens, Rattus norvegicus and Saccharomyces cerevisiae), and hundreds of data sets have been collected from GEO, BioGRID, IRefIndex and I2D, as well as organism-specific functional genomics data sets. Users can customize their search by selecting specific data sets to query and by uploading their own data sets to analyze.


Drewry J.A.,University of Toronto | Gunning P.T.,University of Toronto
Coordination Chemistry Reviews | Year: 2011

Historically, Lewis acidic metal coordination complexes have played a pivotal and defining role in the broad field of molecular recognition and more specifically in the sensing and sequestration of biologically relevant anionic species. More recently, with the expanding interest in chemical biology, there has been a resurgence in the use of coordination complexes, specifically, through their application as medicinal therapeutics and chemo/biosensors. From the disruption of oncogenic protein-protein interactions to the fluorescent sensing of PTP1B phosphatase enzyme activity, the powerful binding potency of coordination complexes has been harnessed to great effect. The ingenuity of the rationally designed coordinating ligands has facilitated the diversity of roles played by Lewis metal complexes. Herein, we will review the recent advances in the application of coordination complexes in medicinal and chemo/biosensory roles over the last decade. In particular, this review will focus on Cu(II) and Zn(II) coordination complexes. © 2010 Elsevier B.V.


Liu K.,University of Toronto | Zhao N.,University of Toronto | Kumacheva E.,University of Toronto
Chemical Society Reviews | Year: 2011

Generation of nanostructures containing from several to thousands of inorganic nanorods (NRs) organized in a highly ordered manner paves the way for applications that exploit directional properties of NR arrays. Self-assembly of NRs provides a simple and cost-efficient strategy for producing NR ensembles. This tutorial review highlights recent advances in the field of NR synthesis, summarizes the types of ligands used for NR synthesis and stabilization, reviews experimental and theoretical work on NR self-assembly that is driven by interactions between the ligands and describes current properties and applications of self-assembled NR structures. © 2011 The Royal Society of Chemistry.


Lowman J.P.,University of Toronto
Tectonophysics | Year: 2011

Arguably, the presence of plate-tectonic-type surface motion for periods that endure over hundreds of millions of years is the primary feature a mantle convection model must possess in order to be considered Earth-like. From the early days of mantle dynamics modeling, research has been dedicated to understanding how mantle convection produces the first order observations of plate tectonics as well as how the plates and deep mantle interact. Fledgling studies of the effect of plates on the mantle recognized the ability of imposed plate-scale surface motion to influence global temperatures and heat flux and organize convective planform. Later studies featuring model plates with dynamically determined velocities discovered that the interaction between convection and the plates could result in cyclic plate motion patterns and other time-dependent behavior that was not manifested in systems in which dynamic plates were absent. Focussing on different aspects of system realism (with respect to terrestrial mantle convection) has spawned multiple approaches for modeling convection with dynamic integrated plates. In broadest terms, the two main approaches can be categorized as rheological modeling methods and methods utilizing evolving surface boundary conditions. Over the past dozen years, studies focussing on the former approach have steadily made progress in modeling the self-generation of plate tectonics from convection dynamics. Continual advances have been encouraging, and a consensus is beginning to form regarding the necessary requirements for obtaining the primary elements of plate-like surface motion. However, despite significant progress, the generation of plates over long periods has not yet been modeled with Earth-like convective vigor. In contrast, models utilizing dynamically determined boundary conditions to achieve plate-like surface motion have relatively little difficulty with emulating terrestrial convective vigor or simulations of billions of years. Instead, their weakness is more fundamental; they can only provide insight into the reciprocating dynamics of the mantle and plates once the existence of the plates is assumed and they cannot model any aspects of the dynamics responsible for the origin of the plates. This paper briefly reviews the evolution of mantle convection models featuring plates and examines the progress that has been made in our understanding of the feedback between the mantle and plate tectonics through the use of both rheological and boundary condition modeling methods. Common findings, recent advances and unbridged problems are identified and discussed. © 2011 Elsevier B.V.


Yeung C.S.,University of Toronto | Dong V.M.,University of Toronto
Chemical Reviews | Year: 2011

Transformations that can be categorized as catalytic dehydrogenative cross-couplings are reviewed providing handy reference for chemists interested in using catalytic dehydrogenative coupling in multistep synthesis and those interested in inventing greener methods for C-C bond construction. In 2002, the groups of de Vries and van Leeuwen reported an exceptionally mild oxidative Heck-type olefination that uses amide directing groups to control reactivity and regioselectivity. The Yu lab reported Pd-catalyzed olefination of electron-deficient arenes that occurs with meta-selectivity and envisioned a novel ligand Pyr with steric encumbrance at the exterior of the ligand. the groups of Hu and You demonstrated that other classes of nitrogen-containing heterocycles undergo facile and regioselective arylation with stoichiometric amounts of Cu(OAc)2.


Konvalinka A.,University of Toronto
Kidney International | Year: 2014

Urine represents a mine for proteomic markers of renal diseases, but its analysis is hindered by unresolved technical issues. Aregger et al. used an unbiased proteomics approach to analyze urine of critically ill patients. They discovered insulin-like growth factor-binding protein 7 (IGFBP-7) and linked it to acute kidney injury (AKI) outcome. Future efforts should address the biology of IGFBP-7 and related proteins to determine their role in AKI. © 2013 International Society of Nephrology.


Tuohy C.H.,University of Toronto
Journal of Health Politics, Policy and Law | Year: 2012

This article examines the cases of three health care states-two of which (Britain and the Netherlands) have undergone major policy reform and one of which (Canada) has experienced only marginal adjustments. The British and Dutch reforms have variously altered the balance of power, the mix of instruments of control, and the organizing principles. As a result, mature systems representing the ideal-typical health care state categories of national health systems and social insurance (Britain and the Netherlands, respectively) were transformed into distinctive national hybrids. These processes have involved a politics of redesign that differs from the politics of earlier phases of establishment and retrenchment. In particular, the redesign phase is marked by the activity of institutional entrepreneurs who exploit specific opportunities afforded by public programs to combine public and private resources in innovative organizational arrangements. Canada stands as a counterpoint: no window of opportunity for major change occurred, and the bilateral monopoly created by its prototypical single-payer model provided few footholds for entrepreneurial activity. The increased significance of institutional entrepreneurs gives greater urgency to one of the central projects of health policy: the design of accountability frameworks to allow for an assessment of performance against objectives. © 2012 by Duke University Press.


Neuromuscular complications of critical illness are common, and can be severe and persistent, with substantial impairment in physical function and long-term quality of life. While the etiology of ICU-acquired weakness (ICUAW) is multifactorial, both direct (ie, critical illness neuromyopathy) and indirect (ie, immobility/disuse atrophy) complications of critical illness contribute to it. ICUAW is often difficult to diagnose clinically during the acute phase of critical illness, due to the frequent use of deep sedation, encephalopathy, and delirium, which impair physical examination for patient strength. Despite its limitations, physical examination is the starting point for identification of ICUAW in the cooperative patient. Given the relative cost, invasiveness, and need for expertise, electrophysiological testing and/or muscle biopsy may be reserved for weak patients with slower than expected improvement on serial clinical examination. Currently there are limited interventions to prevent or treat ICUAW, with tight glycemic control having the greatest supporting evidence. There is a paucity of clinical trials evaluating the specific role of early rehabilitation in the chronic critically ill. However, a number of studies support the benefit of intensive rehabilitation in patients receiving chronic mechanical ventilation. Furthermore, emerging data demonstrate the safety, feasibility, and potential benefit of early mobility in critically ill patients, with the need for multicenter randomized trials to evaluate potential short- and long-term benefits of early mobility, including the potential to prevent the need for prolonged mechanical ventilation and/or the development of chronic critical illness, and other novel treatments on patients' muscle strength, physical function, quality of life, and resource utilization. Finally, the barriers, feasibility, and efficacy of early mobility in both medical and other ICUs (eg, surgical, neurological, pediatric), as well as in the chronic critically ill, have not been formally evaluated and require exploration in future clinical trials. © 2012 Daedalus Enterprises.


Cutter A.D.,University of Toronto
Molecular Phylogenetics and Evolution | Year: 2013

Evolutionary theory is primed to synthesize microevolutionary processes with macroevolutionary divergence by taking advantage of multilocus multispecies genomic data in the molecular evolutionary analysis of biodiversity. While coalescent theory bridges across timescales to facilitate this integration, it is important to appreciate the assumptions, caveats, and recent theoretical advances so as to most effectively exploit genomic analysis. Here I outline the connections between population processes and phylogeny, with special attention to how genomic features play into underlying predictions. I discuss empirical and theoretical complications, and solutions, relating to recombination and multifurcating genealogical processes, predictions about how genome structure affects gene tree heterogeneity, and practical choices in genome sequencing and analysis. I illustrate the conceptual implications and practical benefits of how genomic features generate predictable patterns of discordance of gene trees and species trees along genomes, for example, as a consequence of how regions of low recombination and sex linkage interact with natural selection and with the accumulation of reproductive incompatibilities in speciation. Moreover, treating population genetic parameters as characters to be mapped onto phylogenies offers a new way to understand the evolutionary drivers of diversity within and differentiation between populations. Despite a number of challenges conferred by genomic information, the melding of phylogenetics, phylogeography and population genetics into integrative molecular evolution is poised to improve our understanding of biodiversity at all levels. © 2013 Elsevier Inc.


Allen A.D.,University of Toronto | Tidwell T.T.,University of Toronto
Chemical Reviews | Year: 2013

Cumulenes are a highly varied class of compounds, including such species as ketenes, allenes, ketenimines, and isocyanates, as well as analogues where carbon is replaced by silicon or germanium, oxygen is replaced by sulfur or selenium, and nitrogen by phosphorus or arsenic. The unique structural characteristics of cumulenes lead to their distinctive patterns of reactivity, and the investigations of their structures and properties have enhanced their utility. Silylcyclobutenones prepared by new methodology from dimethoxycyclobutenedione are readily converted to the corresponding stabilized 2-silylvinylketenes, and these give efficient [4 + 2] cycloadditions with tetracyanoethylene (TCNE) and also with imines. There is increasing interest in cumulenes, including the preparation and identification of new members of this family, with new ways of catalyzing their reactivity, and the development of stereoselective processes.


Feld J.J.,University of Toronto
Best Practice and Research: Clinical Gastroenterology | Year: 2012

Great strides have been made in the treatment of hepatitis C virus (HCV) infection in the past decade. Although there is much focus on the development of new direct-acting antivirals (DAA), interferon and ribavirin remain the backbone of therapy for both acute and chronic HCV infections. While DAA therapy will likely eventually largely replace interferon, in much of the world and for genotype non-1 patients, peginterferon and ribavirin remain first-line therapy. Interferon-based therapy is highly effective in acute HCV with high response rates with short courses of therapy. Unfortunately once infection progresses to chronicity, treatment success rates drop off considerably. The indications, pre-treatment evaluation and efficacy of peginterferon and ribavirin therapy in the treatment of acute and chronic HCV infection are discussed with strategies to improve outcomes and manage adverse events. © 2012 Elsevier Ltd. All rights reserved.


Sage R.F.,University of Toronto
Plant Biology | Year: 2013

This paper reviews how terrestrial plants reduce photorespiration and thus compensate for its inhibitory effects. As shown in the equation φ{symbol} = (1/Sc/o)O/C, where φ{symbol} is the ratio of oxygenation to carboxylation, Sc/o is the relative specificity of Rubisco, O is stromal O2 level and C is the stromal CO2 concentration, plants can reduce photorespiration by increasing Sc/o or C, or by reducing O. By far the most effective means of reducing φ{symbol} is by concentrating CO2, as occurs in C4 and CAM plants, and to a lesser extent in plants using a glycine shuttle to concentrate CO2 into the bundle sheath. Trapping and refixation of photorespired CO2 by a sheath of chloroplasts around the mesophyll cell periphery in C3 plants also enhances C, particularly at low atmospheric CO2. O2 removal is not practical because high energy and protein investment is needed to have more than a negligible effect. Sc/o enhancement provides for modest reductions in φ{symbol}, but at the potential cost of limiting the kcat of Rubisco. An effective means of decreasing φ{symbol} and enhancing carbon gain is to lower leaf temperature by reducing absorbance of solar radiation, or where water is abundant, opening stomata. By using a combination of mechanisms, C3 plants can achieve substantial (>30%) reductions in φ{symbol}. This may have allowed many C3 species to withstand severe competition from C4 plants in low CO2 atmospheres of recent geological time, thereby preserving some of the Earth's floristic diversity that accumulated over millions of years. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.


Fisher J.A.,University of Toronto
Journal of Cerebral Blood Flow and Metabolism | Year: 2016

Cerebrovascular reactivity (CVR) studies have elucidated the physiology and pathophysiology of cerebral blood flow regulation. A non-invasive, high spatial resolution approach uses carbon dioxide (CO2) as the vasoactive stimulus and magnetic resonance techniques to estimate the cerebral blood flow response. CVR is assessed as the ratio response change to stimulus change. Precise control of the stimulus is sought to minimize CVR variability between tests, and show functional differences. Computerized methods targeting end-tidal CO2 partial pressures are precise, but expensive. Simpler, improvised methods that fix the inspired CO2 concentrations have been recommended as less expensive, and so more widely accessible. However, these methods have drawbacks that have not been previously presented by those that advocate their use, or those that employ them in their studies. As one of the developers of a computerized method, I provide my perspective on the trade-offs between these two methods. The main concern is that declaring the precision of fixed inspired concentration of CO2 is misleading: it does not, as implied, translate to precise control of the actual vasoactive stimulus-the arterial partial pressure of CO2. The inherent test-to-test, and therefore subject-to-subject variability, precludes clinical application of findings. Moreover, improvised methods imply widespread duplication of development, assembly time and costs, yet lack uniformity and quality control. A tabular comparison between approaches is provided. © 2015 The Author(s).


Cox R.A.,University of Toronto
International Journal of Molecular Sciences | Year: 2011

If a species does not have a finite lifetime in the reaction medium, it cannot be a mechanistic intermediate. This principle was first enunciated by Jencks, as the concept of an enforced mechanism. For instance, neither primary nor secondary carbocations have long enough lifetimes to exist in an aqueous medium, so S N1 reactions involving these substrates are not possible, and an S N2 mechanism is enforced. Only tertiary carbocations and those stabilized by resonance (benzyl cations, acylium ions) are stable enough to be reaction intermediates. More importantly, it is now known that neither H 3O + nor HO - exist as such in dilute aqueous solution. Several recent high-level calculations on large proton clusters are unable to localize the positive charge; it is found to be simply "on the cluster" as a whole. The lifetime of any ionized water species is exceedingly short, a few molecular vibrations at most; the best experimental study, using modern IR instrumentation, has the most probable hydrated proton structure as H 13O 6+, but only an estimated quarter of the protons are present even in this form at any given instant. Thanks to the Grotthuss mechanism of chain transfer along hydrogen bonds, in reality a proton or a hydroxide ion is simply instantly available anywhere it is needed for reaction. Important mechanistic consequences result. Any charged oxygen species (e.g., a tetrahedral intermediate) is also not going to exist long enough to be a reaction intermediate, unless the charge is stabilized in some way, usually by resonance. General acid catalysis is the rule in reactions in concentrated aqueous acids. The Grotthuss mechanism also means that reactions involving neutral water are favored; the solvent is already highly structured, so the entropy involved in bringing several solvent molecules to the reaction center is unimportant. Examples are given. © 2011 by the authors; licensee MDPI, Basel, Switzerland.


Malti T.,University of Toronto
Developmental Review | Year: 2016

An integrated clinical-developmental model is proposed for understanding the development of guilt feelings from early childhood to adolescence. The central goal is to posit a new theoretical framework that expands existing social-cognitive models, social-domain models, and clinical approaches to the study of guilt (i.e., the Affect-Event Model [Arsenio, Gold, & Adams, 2006] and the Affect-Cognition Model [Malti & Keller, 2010]). Because guilt feelings are multifaceted and depend on both contextual variation (e.g., moral transgressions versus conventional issues) and dispositional guilt proneness, they can be associated with both adaptive and maladaptive outcomes for children and adolescents. The proposed model therefore suggests several clinical effects on adaptive, other-oriented behaviors and maladaptive, externalizing and internalizing symptoms across childhood and adolescence. The available evidence for each of these hypotheses is presented. The developmental model of guilt lays the groundwork for a more complete understanding of adaptive and maladaptive behaviors across development and provides new means for developing interventions that will reduce mental health problems and promote adaptive behaviors in children and adolescents. The model assumes that intervention efforts will be effective at producing behavioral change when (a) they are developmentally sensitive, rather than one-size-fits-all, and (b) they acknowledge that both extensively low and extensively high/inappropriate levels of guilt may be pathogenic and need to be targeted. © 2016 Elsevier Inc.


White C.J.,University of Toronto | Yudin A.K.,University of Toronto
Nature Chemistry | Year: 2011

Peptide macrocycles have found applications that range from drug discovery to nanomaterials. These ring-shaped molecules have shown remarkable capacity for functional fine-tuning. Such capacity is enabled by the possibility of adjusting the peptide conformation using the techniques of chemical synthesis. Cyclic peptides have been difficult, and often impossible, to prepare using traditional synthetic methods. For macrocyclization to occur, the activated peptide must adopt an entropically disfavoured pre-cyclization conformation before forming the desired product. Here, we review recent solutions to some of the major challenges in this important area of contemporary synthesis. © 2011 Macmillan Publishers Limited. All rights reserved.


Chanda B.,University of Toronto | Ditadi A.,University of Toronto | Iscove N.N.,University of Toronto | Keller G.,University of Toronto
Cell | Year: 2013

Summary Hematopoietic stem cells (HSCs) develop from a specialized subpopulation of endothelial cells known as hemogenic endothelium (HE). Although the HE origin of HSCs is now well established in different species, the signaling pathways that control this transition remain poorly understood. Here, we show that activation of retinoic acid (RA) signaling in aorta-gonad- mesonephros-derived HE ex vivo dramatically enhanced its HSC potential, whereas conditional inactivation of the RA metabolizing enzyme retinal dehydrogenase 2 in VE-cadherin expressing endothelial cells in vivo abrogated HSC development. Wnt signaling completely blocked the HSC inductive effects of RA modulators, whereas inhibition of the pathway promoted the development of HSCs in the absence of RA signaling. Collectively, these findings position RA and Wnt signaling as key regulators of HSC development and in doing so provide molecular insights that will aid in developing strategies for their generation from pluripotent stem cells. © 2013 Elsevier Inc.


Lofgreen J.E.,University of Toronto | Ozin G.A.,University of Toronto
Chemical Society Reviews | Year: 2014

The wealth of molecular precursors for organic and inorganic polymers has resulted in an incredible volume of molecular imprinting literature. The vast majority of reports deal with organic polymer systems, and molecular imprinting in silica can still be considered a small niche in the field. In this review, we present key concepts of molecular imprinting, sol-gel processing, and the synthesis of templated mesoporous silica. We take a small fraction of the literature and use it to understand the ways in which molecular imprinting in siliceous materials of controlled morphology has achieved success in the past fifteen years. Using selected case studies rather than a comprehensive review of the entire field, our goal is to illustrate the key aspects of imprinted silica-based materials as demonstrated by judiciously controlled systems, looking first at control on the micrometre scale in bulk phase materials, and then on the nanometre scale in templated mesoporous materials. © The Royal Society of Chemistry.


Hounjet L.J.,University of Toronto | Stephan D.W.,University of Toronto
Organic Process Research and Development | Year: 2014

Since the discovery of "frustrated Lewis pairs" in 2006, these metal-free systems have been exploited to activate a variety of small molecules, with H2 being perhaps the most significant among them. This finding has since allowed for the development of metal-free strategies to hydrogenation catalysis. In this review, progress toward the development of these new catalysts for reductions of polar organic substrates, olefins, alkynes, and aromatic systems, is described. © 2014 American Chemical Society.


Braverman M.,University of Toronto | Rao A.,University of Washington
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2011

We show that it is possible to encode any communication protocol between two parties so that the protocol succeeds even if a (1/4-ε) fraction of all symbols transmitted by the parties are corrupted adversarially, at a cost of increasing the communication in the protocol by a constant factor (the constant depends on epsilon). This encoding uses a constant sized alphabet. This improves on an earlier result of Schulman, who showed how to recover when the fraction of errors is bounded by 1/240. We also show how to simulate an arbitrary protocol with a protocol using the binary alphabet, a constant factor increase in communication and tolerating a (1/8-ε) fraction of errors. © 2011 ACM.


Kennedy S.H.,University of Toronto
Primary Care Companion to the Journal of Clinical Psychiatry | Year: 2013

Objective: To provide general practitioners with a comparison of major depressive disorder treatments received in primary care and psychiatric clinic settings, a focus on treatment outcomes related to currently prescribed antidepressants, and a review of new and emerging therapeutic strategies. Data Sources: English-language evidence-based guidelines and peer-reviewed literature published between January 1, 2005, and December 31, 2011, were identified using PubMed, MEDLINE, and EMBASE. All searches contained the terms major depressive disorder and unipolar depression, and excluded the terms bipolar disorder/manic depressive disorder. The following search terms were also included: naturalistic study, antidepressant, relapse, recurrence, residual symptoms, response, remission, sequential medication trials, and treatment-resistant depression. Study Selection: Meta-analyses, systematic reviews, and practice guidelines were included. Bibliographies were used to identify additional articles of interest. Data Extraction: Abstracts and articles were screened for relevance to primary care practice. Population-based studies and those involving patients treated in primary care were used whenever possible. Data Synthesis: Achieving remission from a major depressive episode is important to improve functional outcomes and to reduce relapse and recurrence. Despite the availability of numerous antidepressants, as many as 50% of patients require treatment modifications beyond first-line therapy. Among remitters, 90% report residual symptoms that may interfere with function. Patients treated in primary care often have chronic depression (symptom duration ≥ 24 months at presentation) and medical comorbidities. These are clinical predictors of worse outcomes and require individualized attention when treatment is initiated. Antidepressants differ in efficacy, tolerability, and side effects-factors that may affect adherence to treatment. Conclusions: Major depressive disorder is highly prevalent in primary care and is among the most common causes of loss of disability-adjusted life-years worldwide. There are few differences in clinical profiles between depressed patients in primary care and those in specialist clinics, although differences in symptoms and comorbid conditions among individual depressed patients present a challenge for the physician providing individualized treatment. The goal of treatment is remission with good functional and psychosocial outcomes. Physicians in primary care should have expertise in working with a number of current antidepressant approaches and an awareness of new and emerging treatments. © 2013 Physicians Postgraduate Press, Inc.


Witczak-Krempa W.,Perimeter Institute for Theoretical Physics | Chen G.,University of Colorado at Boulder | Kim Y.B.,University of Toronto | Kim Y.B.,Korea Institute for Advanced Study | Balents L.,University of California at Santa Barbara
Annual Review of Condensed Matter Physics | Year: 2014

We discuss phenomena arising from the combined influence of electron correlation and spin-orbit coupling (SOC), with an emphasis on emergent quantum phases and transitions in heavy transition metal compounds with 4d and 5d elements. A common theme is the influence of spin-orbital entanglement produced by SOC, which influences the electronic and magnetic structure. In the weak-to-intermediate correlation regime, we show how nontrivial band-like topology leads to a plethora of phases related to topological insulators (TIs). We expound these ideas using the example of pyrochlore iridates, showing how many novel phases, such as the Weyl semimetal, axion insulator, topological Mott insulator, and TIs, may arise in this context. In the strong correlation regime, we argue that spin-orbital entanglement fully or partially removes orbital degeneracy, reducing or avoiding the normally ubiquitous Jahn-Teller effect. As we illustrate for the honeycomb-lattice iridates and double perovskites, this leads to enhanced quantum fluctuations of the spin-orbital entangled states and the chance to promote exotic spin liquid and multipolar ordered ground states. Connections to experiments, materials, and future directions are discussed. © Copyright 2014 by Annual Reviews. All rights reserved.


Carlberg R.G.,University of Toronto
Astrophysical Journal | Year: 2012

Dark matter sub-halos create gaps in the stellar streams orbiting in the halos of galaxies. We evaluate the sub-halo stream crossing integral with the guidance of simulations to find that the linear rate of gap creation, R u, in a typical cold dark matter (CDM) galactic halo at 100 kpc is Ru ≈ 0.0066 M̂?0.35 8 kpc?1 Gyr?1, where M̂8(M̂/108M) is the minimum mass halo that creates a visible gap. The relation can be recast entirely in terms of observables, as Ru ≈ 0.059ω ?0.85 kpc?1 Gyr ?1, for w in kpc, normalized at 100 kpc. Using published data, the density of gaps is estimated for M31s NW stream and the Milky Way Pal 5 stream, Orphan stream, and Eastern Banded Structure. The estimated rates of gap creation all have errors of 50% or more due to uncertain dynamical ages and the relatively noisy stream density measurements. The gap-ratewidth data are in good agreement with the CDM-predicted relation. The high density of gaps in the narrow streams requires a total halo population of 105 sub-halos above a minimum mass of 105M⊙. © 2012 The American Astronomical Society. All rights reserved.


Anber M.M.,University of Toronto
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

Recently, it has been conjectured that deconfining phase transition in SU(Nc) pure Yang-Mills theories is continuously connected to a quantum phase transition in softly broken N=1 super Yang-Mills on R1 ,2×S1. We exploit this conjecture to study the strength of the transition and deconfining temperature as a function of the vacuum angle θ in pure Yang-Mills. We find that the transition temperature is a decreasing function of θâ̂̂[0,π), in an excellent agreement with recent lattice simulations. We also predict that the transition becomes stronger for the same range of θ, and comment on the θ dependence in the large Nc limit. More lattice studies are required to test our predictions. © 2013 American Physical Society.


Feizpour A.,University of Toronto | Xing X.,University of Toronto | Steinberg A.M.,University of Toronto
Physical Review Letters | Year: 2011

We show that weak measurement can be used to "amplify" optical nonlinearities at the single-photon level, such that the effect of one properly postselected photon on a classical beam may be as large as that of many unpostselected photons. We find that "weak-value amplification" offers a marked improvement in the signal-to-noise ratio in the presence of technical noise with long correlation times. Unlike previous weak-measurement experiments, our proposed scheme has no classical equivalent. © 2011 American Physical Society.


Weir J.T.,University of Toronto | Price T.D.,University of Chicago
American Naturalist | Year: 2011

Range expansions are critical to renewed bouts of allopatric or parapatric speciation. Limits on range expansions-and, by implication, speciation-include dispersal ability and permeability of geographical barriers. In addition, recently diverged taxa may interfere with each other, preventing mutual expansion of each other's range into sympatry, because reproductive isolation is incomplete and/or ecological competition particularly strong. On the basis of geographical distributions and mitochondrial DNA phylogenetic information for 418 recently diverged species of New World birds, we estimate that secondary sympatry takes on the order of millions of years following population splitting and hence could impose an important limit on the rate of range expansion, thereby limiting further rounds of species formation. Average rates of achievement of sympatry have been faster in the temperate region (we estimate 1.7 million years to sympatry at 60°) than in the tropics (3.2 million years to sympatry at the equator). Evidence from the ages of species with hybrid zones implies that one factor associated with the slowed sympatry in the tropics is the rate of accumulation of reproductive isolation. © 2011 by The University of Chicago.


Liao K.,University of Toronto | Mogridge J.,University of Toronto
Infection and Immunity | Year: 2013

The efficacy of the innate immune system depends on its ability to mount an appropriate response to diverse infections and damaging agents. Key components of this system are pattern recognition receptors that detect pathogen-associated and damage-associated molecular patterns (PAMPs and DAMPs). Nlrp1b is a pattern recognition receptor that forms a caspase-1 activation platform, known as an inflammasome, upon sensing the proteolytic activity of anthrax lethal toxin. The activation of caspase-1 leads to the release of proinflammatory cytokines that aid in the clearance of the anthrax infection. Here, we demonstrate that Nlrp1b also becomes activated in cells that are subjected to energy stress caused by metabolic inhibitors or by nutrient deprivation. Glucose starvation and hypoxia were used to correlate the level of cytosolic ATP to the degree of inflammasome activation. Because lowering the ratio of cytosolic ATP to AMP activates the main cellular energy sensor, AMP-activated protein kinase (AMPK), we assessed whether AMPK promoted inflammasome activity by using a combination of small interfering RNA (siRNA) and transfection of a dominant negative AMPK subunit. We found that AMPK promoted inflammasome activity, but activation of AMPK in the absence of ATP depletion was not sufficient for caspase-1-mediated pro-interleukin 1β (pro-IL-1β) processing. Finally, we found that mutation of the ATP-binding motif of Nlrp1b caused constitutive activation, suggesting that ATP might inhibit the Nlrp1b inflammasome instead of being required for its assembly. ©2013, American Society for Microbiology.


Kruglov S.I.,University of Toronto
Annals of Physics | Year: 2015

A new model of nonlinear electrodynamics with two parameters is investigated. We also consider a model with one dimensional parameter. It was shown that the electric field of a point-like charge is not singular at the origin and there is the finiteness of the static electric energy of point-like charged particle. We obtain the canonical and symmetrical Belinfante energy-momentum tensors and dilatation currents. It is demonstrated that the dilatation symmetry and dual symmetry are broken in the models suggested. We have calculated the static electric energy of point-like particles. © 2014.


Thomas S.C.,University of Toronto
Tree Physiology | Year: 2010

Studies of age-related changes in leaf functional biology have generally been based on dichotomous comparisons of young and mature individuals (e.g., saplings and mature canopy trees), with little data available to describe changes through the entire ontogeny of trees, particularly of broadleaf angiosperms. Leaf-level gas-exchange and morphological parameters were quantified in situ in the upper canopy of trees acclimated to high light conditions, spanning a wide range of ontogenetic stages from saplings (~1 cm in stem diameter) to trees >60 cm d.b.h. and nearing their maximum lifespan, in three temperate deciduous tree species in central Ontario, Canada. Traits associated with growth performance, including leaf photosynthetic capacity (expressed on either an area, mass or leaf N basis), stomatal conductance, leaf size and leaf N content, generally showed a unimodal ('hump-shaped') pattern, with peak values at an intermediate ontogenetic stage. In contrast, leaf mass per area (LMA) and related morphological parameters (leaf thickness, leaf tissue density, leaf C content) increased monotonically with tree size, as did water-use efficiency; these monotonic relationships were well described by simple allometric functions of the form Y = aXb. For traits showing unimodal patterns, tree size corresponding to the trait maximum differed markedly among traits: all three species showed a similar pattern in which the peak for leaf size occurred in trees ~2-6 cm d.b.h., followed by leaf chemical traits and photosynthetic capacity on a mass or leaf N basis and finally by photosynthetic capacity on a leaf area basis, which peaked approximately at the size of reproductive onset. It is argued that ontogenetic increases in photosynthetic capacity and related traits early in tree ontogeny are general among relatively shade-tolerant tree species that have a low capacity for leaf-level acclimation, as are declines in this set of traits late in tree ontogeny. © The Author 2010. Published by Oxford University Press. All rights reserved.


Adeyi O.A.,University of Toronto
Archives of Pathology and Laboratory Medicine | Year: 2011

Context. - Histopathology, like other branches of medicine in West Africa, has suffered largely from economic, political, social, and infrastructural problems, becoming a shadow of the top quality that had been obtained in the past. To address the prevailing problems, one needs to attempt defining them. Objective.-The existing structure of training and practice are discussed, highlighting the author's perception of the problems and suggesting practical ways to address these while identifying potential roles for North American pathology organizations. Design.-The author's past and ongoing association with pathology practice in Nigeria forms the basis for this review. Results.-Pathology practice is largely restricted to academic medical centers. The largest of academic centers each accession around 4000 or fewer surgical specimens per year to train 9 to 12 residents. Histopathology largely uses hematoxylin-eosin routine stains, sometimes with histochemistry but rarely immunohistochemistry. Pathologists depend largely on their skills in morphology (with its limitations) to classify and subclassify tumors on routine stains, including soft tissue and hematolymphoid malignancies. Immunofluorescence, intraoperative frozen section diagnosis, electronic laboratory system, and gross and microscopic imaging facilities are generally not available for clinical use. Conclusion.-The existing facilities and infrastructure can be augmented with provision of material and professional assistance from other pathology associations in more developed countries and should, among other things, focus on supplementing residency education. Virtual residency programs, short-visit observerships, development of simple but practical laboratory information systems, and closer ties with pathologists in these countries are some of the sueeested steps in achieving this goal.


Kirton A.,University of Calgary | De Veber G.,University of Toronto
Stroke | Year: 2013

Life after perinatal stroke can certainly be good. The high level of functioning attained by many children despite large brain lesions is a remarkable testament to the potential power of developmental plasticity. However, it is clear that such early injury places many other children on an abnormal developmental trajectory with functional consequences. How the interplay of multiple disordered functions in individual children may combine to impact the eventual outcome is of great interest. A child with great developmental potential may be stymied by pathological electrographic brain activity during sleep. Another child highly capable of acquiring new motor skills may fail to gain practical function because proprioceptive deficits prevent him or her from knowing where his or her hand is in space. Another with normal intelligence but an attention disorder may not be able to engage in school, therapy, or sports that could each improve function. With improving recognition and measurement, an integrated understanding of how these multiple factors dictate outcomes in individual children will be a major challenge of perinatal stroke research going forward.


Langer J.C.,University of Toronto
Current Opinion in Pediatrics | Year: 2013

Purpose of review: Hirschsprung disease is relatively common in children. Surgical techniques are available to remove the aganglionic bowel and reconstruct the intestinal tract. Despite many advances, these children may still be difficult to diagnose, and may have ongoing functional problems after surgical correction. Recent findings: The genetic basis and cause of Hirschsprung disease are becoming increasingly clearer. Definitive diagnosis is based on rectal biopsy, but more sophisticated techniques are permitting earlier and more accurate diagnosis. Surgical correction has evolved from routine use of a colostomy and open laparotomy to one-stage transanal and laparoscopic approaches. The range of postoperative problems is reviewed so that the practicing pediatrician and primary care physician can effectively care for these children. Future advances may include better genotype-phenotype correlation and development of neuronal stem cell techniques. Summary: Pediatricians and primary care physicians have an important role to play in diagnosing and managing children with Hirschsprung disease. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Greenfield L.K.,University of Toronto | Jones N.L.,University of Toronto
Trends in Microbiology | Year: 2013

Helicobacter pylori infection represents the strongest known risk factor for the development of gastric cancer. The vacuolating cytotoxin (VacA) plays a key role in disease pathogenesis by exerting pleiotrophic effects on the host. One effect of acute VacA exposure is the induction of autophagy. However, prolonged exposure to the toxin disrupts autophagy by preventing maturation of the autolysosome. Novel insights into the mechanism and consequences of this phenomenon have emerged, but many aspects remain largely unknown. Current evidence supports a scenario in which H. pylori-suppressed autophagy facilitates intracellular survival and persistence of the pathogen, while also generating an environment favoring carcinogenesis. © 2013 Elsevier Ltd.


Klotz L.,University of Toronto
Current Urology Reports | Year: 2015

There is ample evidence that low risk and many cases of low-/intermediate-risk prostate cancer, are indolent, have little or no metastatic potential, and do not pose a threat to the patient in his lifetime. Major strides have been made in understanding who these patients are and in encouraging the use of conservative management in such individuals. A component of conservative management is the early identification of those ‘low-risk’ patients who harbour higher risk disease, and benefit from definitive therapy. This represents about 30 % of newly diagnosed low-risk patients. A further small proportion of patients with low-risk disease demonstrate biological progression to higher grade disease. Men with lower risk disease can defer treatment, in most cases for life. Men with higher risk disease that can be localized to a relatively small volume of the prostate can undergo selective therapy. The results of active surveillance, embodying conservative management with selective delayed intervention for the subset who are re-classified as higher risk overtime based on repeat biopsy, imaging or biomarker results have shown that this approach is safe in the intermediate to long term, with a 3 % cancer specific mortality at 10–15 years. Further refinement of the surveillance approach is ongoing, incorporating MRI, targeted biopsies and molecular biomarkers. © 2015, Springer Science+Business Media New York.


Freedman J.,University of Toronto
Transfusion and Apheresis Science | Year: 2014

Blood conservation, or Patient Blood Management (PBM), is a paradigm shift in transfusion practice. Recognizing the potential adverse effects associated with blood transfusion, PBM emphasises the use of alternatives to transfusion in order to minimize unnecessary or inappropriate blood transfusion. The ONTraC program is a network of transfusion coordinators in 25 Ontario hospitals with the focus of implementing PBM. The program has been highly successful in reducing transfusion rates and improving clinical outcomes, and has proven very cost-effective. This paper summarizes results of the program from its inception in 2002-2011. © 2013 Elsevier Ltd.


Yudin A.K.,University of Toronto
Chemical Science | Year: 2015

A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. Macrocycles, which are cyclic compounds comprising 12 atoms or more, are now recognized as molecules that "are up to the task" to interrogate extended protein interfaces. However, because macrocycles (particularly the ones based on peptides) are equipped with large polar surface areas, achieving cellular permeability and bioavailability is anything but straightforward. While one might consider this to be the Achilles' heel of this class of compounds, the synthetic community continues to develop creative approaches toward the synthesis of macrocycles and their site-selective modification. This perspective provides an overview of both mechanistic and structural issues that bear on macrocycles as a unique class of molecules. The reader is offered a historical foray into some of the classic studies that have resulted in the current renaissance of macrocycles. In addition, an attempt is made to overview the more recent developments that give hope that macrocycles might indeed turn into a useful therapeutic modality. This journal is © The Royal Society of Chemistry.


Nano N.,University of Toronto
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Rvb1 and Rvb2 are highly conserved and essential eukaryotic AAA+ proteins linked to a wide range of cellular processes. AAA+ proteins are ATPases associated with diverse cellular activities and are characterized by the presence of one or more AAA+ domains. These domains have the canonical Walker A and Walker B nucleotide binding and hydrolysis motifs. Rvb1 and Rvb2 have been found to be part of critical cellular complexes: the histone acetyltransferase Tip60 complex, chromatin remodelling complexes Ino80 and SWR-C, and the telomerase complex. In addition, Rvb1 and Rvb2 are components of the R2TP complex that was identified by our group and was determined to be involved in the maturation of box C/D small nucleolar ribonucleoprotein (snoRNP) complexes. Furthermore, the Rvbs have been associated with mitotic spindle assembly, as well as phosphatidylinositol 3-kinase-related protein kinase (PIKK) signalling. This review sheds light on the potential role of the Rvbs as chaperones in the assembly and remodelling of these critical complexes.


Physiological tissue repair aims at restoring the mechano-protective properties of the extracellular matrix. Consequently, redundant regulatory mechanisms are in place ensuring that tissue remodeling terminates once matrix homeostasis is re-established. If these mechanisms fail, stromal cells become continuously activated, accumulate excessive amounts of stiff matrix, and fibrosis develops. In this mini-review, I develop the hypothesis that the mechanical state of the extracellular matrix and the pro-fibrotic transforming growth factor (TGF)-β1 cooperate to regulate the remodeling activities of stromal cells. TGF-β1 is stored in the matrix as part of a large latent complex and can be activated by cell contractile force that is transmitted by integrins. Matrix straining and stiffening lower the threshold for TGF-β1 activation by increasing the mechanical resistance to cell pulling. Different elements of this mechanism can be pharmacologically targeted to interrupt the mechanical positive feedback loop of fibrosis, including specific integrins and matrix protein interactions. © 2015.


Piccin D.,University of Toronto | Morshead C.M.,University of Toronto
Stem Cells | Year: 2011

Neural stem cells comprise a small population of subependymal cells in the adult brain that divide asymmetrically under baseline conditions to maintain the stem cell pool and divide symmetrically in response to injury to increase their numbers. Using in vivo and in vitro models, we demonstrate that Wnt signaling plays a role in regulating the symmetric divisions of adult neural stem cells with no change in the proliferation kinetics of the progenitor population. Using BAT-gal transgenic reporter mice to identify cells with active Wnt signaling, we demonstrate that Wnt signaling is absent in stem cells in conditions where they are dividing asymmetrically and that it is upregulated when stem cells are dividing symmetrically, such as (a) during subependymal regeneration in vivo, (b) in response to stroke, and (c) during colony formation in vitro. Moreover, we demonstrate that blocking Wnt signaling in conditions where neural stem cells are dividing symmetrically inhibits neural stem cell expansion both in vivo and in vitro. Together, these findings reveal that the mechanism by which Wnt signaling modulates the size of the stem cell pool is by regulating the symmetry of stem cell division. © AlphaMed Press.


Phenotypic variability is well recognized in severe hemophilia A. A few studies, mainly in adults treated lifelong on demand, suggest that bleeding phenotype correlates with factor VIII gene (F8) mutation type. Because treatment regimens influence outcomes to a large extent, examining bleeding phenotype during the first years of life may be the most suitable way to define this variability. We set out to analyze the very early phenotypic expression of severe hemophilia A in 621 consecutively enrolled, well-characterized previously untreated patients and to correlate this with patients' F8 mutation. Detailed information was collected on bleeds and treatment of the first 75 exposure days or until inhibitor development. F8 mutation type was known for 531 patients; 402 had null mutations and 129 had non-null mutations. Considering only patients who had not started prophylaxis or developed an inhibitor before select bleeding events, we found that patients with null mutations experienced their first bleed and first joint bleed at younger median ages than patients with non-null mutations (9.7 vs 10.9 months and 13.8 vs 16.1 months, respectively). We conclude that F8 mutation type accounts for only a small component of the significant phenotypic variability found among patients with severe hemophilia A.


Charach A.,University of Toronto
Current psychiatry reports | Year: 2013

Safe and effective medication for attention deficit hyperactivity disorder (ADHD) is available and recommended as first-line treatment for the core symptoms of inattention, overactivity and impulsiveness. Despite impaired functioning during adolescence, many discontinue medication treatment. For children, healthcare decisions are usually made by the parent; older youth make their own decisions. Beliefs and attitudes may differ widely. Some families understand that ADHD is a neurobiological condition and accept that medication is indicated, for others, such treatment is unacceptable. Converging evidence describes negative perceptions of the burden associated with medication use as well as concerns about potential short and long term adverse effects. Indeed experiences of adverse effects are a frequent explanation for discontinuation among youth. Ways to improve shared decision making among practitioners, parents and youth, and to monitor effectiveness, safety and new onset of concurrent difficulties are likely to optimize outcomes.


Bolt L.M.,University of Toronto
International Journal of Primatology | Year: 2013

Long calls are sex-specific vocalizations used for mate attraction or mate defense in many animal species. Ring-tailed lemurs (Lemur catta), female-dominant strepsirrhines, have a male-specific long call termed a howl, with proposed functions that have never been empirically tested. I aimed to investigate why ring-tailed lemur males howl and to test whether the mate defense and mate attraction hypotheses for long-calling were applicable to this species. From March to July 2010, I collected 600 h of focal data on 25 males aged ≥3 year at Beza Mahafaly Special Reserve, Madagascar. I observed each male continuously for 30 min at a time and noted all agonism using one-zero sampling at 2. 5-min intervals. I calculated male dominance rank from these data. I recorded days when female estrus occurred and noted howling and intergroup encounters using all-occurrences sampling. Howling rate was not significantly related to female estrus or male dominance rank, providing no support for the mate attraction hypothesis or the intragroup mate defense hypothesis. In contrast, the intergroup mate defense hypothesis was strongly supported. During intergroup encounters, male howling rate significantly increased compared to howling rate at times without other groups present, and a greater number of males participated in multimale howling choruses when compared to times without nongroup members present. My results suggest that male ring-tailed lemurs howl to advertise their presence and location to other groups, but not to male or female members of their own group. Howling could discourage male immigration by advertising the number of males already present in a group. Long calls are used for similar mate defense purposes during intergroup encounters by other primates, including Thomas langurs (Presbytis thomasi) and chacma baboons (Papio ursinus). © 2013 Springer Science+Business Media New York.


Boonstra R.,University of Toronto
Functional Ecology | Year: 2013

Chronic activation of the stress axis caused by long-term uncontrollable and unpredictable factors in the environment has been regarded as causing maladaptive and/or pathological effects, both by those studying animals in the laboratory and in nature. While pathology may apply to the former, I argue that it does not apply to the latter. Our thinking on the role of chronic stress in animals in nature has been heavily influenced by biomedical research, but much less so by the ecological and evolutionary context within which animals actually function. I argue that when such stressors occur (e.g. periods of high predation risk, food limitation, prolonged severe weather, social conflict, etc.), although the animal may be chronically stressed, its responses are adaptive and continue to promote fitness. Chronic stressors in nature can be subdivided into whether they are reactive (direct physiological challenges threatening homeostasis and not requiring cognitive processing - for example, food limitation) or anticipatory (perceived to be threatening and requiring cognitive processing - for example, high predation risk). For anticipatory stressors, their impact on the animal should not be based on their absolute duration (they may be acute), but rather by the duration of their physiological consequences. The anticipatory stressor of persistent high predation risk does not elicit chronic stress in all prey classes. Cyclic snowshoe hare and arctic ground squirrels exhibit evidence of chronic stress when predator numbers are high, but cyclic vole and noncyclic elk populations do not. I suggest that chronic stress has evolved to benefit the fitness of the former and not the later, with the key factors being lifespan and life history. I propose that chronic stress evolves in a species only if it is adaptive. © 2012 The Author. Functional Ecology © 2012 British Ecological Society.


Buys Y.M.,University of Toronto
Current Opinion in Ophthalmology | Year: 2013

Despite a large number of ExPRESS implant procedures worldwide, there is a paucity of high-quality studies comparing ExPRESS to trabeculectomy. From the available literature to date the outcomes (success and early complications) of ExPRESS are similar to trabeculectomy. Reports of late complications related to device extrusion and malposition are beginning to be published; however, the significantly increased cost for ExPRESS surgery is likely to be the main limitation to widespread adoption of this procedure. © 2013 Wolters Kluwer Health.


Rughani A.I.,University of Toronto | Lozano A.M.,University of Toronto
Movement Disorders | Year: 2013

Myoclonus dystonia (M-D) syndrome is a heritable movement disorder characterized by myoclonic jerks and dystonia primarily of the upper extremities. M-D remains poorly responsive to pharmacological treatment. Emerging reports suggest good response to DBS of the internal globus pallidus (GPi) and ventral intermediate nucleus (VIM) of the thalamus. This study aimed to appraise the value of these two DBS targets by evaluating reports available in the literature. A systematic search of published case reports and case series was performed on Medline and Embase. Responses to DBS were evaluated. Myoclonus was assessed with the Unified Myoclonus Rating Scale (UMRS) and dystonia by the Burke-Fahn-Marsden dystonia rating scale (BFMDRS). The primary outcome of interest was the relative improvements noted with GPi, compared to VIM stimulation. A total of 17 publications yielded 40 unique cases, with mean follow-up of 27.2 months. All patients demonstrated improvements in myoclonus scores, with 93.5% showing at least a 50% improvement in UMRS. The mean improvement in myoclonus scores was 72.6%. In contrast, dystonia scores were improved in 87.9% of patients, with 72.7% reporting at least a 50% improvement in BFMDRS. The mean improvement in dystonia scores was 52.6%. Improvements in myoclonus scores were similar for both GPi (75.7%) and VIM (70.4%; P = 0.27). However, the improvements in dystonia scores were greater with GPi (60.2%), compared to VIM (33.3%; P = 0.03). Although both targets achieve similar improvements in myoclonus, GPi stimulation may be a preferred target because it may achieve greater improvements in dystonia, compared to VIM stimulation. © 2013 Movement Disorder Society.


Klotz L.,University of Toronto
Journal of the National Cancer Institute - Monographs | Year: 2012

Active surveillance has evolved to become a standard of care for favorable-risk prostate cancer. This is a summary of the rationale, method, and results of active surveillance beginning in 1995 with the first prospective trial of this approach. This was a prospective, single-arm cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression (to 4+3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data. Since November 1995, 450 patients have been managed with active surveillance. The cohort included men under 70 with favorable-risk disease and men of age more than 70 with favorable- or intermediate-risk cancer (Gleason score 3+4 or PSA 10-15). Median follow-up is 6.8 years (range 1-16 years). Overall survival is 78.6%. Ten-year prostate cancer actuarial survival is 97.2%. Five of 450 patients (1.1%) have died of prostate cancer. Thirty percent of patients have been reclassified as higher-risk patients and offered definitive therapy. The commonest indication for treatment was a PSA doubling time less than 3 years (48%) or Gleason upgrading (26%). Of 117 patients treated radically, the PSA failure rate was 50%. This represents 13% of the total cohort. Most PSA failures occurred early; at 2 years, 44% of the treated patients had PSA failure. The hazard ratio for non-prostate cancer mortality to prostate cancer mortality was 18.6 at 10 years. In conclusion, we observed a very low rate of prostate cancer mortality in an intermediate time frame. Among the one-third of patients who were reclassified as higher risk and retreated, PSA failure was relatively common. However, other-cause mortality accounted for almost all of the deaths. Further studies are warranted to improve the identification of patients who harbor more aggressive disease in spite of favorable clinical parameters at diagnosis [reproduced from Klotz (1) with permission from Wolters Kluwer Health].


Inzlicht M.,University of Toronto
Journal of personality and social psychology | Year: 2010

Stereotype threat spillover is a situational predicament in which coping with the stress of stereotype confirmation leaves one in a depleted volitional state and thus less likely to engage in effortful self-control in a variety of domains. We examined this phenomenon in 4 studies in which we had participants cope with stereotype and social identity threat and then measured their performance in domains in which stereotypes were not "in the air." In Study 1 we examined whether taking a threatening math test could lead women to respond aggressively. In Study 2 we investigated whether coping with a threatening math test could lead women to indulge themselves with unhealthy food later on and examined the moderation of this effect by personal characteristics that contribute to identity-threat appraisals. In Study 3 we investigated whether vividly remembering an experience of social identity threat results in risky decision making. Finally, in Study 4 we asked whether coping with threat could directly influence attentional control and whether the effect was implemented by inefficient performance monitoring, as assessed by electroencephalography. Our results indicate that stereotype threat can spill over and impact self-control in a diverse array of nonstereotyped domains. These results reveal the potency of stereotype threat and that its negative consequences might extend further than was previously thought. (PsycINFO Database Record (c) 2010 APA, all rights reserved).


Becks L.,University of Toronto | Becks L.,University of Cologne | Agrawal A.F.,University of Toronto
Nature | Year: 2010

The evolution and maintenance of sexual reproduction has puzzled biologists for decades. Although this field is rich in hypotheses, experimental evidence is scarce. Some important experiments have demonstrated differences in evolutionary rates between sexual and asexual populations; other experiments have documented evolutionary changes in phenomena related to genetic mixing, such as recombination and selfing. However, direct experiments of the evolution of sex within populations are extremely rare (but see ref. 12). Here we use the rotifer, Brachionus calyciflorus, which is capable of both sexual and asexual reproduction, to test recent theory predicting that there is more opportunity for sex to evolve in spatially heterogeneous environments. Replicated experimental populations of rotifers were maintained in homogeneous environments, composed of either high- or low-quality food habitats, or in heterogeneous environments that consisted of a mix of the two habitats. For populations maintained in either type of homogeneous environment, the rate of sex evolves rapidly towards zero. In contrast, higher rates of sex evolve in populations experiencing spatially heterogeneous environments. The data indicate that the higher level of sex observed under heterogeneity is not due to sex being less costly or selection against sex being less efficient; rather sex is sufficiently advantageous in heterogeneous environments to overwhelm its inherent costs. Counter to some alternative theories for the evolution of sex, there is no evidence that genetic drift plays any part in the evolution of sex in these populations. © 2010 Macmillan Publishers Limited. All rights reserved.


Jha P.,University of Toronto
BMC Medicine | Year: 2014

Background: Most of the 48 million annual deaths in low- and middle-income countries (LMICs) occur without medical attention at the time of death so that the causes of death (COD) are largely unknown. A review of low-cost methods of obtaining nationally representative COD data is timely.Discussion: Despite clear historic evidence of their usefulness, most LMICs lack reliable nationally representative COD data. Indirect methods to estimate COD for most countries are inadequate, mainly because they currently rely on an average ratio of 1 nationally representative COD to every 850 estimated deaths in order to measure the cause of 25 million deaths across 110 LMICs. Direct measurement of COD is far more reliable and relevant for country priorities. Five feasible methods to expand COD data are: sample registration systems (which form the basis for the ongoing Million Death Study in India; MDS); strengthening the INDEPTH network of 42 demographic surveillance sites; adding retrospective COD surveys to the demographic household and health surveys in 90 countries; post-census retrospective mortality surveys; and for smaller countries, systematic assembly of health records. Lessons learned from the MDS, especially on low-cost, high-quality methods of verbal autopsy, paired with emerging use of electronic data capture and other innovations, can make COD systems low-cost and relevant for a wide range of childhood and adult conditions.Summary: Low-cost systems to obtain and report CODs are possible. If implemented widely, COD systems could identify disease control priorities, help detect emerging epidemics, enable evaluation of disease control programs, advance indirect methods, and improve the accountability for expenditures of disease control programs. © 2014 Jha; licensee BioMed Central Ltd.


Tator C.H.,University of Toronto
British Journal of Sports Medicine | Year: 2014

It is now recognised that there is a spectrum of concussion disorders ranging from acute concussion at one end to various forms of brain degeneration at the other end. The spectrum includes acute concussion, second impact syndrome or acute cerebral swelling, postconcussion syndrome, depression or anxiety, chronic traumatic encephalopathy (CTE) and possibly other forms of central nervous system degeneration. It is essential to carefully evaluate the clinical and neuropathological correlations of CTE that have been published. This has been accomplished in an excellent paper on this subject by Gardner and colleagues in this issue. There have been significant advances in our knowledge of the clinical and neuropathological features of CTE in athletes in the past 10 years. However, we are just at the beginning of our appreciation of this entity due to the paucity of research and the inability to diagnose CTE during life. At present, it is not possible to assess the validity of the proposed methods of classification and grading of the severity of the disease. Additional studies of large numbers of atrisk athletes are essential, especially prospective longitudinal studies. Obviously, such studies would be even more effective if reliable in vivo biomarkers were discovered, especially non-invasive ones such as advanced MRI or MR spectroscopy or invasive ones such as blood or cerebrospinal fluid tests. The major questions that remain unanswered include the frequency of CTE in various collision sports, the causal or otherwise relationship between concussions and CTE, the number of concussions that need to be involved and their management.


Kabakchiev B.,University of Toronto | Silverberg M.S.,University of Toronto
Gastroenterology | Year: 2013

Background & Aims: Genome-wide association studies have greatly increased our understanding of intestinal disease. However, little is known about how genetic variations result in phenotypic changes. Some polymorphisms have been shown to modulate quantifiable phenotypic traits; these are called quantitative trait loci. Quantitative trait loci that affect levels of gene expression are called expression quantitative trait loci (eQTL), which can provide insight into the biological relevance of data from genome-wide association studies. We performed a comprehensive eQTL scan of intestinal tissue. Methods: Total RNA was extracted from ileal biopsy specimens and genomic DNA was obtained from whole-blood samples from the same cohort of individuals. Cis- and trans-eQTL analyses were performed using a custom software pipeline for samples from 173 subjects. The analyses determined the expression levels of 19,047 unique autosomal genes listed in the US National Center for Biotechnology Information database and more than 580,000 variants from the Single Nucleotide Polymorphism database. Results: The presence of more than 15,000 cis- and trans-eQTL was detected with statistical significance. eQTL associated with the same expression trait were in high linkage disequilibrium. Comparative analysis with previous eQTL studies showed that 30% to 40% of genes identified as eQTL in monocytes, liver tissue, lymphoblastoid cell lines, T cells, and fibroblasts are also eQTL in ileal tissue. Conversely, most of the significant eQTL have not been previously identified and could be tissue specific. These are involved in many cell functions, including division and antigen processing and presentation. Our analysis confirmed that previously published cis-eQTL are single nucleotide polymorphisms associated with inflammatory bowel disease: rs2298428/UBE2L3, rs1050152/SLC22A4, and SLC22A5. We identified many new associations between inflammatory bowel disease susceptibility loci and gene expression. Conclusions: eQTL analysis of intestinal tissue supports findings that some eQTL remain stable across cell types, whereas others are specific to the sampled location. Our findings confirm and expand the number of known genotypes associated with expression and could help elucidate mechanisms of intestinal disease. © 2013 AGA Institute.


Perry J.R.,University of Toronto
Neuro-Oncology | Year: 2012

Venous thromboembolism (VTE) is common throughout the course of disease in high-grade glioma (HGG). The interactions between the coagulation cascade, endothelium, and regulation of angiogenesis are complex and drive glioblastoma growth and invasion. We reviewed the incidence of VTE in HGG, the biology of the coagulome as related to glioblastoma progression, prevention and treatment of thrombosis, and the putative role of anticoagulants as anti-cancer therapy. VTE can be significantly reduced during the postoperative period with adherence to the use of mechanical and medical thromboprophylaxis. Activation of the coagulation cascade occurs throughout the course of disease because of a variety of complex interactions, including tumor hypoxia, upregulation of VEGR expression, and increases in both tumor cell-specific tissue factor (TF) expression and inducible TF expression in numerous intrinsic regulatory pathways. Long-term anticoagulation to prevent VTE is an attractive therapy; however, the therapeutic window is narrow and current data do not support its routine use. Most patients with proven symptomatic VTE can be safely anticoagulated, including those receiving anti-VEGF therapy, such as bevacizumab. Initial therapy should include low molecular weight heparin (LMWH), and protracted anticoagulant treatment, perhaps indefinitely, is indicated for patients with HGG because of the ongoing risk of thrombosis. A variety of coagulation- and tumor-related proteins, such as TF and circulating microparticles, may serve as potential disease-specific biomarkers in relation to disease recurrence, monitoring of therapy, and as potential therapeutic targets. © 2012 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.


Li C.X.,University of Toronto
Nature Materials | Year: 2016

Expansion on stiff culture substrates activates pro-fibrotic cell programs that are retained by mechanical memory. Here, we show that priming on physiologically soft silicone substrates suppresses fibrogenesis and desensitizes mesenchymal stem cells (MSCs) against subsequent mechanical activation in vitro and in vivo, and identify the microRNA miR-21 as a long-term memory keeper of the fibrogenic program in MSCs. During stiff priming, miR-21 levels were gradually increased by continued regulation through the acutely mechanosensitive myocardin-related transcription factor-A (MRTF-A/MLK-1) and remained high over 2 weeks after removal of the mechanical stimulus. Knocking down miR-21 once by the end of the stiff-priming period was sufficient to erase the mechanical memory and sensitize MSCs to subsequent exposure to soft substrates. Soft priming and erasing mechanical memory following cell culture expansion protects MSCs from fibrogenesis in the host wound environment and increases the chances for success of MSC therapy in tissue-repair applications. © 2016 Nature Publishing Group


Kingdom J.C.P.,University of Toronto | Drewlo S.,University of Toronto
Blood | Year: 2011

Randomized control trials show beneficial effects of heparin in high-risk pregnancies to prevent preeclampsia and intrauterine growth restriction. However, the lack of placental pathology data in these trials challenges the assumption that heparin is a placental anticoagulant. Recent data show that placental infarction is probably associated with abnormalities in development of the placenta, characterized by poor maternal perfusion and an abnormal villous trophoblast compartment in contact with maternal blood, than with maternal thrombophilia. At-risk pregnancies may therefore be predicted by noninvasive prenatal testing of placental function in mid-pregnancy. Heparin has diverse cellular functions that include direct actions on the trophoblast. Dissecting the non-anticoagulant actions of heparin may indicate novel and safer therapeutic targets to prevent the major placental complications of pregnancy. © 2011 by The American Society of Hematology.


Bioactive molecules typically mediate their biological effects through direct physical association with one or more cellular proteins. The detection of drug-target interactions is therefore essential for the characterization of compound mechanism of action and off-target effects, but generic label-free approaches for detecting binding events in biological mixtures have remained elusive. Here, we report a method termed target identification by chromatographic co-elution (TICC) for routinely monitoring the interaction of drugs with cellular proteins under nearly physiological conditions in vitro based on simple liquid chromatographic separations of cell-free lysates. Correlative proteomic analysis of drug-bound protein fractions by shotgun sequencing is then performed to identify candidate target(s). The method is highly reproducible, does not require immobilization or derivatization of drug or protein, and is applicable to diverse natural products and synthetic compounds. The capability of TICC to detect known drug-protein target physical interactions (K(d) range: micromolar to nanomolar) is demonstrated both qualitatively and quantitatively. We subsequently used TICC to uncover the sterol biosynthetic enzyme Erg6p as a novel putative anti-fungal target. Furthermore, TICC identified Asc1 and Dak1, a core 40 S ribosomal protein that represses gene expression, and dihydroxyacetone kinase involved in stress adaptation, respectively, as novel yeast targets of a dopamine receptor agonist.


Filewod B.,University of Toronto | Thomas S.C.,University of Toronto
Global Change Biology | Year: 2014

Heat wave frequency, duration, and intensity are predicted to increase with global warming, but the potential impacts of short-term high temperature events on forest functioning remain virtually unstudied. We examined canopy processes in a forest in Central Ontario following 3 days of record-setting high temperatures (31-33 °C) that coincided with the peak in leaf expansion of dominant trees in late May 2010. Leaf area dynamics, leaf morphology, and leaf-level gas-exchange were compared to data from prior years of sampling (2002-2008) at the same site, focusing on Acer saccharum Marsh., the dominant tree in the region. Extensive shedding of partially expanded leaves was observed immediately following high temperature days, with A. saccharum losing ca. 25% of total leaf production but subsequently producing an unusual second flush of neoformed leaves. Both leaf losses and subsequent reflushing were highest in the upper canopy; however, retained preformed leaves and neoformed leaves showed reduced size, resulting in an overall decline in end-of-season leaf area index of 64% in A. saccharum, and 16% in the entire forest. Saplings showed lower leaf losses, but also a lower capacity to reflush relative to mature trees. Both surviving preformed and neoformed leaves had severely depressed photosynthetic capacity early in the summer of 2010, but largely regained photosynthetic competence by the end of the growing season. These results indicate that even short-term heat waves can have severe impacts in northern forests, and suggest a particular vulnerability to high temperatures during the spring period of leaf expansion in temperate deciduous forests. © 2013 John Wiley & Sons Ltd.


Kitevski-LeBlanc J.L.,University of Toronto | Prosser R.S.,University of Toronto
Progress in Nuclear Magnetic Resonance Spectroscopy | Year: 2012

Highlights: 19F molecular tags and labeling protocols for 19F NMR studies of proteins are reviewed and contrasted. 19F NMR biosynthetic labeling strategies are presented. Experimental challenges (loss of function through labeling, line broadening, assignment ambiguities) are discussed. Approaches to the study of protein topology, using 19F NMR, are presented. Current examples of protein NMR studies are given. © 2011 Elsevier B.V. All rights reserved.


Chiang E.,University of California at Berkeley | Youdin A.N.,University of Toronto
Annual Review of Earth and Planetary Sciences | Year: 2010

Planets are built from planetesimals: solids larger than a kilometer that grow by colliding in pairs. Planetesimals themselves are unlikely to form by two-body collisions alone; subkilometer objects have gravitational fields individually too weak, and electrostatic attraction is too feeble for growth beyond a few centimeters. We review the possibility that planetesimals form when self-gravity brings together vast ensembles of small particles. Even when self-gravity is weak, aerodynamic processes can accumulate solids relative to gas, paving the way for gravitational collapse. Particles pile up as they drift radially inward. Gas turbulence stirs particles but can also seed collapse by clumping them. Whereas the feedback of solids on gas triggers vertical-shear instabilities that obstruct self-gravity, this same feedback triggers streaming instabilities that strongly concentrate particles. Numerical simulations find that solids ∼10-100 cm in size gravitationally collapse in turbulent disks. We outline areas for progress, including the possibility that still smaller objects self-gravitate. Copyright © 2010 by Annual Reviews. All rights reserved.


Leblanc V.R.,University of Toronto
Canadian Journal of Anesthesia | Year: 2012

Purpose: Within the field of anesthesia, simulation has been used as a tool for training and assessment for over 30 years. The purpose of this review is to evaluate the state of the science in terms of its effectiveness as an approach to both training and assessment in anesthesia. Articles in the area of simulation and anesthesia published up to and including 2011 were reviewed for inclusion in this narrative review. Principal findings: Simulation-based training is generally well received by participants, it can lead to improved performance in subsequent simulation events, and some transfer of learning to the clinical setting is evident. There is also some early evidence that well-designed performance assessments could have the required reliability and validity to support high-stakes examinations. However, further work is needed in order to set standards and establish the predictive validity to support such assessments. Conclusion: For simulation to realize its potential impact, further research is needed to understand how to optimize this modality of learning more effectively, how to transfer knowledge of research findings to practice, and also how to broaden the simulation modalities used in anesthesia. In future, the optimal use of simulation will depend on a clear understanding of what can and cannot be accomplished with simulation and its various modalities. © 2011 Canadian Anesthesiologists' Society.


Treanor B.,University of Toronto
Immunology | Year: 2012

B-cell activation is triggered by the binding of antigen to the B-cell receptor (BCR). The early molecular events triggered by BCR binding of ligand have been well-characterized both biochemically and using optical microscopy techniques to visualize B-cell activation as it happens. However, we understand much less about the BCR before activation. For this reason, this review will address recent advances in our view of the structure, organization and dynamics of the resting, unstimulated BCR. These parameters have important implications for our understanding of the initiation of B-cell activation and will be discussed in the context of current models for BCR activation. These models include the conformation-induced oligomerization model, in which binding of antigen to monomeric BCR induces a pulling or twisting force causing conformational unmasking of a clustering interface in the Cμ4 domain. Conversely, the dissociation activation model proposes that BCRs exist in auto-inhibitory oligomers on the resting B-cell surface and binding of antigen promotes the dissociation of the BCR oligomer exposing phosphorylation residues within Igα/Igβ. Finally, the collision coupling model suggests that BCR are segregated from activating co-receptors or kinases and activation is associated with changes in BCR mobility on the cell surface, which allows for the functional interaction of these elements. © 2012 The Author. Immunology © 2012 Blackwell Publishing Ltd.


Rogers R.S.,University of Toronto
Molecular & cellular proteomics : MCP | Year: 2012

We investigate the role of glial cell activation in the human optic nerve caused by raised intraocular pressure, and their potential role in the development of glaucomatous optic neuropathy. To do this we present a proteomics study of the response of cultured, optic nerve head astrocytes to biomechanical strain, the magnitude and mode of strain based on previously published quantitative models. In this case, astrocytes were subjected to 3 and 12% stretches for either 2 h or 24 h. Proteomic methods included nano-liquid chromatography, tandem mass spectrometry, and iTRAQ labeling. Using controls for both stretch and time, a six-plex iTRAQ liquid chromatography- tandem MS (LC/MS/MS) experiment yielded 573 proteins discovered at a 95% confidence limit. The pathways included transforming growth factor β1, tumor necrosis factor, caspase 3, and tumor protein p53, which have all been implicated in the activation of astrocytes and are believed to play a role in the development of glaucomatous optic neuropathy. Confirmation of the iTRAQ analysis was performed by Western blotting of various proteins of interest including ANXA 4, GOLGA2, and αB-Crystallin.


Stanovich K.E.,University of Toronto
Behavioral and Brain Sciences | Year: 2011

Elqayam & Evans (E&E) drive a wedge between Bayesianism and instrumental rationality that most decision scientists will not recognize. Their analogy from linguistics to judgment and decision making is inapt. Normative models remain extremely useful in the progressive research programs of the judgment and decision making field. © 2011 Cambridge University Press.


Charron M.,University of Toronto
Quarterly Journal of Nuclear Medicine and Molecular Imaging | Year: 2013

The diagnostic value of Metaiodobenzylguanidine (MIBG) scintigraphy in the management of neuroblastoma is well established. The specificity of MIBG is virtually 100% and remains the most specific imaging modality. Numerous semi-quantitative scores and guidelines have emerged in the last decade that illustrate standardization of the procedure. Other pharmaceuticals such as norcholesterol derivatives, [111In]pentetreotide and [ 68Ga]somatostatin analogs, [18F]fluorodeoxyglucose, [ 18F]fluorodopa, [18F]fluorodopamine, [11C]meta hydroxyephedrine, and [11C]/[18F]/[123I] Metomidate (MTO) have been or are being evaluated currently (including development of new analogues labeled with positron emitting radionuclides such as [124I], [18F], and [76Br]. Radiopharmaceutical therapy of neuroblastoma, initiated over 30 years ago, demonstrates that a significant fraction of patients enter partial remission but complete remission is rare and relapse is frequent. With the combination of chemotherapy, radiosensitizers, and autologous stem cell support, some centers have seen overall response rates of up to 30% in refractory or recurrent diseases. Topoisomerase I inhibitor topotecan may improve upon existing [ 131I]MIBG therapy. Areas of future development may be in vitro cultures and animal models, proper instrumentation to acquire sub-centimeter resolution and human clinical trials to evaluate treatment at earlier times or stages of disease, evaluation with concomitant immunotherapy with monoclonal antibodies targeting the GD2 ganglioside or inhibitors of anaplastic lymphoma kinase. Because of the complexity of those trials, progress remains extremely slow as well designed multicenter studies are required. Nonetheless, the future has never been so hopeful.


Allali-Hassani A.,University of Toronto
Journal of biomolecular screening | Year: 2012

The histone methyltransferase (HMT) family of proteins consists of enzymes that methylate lysine or arginine residues on histone tails as well as other proteins. Such modifications affect chromatin structure and play a significant regulatory role in gene expression. Many HMTs have been implicated in tumorigenesis and progression of multiple malignancies and play essential roles in embryonic development and stem cell renewal. Overexpression of some HMTs has been observed and is correlated positively with various types of cancer. Here the authors report development of a continuous fluorescence-based methyltransferase assay in a 384-well format and its application in determining kinetic parameters for EHMT1, G9a, PRMT3, SETD7, and SUV39H2 as well as for screening against libraries of small molecules to identify enzyme inhibitors. They also report the development of a peptide displacement assay using fluorescence polarization in a 384-well format to assay and screen protein peptide interactions such as those of WDR5 and EED, components of MLL and EZH2 methyltransferase complexes. Using these high-throughput screening methods, the authors have identified potent inhibitors and ligands for some of these proteins.


Lo H.-K.,University of Toronto | Curty M.,University of Vigo | Qi B.,University of Toronto
Physical Review Letters | Year: 2012

How to remove detector side channel attacks has been a notoriously hard problem in quantum cryptography. Here, we propose a simple solution to this problem-measurement-device-independent quantum key distribution (QKD). It not only removes all detector side channels, but also doubles the secure distance with conventional lasers. Our proposal can be implemented with standard optical components with low detection efficiency and highly lossy channels. In contrast to the previous solution of full device independent QKD, the realization of our idea does not require detectors of near unity detection efficiency in combination with a qubit amplifier (based on teleportation) or a quantum nondemolition measurement of the number of photons in a pulse. Furthermore, its key generation rate is many orders of magnitude higher than that based on full device independent QKD. The results show that long-distance quantum cryptography over say 200km will remain secure even with seriously flawed detectors. © 2012 American Physical Society.


Despite the important instrumental and emotional role that parents play in the lives of children with cystic fibrosis (CF) and congenital heart disease (CHD), qualitative researchers have not examined the similarities and differences between caregivers' experiences. Informed by thematic analysis, in this qualitative study I explored what it is like to care for a child with a chronic illness from the perspective of CF and CHD parents at a children's hospital in Canada. Pediatric caregiver stress was qualitatively different between CF and CHD parents, whereas temporal dilemmas were unique sources of stress for CF parents only. To alleviate stress, all parents drew on a three-way, interrelated process to comprehend their child's illness and acquire perspective. By opening up the social worlds of parents, I illuminate important similarities and differences in the caregiving experience of parents of youth with CF and CHD, and offer novel contributions to the literature. © SAGE Publications 2012.


Background/Objectives:Vitamin D is an anti-inflammatory nutrient and a determinant of bone health. Some prospective studies suggest that maternal vitamin D status is positively associated with offspring bone mass. We found that serum concentrations of lipopolysaccharide (LPS), an inflammatory molecule related to adiposity, insulin resistance and bone resorption, is lower in healthy mouse offspring exposed to high dietary vitamin D during pregnancy and lactation. LPS reaches the circulation via the gut. This study investigated whether maternal vitamin D programs metabolic, gut and bone health of male offspring in an obesogenic environment.Methods:C57BL/6J dams received an AIN-93G diet with high (H) or low (L) vitamin D during pregnancy and lactation. At weaning, offspring remained on their dam’s vitamin D level (LL or HH) or were switched (LH or HL) and fed a high fat (44.2%) and sucrose (19.8%) diet. Glucose response, adiposity, systemic inflammation (LPS, cytokines), intestinal permeability and mass, strength and microarchitecture of trabecular and cortical bone were assessed in 7-month-old male offsprings.Results:Higher maternal dietary vitamin D resulted in lower intestinal permeability (fecal albumin, P=0.010) and benefited trabecular but not cortical bone structure at the distal femur (higher trabecular number, P=0.022; less trabecular separation, P=0.015) and lumbar vertebra 2 (bone volume/total volume%, P=0.049). Higher maternal and offspring vitamin D resulted in lower fasting glucose (HH versus LL, P=0.039) and serum LPS concentrations (dam diet, P=0.011; pup diet, P=0.002). Higher offspring vitamin D resulted in lower epididymal fat pad relative weight (P=0.006). The serum concentrations of IL-6 and TNF-α did not differ among groups.Conclusions:Maternal dietary vitamin D beneficially programs intestinal permeability and systemic LPS concentration, which is accompanied by stronger trabecular bone in an obesogenic environment. Thus, the gut may mediate vitamin D effects. Moreover, optimizing vitamin D in early life may be critical for later health.International Journal of Obesity advance online publication, 25 October 2016; doi:10.1038/ijo.2016.177. © 2016 Macmillan Publishers Limited, part of Springer Nature.


Harris K.P.,University of Toronto | Tepass U.,University of Toronto
Traffic | Year: 2010

Cdc42, a highly conserved small GTPase of the Rho family, acts as a molecular switch to modulate a wide range of signaling pathways. Vesicle trafficking and cell polarity are two processes Cdc42 is known to regulate. Although the trafficking and polarity machineries are each well understood, how they interact to cross-regulate each other in cell polarization is still a mystery. Cdc42 is an interesting candidate that may integrate these two networks within the cell. Here we review findings on the interplay between Cdc42 and trafficking in yeast, Caenorhabditis elegans, Drosophila and mammalian cell culture systems, and discuss recent advances in our understanding of the function of Cdc42 and two of its effectors, the WASp-Arp2/3 and Par complexes, in regulating polarized traffic. Work in yeast suggests that the polarized distribution of Cdc42, which acts here as a key polarity determinant, requires input from multiple processes including endocytosis and recycling. In metazoan cells, Cdc42 can regulate several steps in the biosynthetic as well as endocytotic and recycling pathways. The recent discovery that the Par polarity complex co-operates with Cdc42 in the regulation of endocytosis and recycling opens exciting possibilities for the integration of polarity protein function and endocytotic machinery. © 2010 John Wiley & Sons A/S.


Weksberg R.,University of Toronto
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2010

This issue of Seminars of Medical Genetics features a series of articles on human disorders caused by the dysregulation of imprinted genes. At the outset, there is a review of the general mechanisms by which genomic imprinting is normally regulated followed by an exploration of the clinical and molecular aspects of human imprinting disorders. As we enter an era of bioinformatics and genome-wide analyses with increasing access to high density microarrays and next generation sequencing, it is becoming apparent that the concept of a single mutation or epimutation leading to a disease is outdated. The role of the clinician will become increasingly important, in concert with these molecular advances, in terms of evaluating phenotypic variation to further our understanding of imprinting disorders. Such investigations will benefit children and families as we become better able to define recurrence risk, predict phenotype, and tailor medical management. © 2010 Wiley-Liss, Inc.


This article reviews the design approaches and technologies that have been used to reduce the energy requirements of new buildings by a factor of 2 to 4 compared to the energy use of otherwise comparable recent new buildings or that have been used to achieve comparable savings in retrofits of existing buildings. This is followed by a critical discussion of documented studies of the energy performance of new and retrofitted buildings from around the world, along with cost ormation where-ever available. The additional costs of meeting the Passive Standard for heating loads in new buildings, which represents a factor of 5 to 10 reduction of heating load compared to current standard practice, have ranged from 0% to 16% of the construction costs of reference buildings. High-performance commercial buildings, with overall energy intensities of 25-50% that of recent conventional buildings, have been built at less cost, or only at a few percent more cost, than conventional buildings. © 2013 by Annual Reviews. All rights reserved.


Katz P.R.,University of Toronto
Journal of the American Medical Directors Association | Year: 2011

The world is facing an unprecedented growth of older adults, a sizable number of whom will require nursing home services. Although community-based care delivery systems strive to keep most of those in need at home, nursing homes are increasingly accommodating a more frail population that is straining available resources. This article focuses on common themes evident around the world regarding long-term care of the elderly. Issues related to service delivery, financing, and quality are highlighted. © 2011 American Medical Directors Association.


Murray N.,University of Toronto
Astrophysical Journal | Year: 2011

We use a sample of the 13 most luminous WMAP Galactic free-free sources, responsible for 33% of the free-free emission of the Milky Way, to investigate star formation. The sample contains 40 star-forming complexes; we combine this sample with giant molecular cloud (GMC) catalogs in the literature to identify the host GMCs of 32 of the complexes. We estimate the star formation efficiency εGMC and star formation rate per free-fall time εff. We find that εGMC ranges from 0.002 to 0.2, with an ionizing luminosity-weighted average 〈εGMC〉 Q = 0.08, compared to the Galactic average ≈0.005. Turning to the star formation rate per free-fall time, we find values that range up to . Weighting by ionizing luminosity, we find an average of 〈ε ff〉Q = 0.14-0.24 depending on the estimate of the age of the system. Once again, this is much larger than the Galaxy-wide average value εff = 0.006. We show that the lifetimes of GMCs at the mean mass found in our sample is 27±12 Myr, a bit less than three free-fall times. The GMCs hosting the most luminous clusters are being disrupted by those clusters. Accordingly, we interpret the range in εff as the result of a time-variable star formation rate; the rate of star formation increases with the age of the host molecular cloud, until the stars disrupt the cloud. These results are inconsistent with the notion that the star formation rate in Milky Way GMCs is determined by the properties of supersonic turbulence. © 2011. The American Astronomical Society. All rights reserved.


Katzberg H.D.,University of Toronto
Cochrane database of systematic reviews (Online) | Year: 2011

Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss. To examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival;(2) nutritional status; (3) quality of life;(4) minor and major complications of percutaneous endoscopic gastrostomy. We searched the Cochrane Neuromuscular Disease Group Trials Register (24 November 2009), MEDLINE (from January 1966 to September 2009), and EMBASE (from January 1980 to September 2009) for all papers on enteral tube feeding in amyotrophic lateral sclerosis/motor neuron disease. The results were screened to identify randomised controlled trials and to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles and enlisted personal communications to identify any additional references.  A priori selection criteria included randomised and quasi-randomized controlled trials evaluating the efficacy of percutaneous endoscopic gastrostomy or other feeding tube placement. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review. We independently assessed study design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, (3) self-perceived quality of life and (4) safety of the procedure as indicated by minor and major complications of surgical or radiological guided PEG tube insertion.  We found no randomised controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective studies in the 'Discussion' section. There are no randomised controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for any of the outcome measures. The 'best' evidence to date suggests a survival advantage for some people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable.  Quality of life has been addressed in studies and needs more attention. Based on a number of recent non-randomized studies comparing surgical and radiographic approaches to feeding tube insertion these two procedures for PEG tube insertion appear to be equivalent.


Scholes G.D.,University of Toronto
Journal of Physical Chemistry Letters | Year: 2010

Recent research suggests that electronic energy transfer in complex biological and chemical systems can involve quantum coherence, even at ambient temperature conditions. It is particularly notable that this phenomenon has been found in some photosynthetic proteins. The role of these proteins in photosynthesis is introduced. The meaning of quantum-coherent energy transfer is explained, and it is compared to Forster energy transfer. Broad, interdisciplinary questions for future work are noted. For example, how can chemists use quantum coherence in synthetic systems (perhaps in organic photovoltaics)? Why did certain photosynthetic organisms evolve to use quantum coherence in light harvesting? Are these electronic excitations entangled?. © 2010 American Chemical Society.


McCrindle B.W.,University of Toronto
Current Opinion in Lipidology | Year: 2012

PURPOSE OF REVIEW: This review provides an update and highlights the controversies regarding recent advances and recommendations regarding screening, diagnosis and treatment of children and adolescents with familial hypercholesterolemia. RECENT FINDINGS: Both general cardiovascular risk and specific familial hypercholesterolemia guidelines for children and adolescents have recently been released. Universal lipid screening of children has been recommended, in addition to targeted screening. The role of genetic testing for targeted screening and diagnostic confirmation is less clear. Although lifestyle therapy remains of key importance, increasing evidence of safety and efficacy support the use of statin therapy. Early therapy has been associated with improvements in noninvasive measures of early atherosclerosis in children, which likely can be extrapolated to improved freedom from cardiovascular disease events over the lifespan, as has been observed in adults. The new guidelines provide general and specific recommendations as to how family history and additional risk factors and risk conditions should be incorporated in decisions regarding initiation of statin therapy at LDL-cholesterol cutpoints. Emerging evidence from observational studies are beginning to address concerns regarding the initiation at young ages and longer-term efficacy and safety. SUMMARY: Children and adolescents with familial hypercholesterolemia can be identified and effective therapy with a statin initiated with consideration of the patients' overall cardiovascular risk profile, remaining mindful of the uncertainties regarding long-term safety. © 2012 Wolters Kluwer Health|Lippincott Williams & Wilkins.


Garcia Dominguez L.,University of Toronto
PloS one | Year: 2014

OBJECTIVE: Long-interval cortical inhibition (LICI) can be recorded from motor and non-motor regions of the cortex through combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). This study aimed to evaluate additional dimensions of LICI characteristics over an extended time-frequency and spatial domain. This was done by introducing two alternative measures of LICI signal amplitude: the Discrete Fourier Transform (DFT) and the Hilbert transform (HT). Both approaches estimate signal amplitude not taking into account the phase. In both cases LICI was measured as the difference between the unconditioned and conditioned activity evoked by the test pulse. Finally, we evaluated whether the topographical patterns of single and paired responses differed beyond the expected variations in amplitude.MATERIALS AND METHODS: LICI was delivered as single and paired pulses to the motor cortex (MC) and dorsolateral prefrontal cortex (DLPFC) in 33 healthy subjects with TMS-EEG.RESULTS: Significant differences (p<0.0001) between the unconditioned and conditioned evoked activity were found for both the DLPFC and MC using both methods (i.e., DFT and HT) after correcting for multiple comparisons in the time-frequency domain. The influence of inhibition was found to be significantly larger in space and time than previously considered. Single and paired conditions differ in intensity, but also in their topographic pattern (i.e., the specific spatiotemporal configuration of active sources).CONCLUSION: Similar results were found by both DFT and HT. The effect of inhibition across the cortex was also found to be complex and extended. In particular, it was found that LICI may be measured with high sensitivity in areas that were relatively distant from the stimulation site, which may have important practical applications. The analysis presented in this study overcomes some limitations of previous studies and could serve as a key reference for future studies examining TMS-indices of inhibition/excitation in healthy and diseased states.