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.
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.
Tepass U.,University of Toronto
Annual Review of Cell and Developmental Biology | Year: 2012
Epithelial tissue formation and function requires the apical-basal polarization of individual epithelial cells. Apical polarity regulators (APRs) are an evolutionarily conserved group of key factors that govern polarity and several other aspects of epithelial differentiation. APRs compose a diverse set of molecules including a transmembrane protein (Crumbs), a serine/threonine kinase (aPKC), a lipid phosphatase (PTEN), a small GTPase (Cdc42), FERM domain proteins (Moesin, Yurt), and several adaptor or scaffolding proteins (Bazooka/Par3, Par6, Stardust, Patj). These proteins form a dynamic cooperative network that is engaged in negative-feedback regulation with basolateral polarity factors to set up the epithelial apical-basal axis. APRs port the formation of the apical junctional complex and the segregation of the junctional domain from the apical membrane. It is becoming increasingly clear that APRs interact with the cytoskeleton and vesicle trafficking machinery, regulate morphogenesis, and modulate epithelial cell growth and survival. Not surprisingly, APRs have multiple fundamental links to human diseases such as cancer and blindness. Copyright © 2012 by Annual Reviews. All rights reserved.
Warner E.,University of Toronto
New England Journal of Medicine | Year: 2011
A healthy, 42-year-old white woman wants to discuss breast-cancer screening. She has no breast symptoms, had menarche at the age of 14 years, gave birth to her first child at the age of 26 years, is moderately overweight, drinks two glasses of wine most evenings, and has no family history of breast or ovarian cancer. She has never undergone mammography. She notes that a friend who maintained the "healthiest lifestyle possible" is now being treated for metastatic breast cancer, and she wants to avoid the same fate. What would you advise? Copyright © 2011 Massachusetts Medical Society.
Stephan D.W.,University of Toronto
Accounts of Chemical Research | Year: 2015
ConspectusFrustrated Lewis pair (FLP) chemistry has emerged in the past decade as a strategy that enables main-group compounds to activate small molecules. This concept is based on the notion that combinations of Lewis acids and bases that are sterically prevented from forming classical Lewis acid-base adducts have Lewis acidity and basicity available for interaction with a third molecule. This concept has been applied to stoichiometric reactivity and then extended to catalysis. This Account describes three examples of such developments: hydrogenation, hydroamination, and CO2 reduction.The most dramatic finding from FLP chemistry was the discovery that FLPs can activate H2, thus countering the long-existing dogma that metals are required for such activation. This finding of stoichiometric reactivity was subsequently evolved to employ simple main-group species as catalysts in hydrogenations. While the initial studies focused on imines, subsequent studies uncovered FLP catalysts for a variety of organic substrates, including enamines, silyl enol ethers, olefins, and alkynes. Moreover, FLP reductions of aromatic anilines and N-heterocycles have been developed, while very recent extensions have uncovered the utility of FLP catalysts for ketone reductions.FLPs have also been shown to undergo stoichiometric reactivity with terminal alkynes. Typically, either deprotonation or FLP addition reaction products are observed, depending largely on the basicity of the Lewis base. While a variety of acid/base combinations have been exploited to afford a variety of zwitterionic products, this reactivity can also be extended to catalysis. When secondary aryl amines are employed, hydroamination of alkynes can be performed catalytically, providing a facile, metal-free route to enamines.In a similar fashion, initial studies of FLPs with CO2 demonstrated their ability to capture this greenhouse gas. Again, modification of the constituents of the FLP led to the discovery of reaction systems that demonstrated stoichiometric reduction of CO2 to either methanol or CO. Further modification led to the development of catalytic systems for the reduction of CO2 by hydrosilylation and hydroboration or deoxygenation.As each of these areas of FLP chemistry has advanced from the observation of unusual stoichiometric reactions to catalytic processes, it is clear that the concept of FLPs provides a new strategy for the design and application of main-group chemistry and the development of new metal-free catalytic processes. © 2014 American Chemical Society.
Cutter A.D.,University of Toronto
Trends in Ecology and Evolution | Year: 2012
Speciation research has largely assumed that the genetic causes of reproductive isolation are the work of fixed, divergent alleles that interact to cause genetic problems in hybrids: Bateson-Dobzhansky-Muller incompatibilities. However, many recent studies demonstrate substantial heritable polymorphism within species for hybrid incompatibility, herein called variable reproductive isolation (VRI). In this review, I outline the causes and importance of this general phenomenon. I also identify the new challenges of quantifying the relative contributions to reproductive isolation of fixed alleles versus polymorphisms, and the change in these contributions over the course of speciation. Explicit integration of VRI into speciation theory will help to quantify the relative roles of genetic drift and selection in speciation, but this synthesis requires substantial new contributions from both theory and empirical studies. © 2011 Elsevier Ltd.