Introduction to the Douglass C. North Memorial Issue

This is the accepted version of the following article: Geoffrey M. Hodgson, ‘Introduction to the Douglass C. North memorial issue’, Journal of Institutional Economics, (early view) 1 December 2016, which has been published in final form at DOI: https://doi.org/10.1017/S1744137416000400 ©Cambridge UniversityPress 2016This introduction considers the highly influential contribution of Douglass C. North to economic history and institutional economics, as it developed from the 1960s until his death in 2015. It sketches the evolution of his arguments concerning the roles of institutions, organizations and human agency. North’s conception of the economic actor became progressively more sophisticated, by acknowledging the role of ideology and adopting insights from cognitive science. Eventually he abandoned the proposition that institutions are generally efficient, to propose instead that sub-optimal institutional forms could persist. A few noted criticisms of North’s work are also considered here, ranging from those which are arguably off the mark, to others that retain some force. The contributions to this memorial issue are outlined at the end of this introduction.Peer reviewe

Driving under the influence behaviours among high school students who mix alcohol with energy drinks

Published by Elsevier via http://dx.doi.org/10.1016/j.ypmed.2017.11.035 © 2017. Made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Alcohol and energy drinks are commonly used substances by youth in Canada, and are often mixed (AmED). While several studies have shown that AmED can have dangerous effects, less well understood is how AmED is associated with driving under the influence of either alcohol or drugs. This study sought to determine whether youth who use AmED were more likely to engage in driving, or being a passenger of a driver, under the influence of alcohol or cannabis compared to youth who use either alcohol or energy drinks alone. This study used data from grade 10–12 students who took part in the 2014/2015 Canadian Student Tobacco, Alcohol and Drugs Survey (N=17,450). The association of past-year AmED use with past-30day: driving under the influence of alcohol or cannabis, and riding with an alcohol- or cannabis-influenced driver, was assessed using logistic regression. One in four youth had consumed AmED in the previous 12months. AmED users were more likely to engage in all risk behaviours except riding with a drinking driver, relative to youth who only consumed alcohol. No association was observed for youth who consumed alcohol and energy drinks on separate occasions. Youth who use AmED demonstrate a higher risk profile for driving under the influence of alcohol or cannabis, than youth who use alcohol alone. Future research should explore the biopsychosocial pathways that may explain why using energy drinks enhances the already heightened risk posed by alcohol on other health-related behaviours such as driving under the influence.Canadian Cancer Society (grant #2011-701019

Acceleration of Solar Wind Ions by Nearby Interplanetary Shocks: Comparison of Monte Carlo Simulations with Ulysses Observations

The most stringent test of theoretical models of the first-order Fermi mechanism at collisionless astrophysical shocks is a comparison of the theoretical predictions with observational data on particle populations. Such comparisons have yielded good agreement between observations at the quasi-parallel portion of the Earth's bow shock and three theoretical approaches, including Monte Carlo kinetic simulations. This paper extends such model testing to the realm of oblique interplanetary shocks: here observations of proton and alpha particle distributions made by the SWICS ion mass spectrometer on Ulysses at nearby interplanetary shocks are compared with test particle Monte Carlo simulation predictions of accelerated populations. The plasma parameters used in the simulation are obtained from measurements of solar wind particles and the magnetic field upstream of individual shocks. Good agreement between downstream spectral measurements and the simulation predictions are obtained for two shocks by allowing the the ratio of the mean-free scattering length to the ionic gyroradius, to vary in an optimization of the fit to the data. Generally small values of this ratio are obtained, corresponding to the case of strong scattering. The acceleration process appears to be roughly independent of the mass or charge of the species.Comment: 26 pages, 6 figures, AASTeX format, to appear in the Astrophysical Journal, February 20, 199

Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2

TDP2 is a 5’-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II. TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain. We have confirmed that the deazaflavin series inhibits TDP2 enzyme activity in a fluorescence-based assay, suitable for HTS-screening. We have gone on to determine crystal structures of these compounds bound to a ‘humanised’ form of murine TDP2. The structures reveal their novel mode of action as competitive ligands for the binding site of an incoming DNA substrate, and point the way to generating novel and potent inhibitors of TDP2

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 mmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 mmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC 50 ∼ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ( 18F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2 + breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials. ©2012 AACR

Cell-active Small Molecule Inhibitors of the DNA-damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG) : Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides

DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly­(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone <b>8a</b>, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives <b>33d</b> and <b>35d</b> were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure–activity relationships of these novel inhibitors

The seeds of divergence: the economy of French North America, 1688 to 1760

Generally, Canada has been ignored in the literature on the colonial origins of divergence with most of the attention going to the United States. Late nineteenth century estimates of income per capita show that Canada was relatively poorer than the United States and that within Canada, the French and Catholic population of Quebec was considerably poorer. Was this gap long standing? Some evidence has been advanced for earlier periods, but it is quite limited and not well-suited for comparison with other societies. This thesis aims to contribute both to Canadian economic history and to comparative work on inequality across nations during the early modern period. With the use of novel prices and wages from Quebec—which was then the largest settlement in Canada and under French rule—a price index, a series of real wages and a measurement of Gross Domestic Product (GDP) are constructed. They are used to shed light both on the course of economic development until the French were defeated by the British in 1760 and on standards of living in that colony relative to the mother country, France, as well as the American colonies. The work is divided into three components. The first component relates to the construction of a price index. The absence of such an index has been a thorn in the side of Canadian historians as it has limited the ability of historians to obtain real values of wages, output and living standards. This index shows that prices did not follow any trend and remained at a stable level. However, there were episodes of wide swings—mostly due to wars and the monetary experiment of playing card money. The creation of this index lays the foundation of the next component. The second component constructs a standardized real wage series in the form of welfare ratios (a consumption basket divided by nominal wage rate multiplied by length of work year) to compare Canada with France, England and Colonial America. Two measures are derived. The first relies on a “bare bones” definition of consumption with a large share of land-intensive goods. This measure indicates that Canada was poorer than England and Colonial America and not appreciably richer than France. However, this measure overestimates the relative position of Canada to the Old World because of the strong presence of land-intensive goods. A second measure is created using a “respectable” definition of consumption in which the basket includes a larger share of manufactured goods and capital-intensive goods. This second basket better reflects differences in living standards since the abundance of land in Canada (and Colonial America) made it easy to achieve bare subsistence, but the scarcity of capital and skilled labor made the consumption of luxuries and manufactured goods (clothing, lighting, imported goods) highly expensive. With this measure, the advantage of New France over France evaporates and turns slightly negative. In comparison with Britain and Colonial America, the gap widens appreciably. This element is the most important for future research. By showing a reversal because of a shift to a different type of basket, it shows that Old World and New World comparisons are very sensitive to how we measure the cost of living. Furthermore, there are no sustained improvements in living standards over the period regardless of the measure used. Gaps in living standards observed later in the nineteenth century existed as far back as the seventeenth century. In a wider American perspective that includes the Spanish colonies, Canada fares better. The third component computes a new series for Gross Domestic Product (GDP). This is to avoid problems associated with using real wages in the form of welfare ratios which assume a constant labor supply. This assumption is hard to defend in the case of Colonial Canada as there were many signs of increasing industriousness during the eighteenth and nineteenth centuries. The GDP series suggest no long-run trend in living standards (from 1688 to circa 1765). The long peace era of 1713 to 1740 was marked by modest economic growth which offset a steady decline that had started in 1688, but by 1760 (as a result of constant warfare) living standards had sunk below their 1688 levels. These developments are accompanied by observations that suggest that other indicators of living standard declined. The flat-lining of incomes is accompanied by substantial increases in the amount of time worked, rising mortality and rising infant mortality. In addition, comparisons of incomes with the American colonies confirm the results obtained with wages— Canada was considerably poorer. At the end, a long conclusion is provides an exploratory discussion of why Canada would have diverged early on. In structural terms, it is argued that the French colony was plagued by the problem of a small population which prohibited the existence of scale effects. In combination with the fact that it was dispersed throughout the territory, the small population of New France limited the scope for specialization and economies of scale. However, this problem was in part created, and in part aggravated, by institutional factors like seigneurial tenure. The colonial origins of French America’s divergence from the rest of North America are thus partly institutional

Investigations of peripheral and central aspects of control of breathing

The control of breathing was examined at two levels. (1) Slowly adapting pulmonary stretch receptors (SAR) provide afferent information to the respiratory controller. Experiments were performed to elucidate the responses of SAR during both dynamic and static inflations of the airways. Improved characterization of the receptor stimulus was achieved by reducing the preparation from the whole lung to an in vivo isolated trachea and an in vitro tracheal segment. The components of SAR discharge related to the rate and magnitude of lung inflation were quantified. The proposed existence of receptor subtypes was not confirmed. Based on the variation of interspike intervals during adaptation of SAR discharge, a single spike generating site for the receptor is probable. (2) A mathematical model simulating the three-phase respiratory network oscillator proposed by Richter et al. is discussed. Such a network oscillator is suggested as the neural structure responsible for generating the rhythmic neuronal discharge pattern which controls the respiratory muscles during breathing. (An alternative mechanism invoking pacemaker neurons has also been proposed.) The component neurons of the model exhibit the property of adaptation. Their activity, reflecting both the membrane potential and firing frequency, was represented by continuous variables. The behavior of the mathematical model to simulated experiments was investigated. Input parameters were systematically varied in a stepwise manner and the subsequent model behavior was related to physiologically observed phenomena. Perturbing stimuli which produced phase-resetting were used in order to apply the methods for characterizing oscillators. Phasic changes in selected input parameters simulated SAR input during the breathing cycle. The model reproduced the reported trajectories of membrane potential for the five types of neurons included. Stepwise parameter changes altered the three-phase rhythm to two phases, resulted in apnea, or produced multiphasic patterns. Results of pulse perturbations showed the discontinuous phase-resetting observed at the expiratory-inspiratory and inspiratory-expiratory transitions. A hyperbolic V\sb{\rm T} versus T\sb{\rm I} plot was produced with phasic alterations in input parameters. The model performance is consistent with, and to that extent supports, a network type oscillator as the mechanism underlying the respiratory rhythm