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

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Exposure of the Canadian Wildland-Human Interface (WHI) and population to wildland fire, under current and future climate conditions

In Canada, recent fire seasons have demonstrated the threat of wildland fire in the Wildland-Human Interface (WHI) areas, where forest fuels intermingle with or abut housing, industry, and infrastructure. Although fire activity is expected to increase further in the coming decades as a result of climate change, no WHI-specific estimates of wildland fire exposure are currently available. This study combines spatial and demographic information sources to estimate the current and future wildland fire exposures, as reflected by fire return intervals (FRI) of WHI areas and populations across Canada. The WHI covers 17.3% of the forested area in Canada. Within the WHI, we found that 19.4% of the area currently experiences FRI ≤ 250 years but, by the end of the century, this could increase to 28.8% under RCP 2.6 and to 43.3% under RCP 8.5. Approximately 12.3% of the Canadian population currently live in the Wildland-Urban Interface (WUI), which includes 32.1% of the on-reserve First Nations population. Currently, 17.8% of the on-reserve WUI population is exposed to FRI ≤ 250 years, compared to only 4.7% of the remaining WUI population. By 2100, these proportions could reach 39.3% and 17.4% respectively, under the less optimistic climatic scenarios (RCP 8.5).The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Discovery of Clinical Candidate GSK1842799 As a Selective S1P₁ Receptor Agonist (Prodrug) for Multiple Sclerosis

To develop effective oral treatment for multiple sclerosis (MS), we discovered a series of alkyl-substituted biaryl amino alcohols as selective S1P₁ modulators. One exemplar is (<i>S</i>)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)­phenyl)-1,3,4-thiadiazol-2-yl)­propan-1-ol (<b>10</b>, GSK1842799). Upon phosphorylation, the compound (<b>10</b>-P) showed subnanomole S1P₁ agonist activity with >1000× selectivity over S1P₃. The alcohol <b>10</b> demonstrated good oral bioavailability and rapid in vivo conversion to <b>10</b>-P. Dosed orally at 0.1 mg/kg, <b>10</b> significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, <b>10</b> achieved efficacy equivalent to FTY720 in the mouse EAE model of MS. Further pharmacokinetic/pharmacodynamic (PK/PD) study with cynomolgus monkeys indicated that, after oral dosing of <b>10</b> at 3.8 mg/kg, the active phosphate reached plasma levels that are comparable to FTY-720 phosphate (FTY-P) revealed in human clinical pharmacokinetics studies. On the basis of the favorable in vitro ADME and in vivo PK/PD properties as well as broad toxicology evaluations, compound <b>10</b> (GSK1842799) was selected as a candidate for further clinical development

Discovery of stimulator binding to a conserved pocket in the heme domain of soluble guanylyl cyclase

Soluble guanylyl cyclase (sGC) is the receptor for nitric oxide and a highly sought-after therapeutic target for the management of cardiovascular diseases. New compounds that stimulate sGC show clinical promise, but where these stimulator compounds bind and how they function remains unknown. Here, using a photolyzable diazirine derivative of a novel stimulator compound, IWP-051, and MS analysis, we localized drug binding to the 1 heme domain of sGC proteins from the hawkmoth Manduca sexta and from human. Covalent attachments to the stimulator were also identified in bacterial homologs of the sGC heme domain, referred to as H-NOX domains, including those from Nostoc sp. PCC 7120, Shewanella oneidensis, Shewanella woodyi, and Clostridium botulinum, indicating that the binding site is highly conserved. The identification of photoaffinity-labeled peptides was aided by a signature MS fragmentation pattern of general applicability for unequivocal identification of covalently attached compounds. Using NMR, we also examined stimulator binding to sGC from M. sexta and bacterial H-NOX homologs. These data indicated that stimulators bind to a conserved cleft between two subdomains in the sGC heme domain. L12W/T48W substitutions within the binding pocket resulted in a 9-fold decrease in drug response, suggesting that the bulkier tryptophan residues directly block stimulator binding. The localization of stimulator binding to the sGC heme domain reported here resolves the longstanding question of where stimulators bind and provides a path forward for drug discovery.National Institutes of Health from NIEHS [ES06694]; National Institutes of Health from NCI [CA023074]; BIO5 Institute of the University of Arizona; National Institutes of Health from the National Center for Research Resources (NCRR) [1S10 RR028868-01]; National Institutes of Health from NIGMS [P41GM103399, P41RR002301]; University of Wisconsin-Madison; National Institutes of Health [P41GM103399, S10RR02781, S10RR08438, S10RR023438, S10RR025062, S10RR029220]; National Science Foundation [DMB-8415048, OIA-9977486, BIR-9214394]; U.S. Department of Agriculture12 month embargo; published online: 8 December 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Plateletactivating factor in vasoobliteration of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 43

PURPOSE. To test whether platelet-activating factor (PAF) directly causes retinovascular endothelial cell (EC) death. METHODS. Retinovascular density was calculated in rat pups exposed to 80% O 2 from postnatal days (P)6 to P14 (to produce oxygen-induced retinopathy [OIR]), using the adenosine diphosphatase (ADPase) technique, in animals treated with distinct PAF receptor blockers (PCA-4248, BN52021, or THG315). PAF levels were then measured in the retinas. Viability of ECs from piglets and humans in response to C-PAF (a stable PAF analogue) was determined by the reduction of the tetrazolium salt 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) by viable cells, incorporation of propidium iodide (PI), TUNEL assay, and release of lactate dehydrogenase. Release of thromboxane (TX) was measured in the cell media. RESULTS. PAF levels in retina were markedly increased by exposure of isolated rat retinas to H 2 O 2 (1 M) and of rat pups placed in 80% O 2 . Exposure to 80% O 2 induced retinal vasoobliteration, which was equally significantly inhibited (ϳ60%) by all PAF receptor blockers tested. C-PAF increased incorporation of PI by isolated rat retinal microvasculature. Also, C-PAF caused time-and concentration-dependent death of cultured retinal ECs, which was prevented by the PAF receptor antagonist CV-3988. This effect of C-PAF was selective on retinal and neurovascular ECs, but not on other ECs. DNA fragmentation (TUNEL) was hardly detected, and inhibition of apoptosis-related processes by nicotinamide, cyclosporin A, and Z-DEVD-FMK and Z-VAD-FMK (caspase inhibitors) barely protected against death in EC, whereas C-PAF increased release of lactate dehydrogenase, implying that necrosis is the nature of EC death. Finally, C-PAF-induced cell death was preceded by an increase in TXB 2 levels and was prevented by TXA 2 synthase inhibition (with CGS12970). CONCLUSIONS. The data suggest PAF plays a major role in vasoobliteration in OIR by triggering death of neuroretinal microvascular ECs. The cell death seems to be mediated at least in part by TXA 2 . These effects of PAF may participate in ischemic retinopathies such as diabetes and retinopathy of prematurity. (Invest Ophthalmol Vis Sci. 2002;43:3327-3337