Hepatitis C Virus Infection in Guinea-Bissau: A Sexually Transmitted Genotype 2 with Parenteral Amplification?

BACKGROUND: Sub-Saharan Africa is the continent with the highest prevalence of Hepatitis C virus (HCV) infection. Genotype 2 HCV is thought to have originated from West Africa several hundred years ago. Mechanisms of transmission remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: To delineate mechanisms for HCV transmission in West Africa, we conducted a cross-sectional survey of individuals aged ≥50 years in Bissau, Guinea-Bissau. Dried blood spots were obtained for HCV serology and PCR amplification. Prevalence of HCV was 4.4% (47/1066) among women and 5.0% (27/544) among men. In multivariate analysis, the independent risk factors for HCV infection were age (baseline: 50–59 y; 60–69 y, adjusted odds ratio [AOR]: 1.67, 95% CI: 0.91–3.06; ≥70 y, AOR: 3.47, 95% CI: 1.89–6.39), belonging to the Papel, Mancanha, Balanta or Mandjako ethnic groups (AOR: 2.45, 95% CI:1.32–4.53), originating from the Biombo, Cacheu or Oio regions north of Bissau (AOR: 4.16, 95% CI: 1.18–14.73) and having bought or sold sexual services (AOR: 3.60, 95% CI: 1.88–6.89). Of 57 isolates that could be genotyped, 56 were genotype 2. CONCLUSIONS: Our results suggest that transmission of HCV genotype 2 in West Africa occurs through sexual intercourse. In specific locations and subpopulations, medical interventions may have amplified transmission parenterally

Studies of a Ring-Cleaving Dioxygenase Illuminate the Role of Cholesterol Metabolism in the Pathogenesis of Mycobacterium tuberculosis

Mycobacterium tuberculosis, the etiological agent of TB, possesses a cholesterol catabolic pathway implicated in pathogenesis. This pathway includes an iron-dependent extradiol dioxygenase, HsaC, that cleaves catechols. Immuno-compromised mice infected with a ΔhsaC mutant of M. tuberculosis H37Rv survived 50% longer than mice infected with the wild-type strain. In guinea pigs, the mutant disseminated more slowly to the spleen, persisted less successfully in the lung, and caused little pathology. These data establish that, while cholesterol metabolism by M. tuberculosis appears to be most important during the chronic stage of infection, it begins much earlier and may contribute to the pathogen's dissemination within the host. Purified HsaC efficiently cleaved the catecholic cholesterol metabolite, DHSA (3,4-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione; kcat/Km = 14.4±0.5 µM−1 s−1), and was inactivated by a halogenated substrate analogue (partition coefficient<50). Remarkably, cholesterol caused loss of viability in the ΔhsaC mutant, consistent with catechol toxicity. Structures of HsaC:DHSA binary complexes at 2.1 Å revealed two catechol-binding modes: bidentate binding to the active site iron, as has been reported in similar enzymes, and, unexpectedly, monodentate binding. The position of the bicyclo-alkanone moiety of DHSA was very similar in the two binding modes, suggesting that this interaction is a determinant in the initial substrate-binding event. These data provide insights into the binding of catechols by extradiol dioxygenases and facilitate inhibitor design

Optimum Saving and Growth: Harrod on Dynamic Welfare Economics

In the 1960s and 1970s Harrod shifted the emphasis of his research in economic dynamics from the study of business cycles (instability principle) to the investigation of the growth process. As part of that, he restated his concept of the natural growth rate as an optimum welfare rate. The present paper examines Harrod's dynamic welfare economics, built around his concept of optimum saving developed as a reaction to Ramsey's approach to capital accumulation. It is shown that, according to Harrod, the saving rate does not affect the long-run growth rate of per capita income, which is determined by technical progress. Moreover, the economy will grow at the natural (full employment) rate only if economic policy is able to bring saving to its "optimum" level in macroeconomic equilibrium. Harrod's interest in optimal growth was motivated by his double concern with growth policy in mature economies and economic development in poor countries

Innovation and entrepreneurship as strategies for success among Cuban-based firms in the late years of the transatlantic slave trade

This article examines how Cuban-based firms and entrepreneurs circumvented ever- increasing risks in the illegal slave trade. The article sheds light to this question by analyzing new qualitative information of 65 Cuban-based firms against the Slavevoyages database. Our findings indicate that Cuban-based firms were entrepreneurial as they exploited the opportunities arising from the volatility of the slave trade by: (a) internalizing networks of agents which allowed the rapid diffusion of information, (b) diversifying trading goods and expanding the number of partnerships to reduce transaction costs and risk, and (c) adopting technological innovations that modified the design and use of vessels

Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29–14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni

Adam Smith and Competitive Equilibrium

A view has emerged which sees Adam Smith’s main contribution to economics in terms of his equilibrium theory. This paper argues that equilibrium economics was neither Smith’s main contribution nor his chief concern. It is true that Smith made a few observations which may be construed as equilibrium economics in some loose sense. For example, his observation that the market price of a commodity has a tendency to gravitate towards its natural price; or the rate of profit in different employments tends towards equality. But from this it cannot be concluded that Smith was chiefly an equilibrium theorist. In the first place, it needs to be emphasised that the ‘tendency’ towards equilibrium, which Smith talked about, is not the same thing as an equilibrium ‘outcome’. Equilibrium as an outcome is more likely to be reached in a stationary state than in an evolutionary system in the process of continuous dynamic motion. Smith’s evolutionary perspective, his analysis of the division of labour, capital accumulation, and the institutions most conducive to the generation of wealth, all point to the fact that Smith was more concerned with dynamic analysis than with static equilibrium. Finally, barring a few observations on the equilibrating tendency in the system, most of the Wealth of Nations is not devoted to this question

Historical geography II: Digital imaginations

In my second report discussing the state of historical geography, I review some of the ways historical geographers have made use of digital technologies and digital media. I also highlight how digital data, research, and presentation are affecting related humanities disciplines and inspiring their practitioners to engage more fully with geographic concepts of space, place, and cartography. I argue that information technologies and digital media can deepen the place of historical geography in the academy and in the public’s eye.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline