O obračunu kamata i kredita

<div><p>Background</p><p>Infection with <i>Trypanosoma cruzi</i> causes Chagas disease, a major public health problem throughout Latin America. There is no vaccine and the only drugs have severe side effects. Efforts to generate new therapies are hampered by limitations in our understanding of parasite biology and disease pathogenesis. Studies are compromised by the complexity of the disease, the long-term nature of the infection, and the fact that parasites are barely detectable during the chronic stage. In addition, functional dissection of <i>T</i>. <i>cruzi</i> biology has been restricted by the limited flexibility of the genetic manipulation technology applicable to this parasite.</p><p>Methodology/Principal findings</p><p>Here, we describe two technical innovations, which will allow the role of the parasite in disease progression to be better assessed. First, we generated a <i>T</i>. <i>cruzi</i> reporter strain that expresses a fusion protein comprising red-shifted luciferase and green fluorescent protein domains. Bioluminescence allows the kinetics of infection to be followed within a single animal, and specific foci of infection to be pinpointed in excised tissues. Fluorescence can then be used to visualise individual parasites in tissue sections to study host-parasite interactions at a cellular level. Using this strategy, we have been routinely able to find individual parasites within chronically infected murine tissues for the first time. The second advance is the incorporation of a streamlined CRISPR/Cas9 functionality into this reporter strain that can facilitate genome editing using a PCR-based approach that does not require DNA cloning. This system allows the rapid generation of null mutants and fluorescently tagged parasites in a background where the <i>in vivo</i> phenotype can be rapidly assessed.</p><p>Conclusions/Significance</p><p>The techniques described here will have multiple applications for studying aspects of <i>T</i>. <i>cruzi</i> biology and Chagas disease pathogenesis previously inaccessible to conventional approaches. The reagents and cell lines have been generated as a community resource and are freely available on request.</p></div

Nitroheterocyclic drugs cure experimental <i>Trypanosoma cruzi</i> infections more effectively in the chronic stage than in the acute stage

The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies

Do borrão às aguadas: os engenheiros militares e a representação da Capitania de São Paulo

A análise do papel dos engenheiros militares perpassa as discussões sobre regiões específicas, mesmo quando eles, aparentemente, estão ausentes delas. Sua presença ou ausência sempre foi sinônimo de interesse e de projeto colonizador mais ou menos dirigido. Este ensaio tem como objeto de estudo a cartografia dos engenheiros militares atuantes na Capitania de São Paulo, território comumente visto como economicamente periférico e mais autônomo face aos desígnios da Coroa portuguesa. Com foco no corpus cartográfico de alguns profissionais que aqui atuaram, trata indiretamente da multifacetada atuação desses engenheiros, bem como do processo de feitura das cartas geográficas, corográficas e topográficas, do borrão às aguadas. Investigar a cartografia de alguns desses profissionais permite não apenas explorar a riqueza de suas biografias, como, também, acompanhar o processo de produção técnica dos mapas e os desígnios políticos envolvidos no devassamento e representação das terras descobertas no Novo Mundo.Analyzing the role of military engineers means venturing into discussions about specific regions, even those from which they are apparently absent. Their presence or absence has always been synonymous with interest and a more or less directed colonization project. This essay examines the maps produced by the military engineers working in the Captaincy of São Paulo, a territory often looked upon as one of little economic import and a rather autonomous area in light of the plans of the Portuguese Crown. By focusing on the cartographic corpus bequeathed by certain professionals serving in this region, we deal indirectly with the multifaceted role of these engineers as well as with the process of making geographic, chorographic and topographic charts - all the way from the sketch to watercolored maps. Perusing the charts constructed by some of these professionals enabled us not only to delve into the rich details of their biographies but also to observe the technical mapmaking process and to unravel the political designs behind the exploration and representation of the lands discovered in the New World