Is There a Trade-off between Fertility and Longevity? A Comparative Study of Three Large Historical Demographic Databases Accounting for Mortality Selection

Frontier populations provide exceptional opportunities to test the hypothesis of a trade‐off between fertility and longevity. In such populations, mechanisms favoring reproduction usually find fertile ground, and if these mechanisms reduce the chances for survival in old age, demographers should observe higher post‐reproductive mortality rates among highly fertile women. We test this hypothesis using complete female reproductive histories from three large demographic databases: the Registre de la population du Québec ancien (Université de Montréal), which covers the first centuries of settlement in Quebec; the BALSAC database (Université du Québec à Chicoutimi), including comprehensive records for the region of Saguenay‐Lac‐St‐Jean (SLSJ) in the 19th and 20th centuries; and the Utah Population Database (University of Utah), including all individuals who experienced a vital event on the Mormon Trail since the early 1800s. From these databases, we extracted, respectively, 5447, 1610, and 11395 women who survived married to age 50. Together, the three samples allow for comparisons over time (Old Quebec versus more recent Quebec and Utah) and space (Quebec versus Utah), and represent the largest data collection used to assess the impact of female reproduction on post‐reproductive survival in a natural fertility context. Using survival analyses controlling for observed and unobserved factors we found a negative influence of parity and a positive influence of age at last child on post‐reproductive survival in the three populations, with remarkably similar effect sizes in the three samples. However, we found little evidence of early fertility effects. We used Heckman’s two‐stage procedure to assess the impact of mortality selection during reproductive years, with no appreciable alteration of the main results. We conclude our empirical investigation by discussing the needs and the advantages of collaborative and comparative approaches

Is there a trade-off between fertility and longevity? A comparative study of women from three large historical databases accounting for mortality selection

Frontier populations provide exceptional opportunities to test the hypothesis of a trade-off between fertility and longevity. In such populations, mechanisms favoring reproduction usually find fertile ground, and if these mechanisms reduce longevity, demographers should observe higher postreproductive mortality among highly fertile women. We test this hypothesis using complete female reproductive histories from three large demographic databases: the Registre de la population du Québec ancien (Université de Montréal), which covers the first centuries of settlement in Quebec; the BALSAC database (Université du Québec à Chicoutimi), including comprehensive records for the Saguenay-Lac-St-Jean (SLSJ) in Quebec in the nineteenth and twentieth centuries; and the Utah Population Database (University of Utah), including all individuals who experienced a vital event on the Mormon Trail and their descendants. Together, the three samples allow for comparisons over time and space, and represent one of the largest set of natural fertility cohorts used to simultaneously assess reproduction and longevity. Using survival analyses, we found a negative influence of parity and a positive influence of age at last child on postreproductive survival in the three populations, as well as a significant interaction between these two variables. The effect sizes of all these parameters were remarkably similar in the three samples. However, we found little evidence that early fertility affects postreproductive survival. The use of Heckman's procedure assessing the impact of mortality selection during reproductive ages did not appreciably alter these results. We conclude our empirical investigation by discussing the advantages of comparative approaches

Isothermal Microcalorimetry, a New Tool to Monitor Drug Action against Trypanosoma brucei and Plasmodium falciparum

Isothermal microcalorimetry is an established tool to measure heat flow of physical, chemical or biological processes. The metabolism of viable cells produces heat, and if sufficient cells are present, their heat production can be assessed by this method. In this study, we investigated the heat flow of two medically important protozoans, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Heat flow signals obtained for these pathogens allowed us to monitor parasite growth on a real-time basis as the signals correlated with the number of viable cells. To showcase the potential of microcalorimetry for measuring drug action on pathogenic organisms, we tested the method with three antitrypanosomal drugs, melarsoprol, suramin and pentamidine and three antiplasmodial drugs, chloroquine, artemether and dihydroartemisinin, each at two concentrations on the respective parasite. With the real time measurement, inhibition was observed immediately by a reduced heat flow compared to that in untreated control samples. The onset of drug action, the degree of inhibition and the time to death of the parasite culture could conveniently be monitored over several days. Microcalorimetry is a valuable element to be added to the toolbox for drug discovery for protozoal diseases such as human African trypanosomiasis and malaria. The method could probably be adapted to other protozoan parasites, especially those growing extracellularly

A Plant-Derived Morphinan as a Novel Lead Compound Active against Malaria Liver Stages

BACKGROUND: The global spread of multidrug–resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s. METHODS AND FINDINGS: Using bioassay-guided fractionation based on the parasite's hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC(50)] 3.1 μM, therapeutic index [TI] 14) and P. falciparum (IC(50) 4.2 μM, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC(50) 3.3 μM, TI 46, and IC(50) 42.4 μM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages. CONCLUSIONS: A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

RUN and FYVE domain-containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4

Autophagy is a key degradative pathway coordinated by external cues, including starvation, oxidative stress, or pathogen detection. Rare are the molecules known to contribute mechanistically to the regulation of autophagy and expressed specifically in particular environmental contexts or in distinct cell types. Here, we unravel the role of RUN and FYVE domain–containing protein 4 (RUFY4) as a positive molecular regulator of macroautophagy in primary dendritic cells (DCs). We show that exposure to interleukin-4 (IL-4) during DC differentiation enhances autophagy flux through mTORC1 regulation and RUFY4 induction, which in turn actively promote LC3 degradation, Syntaxin 17– positive autophagosome formation, and lysosome tethering. Enhanced autophagy boosts endogenous antigen presentation by MHC II and allows host control of Brucella abortus replication in IL-4–treated DCs and in RUFY4-expressing cells. RUFY4 is therefore the first molecule characterized to date that promotes autophagy and influences endosome dynamics in a subset of immune cells