Rocaglates as dual-targeting agents for experimental cerebral malaria

Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by Plasmodium parasites that is associated with high rates of mortality and morbidity. Treatment options are currently few, and intervention with artemisinin (Art) has limited efficacy, a problem that is compounded by the emergence of resistance to Art in Plasmodium parasites. Rocaglates are a class of natural products derived from plants of the Aglaia genus that have been shown to interfere with eukaryotic initiation factor 4A (eIF4A), ultimately blocking initiation of protein synthesis. Here, we show that the rocaglate CR-1-31B perturbs association of Plasmodium falciparum eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with Plasmodium berghei (CM) and Plasmodium chabaudi (blood-stage malaria), and can also block replication of different clinical isolates of P. falciparum in human erythrocytes infected ex vivo, including drug-resistant P. falciparum isolates. In vivo, a single dosing of CR-1-31B in P. berghei-infected animals is sufficient to provide protection against lethality. CR-1-31B is shown to dampen expression of the early proinflammatory response in myeloid cells in vitro and dampens the inflammatory response in vivo in P. berghei-infected mice. The dual activity of CR-1-31B as an antiplasmodial and as an inhibitor of the inflammatory response in myeloid cells should prove extremely valuable for therapeutic intervention in human cases of CM.We thank Susan Gauthier, Genevieve Perreault, and Patrick Senechal for technical assistance. This work was supported by a research grant (to P.G.) from the Canadian Institutes of Health Research (CIHR) (Foundation Grant). J.P. and P.G. are supported by a James McGill Professorship salary award. D.L. is supported by fellowships from the Fonds de recherche sante Quebec, the CIHR Neuroinflammation training program. J.P. is supported by CIHR Research Grant FDN-148366. M.S. is supported by a CIHR Foundation grant. J.A.P. is supported by NIH Grant R35 GM118173. Work at the Boston University Center for Molecular Discovery is supported by Grant R24 GM111625. K.C.K. was supported by a CIHR Foundation Grant and the Canada Research Chair program. (Canadian Institutes of Health Research (CIHR); James McGill Professorship salary award; Fonds de recherche sante Quebec; CIHR Neuroinflammation training program; FDN-148366 - CIHR Research Grant; CIHR Foundation grant; R35 GM118173 - NIH; Canada Research Chair program; R24 GM111625

(+)-Hexacyclinol

A sample of the title compound [systematic name: (1aS,2aS,3S,5aS,6aS,7R,7aS,7bS,8R,8aS,10R)-7-hydr­oxy-3-(1-meth­oxy-1-methyl­ethyl)-10-(2-methyl-1-propen­yl)-1a,5a,6a,7,7a,7b,8,8a-octa­hydro-2H-8,2a-(epoxy­methano)phenanthro[2,3-b:6,7-b′]bis­oxirene-2,5(3H)-dione], C23H28O7, was generated by enanti­oselective synthesis. There are three mol­ecules of the compound in the crystallographic asymmetric unit. Hydrogen bonding between alcohol H atoms and keto groups of adjacent mol­ecules appears to stabilize the structure. The compound is enanti­omerically pure but the absolute configuration could not be determined directly in this study. Accordingly, the illustrated configuration was assigned on the basis of the nature of the chiral nonracemic precursor used in the synthesis

Mitonuclear discordance and patterns of reproductive isolation in a complex of simultaneously hermaphroditic species, the Allolobophora chlorotica case study

Historical events of population fragmentation, expansion and admixture over geological time may result in complex patterns of reproductive isolation and may explain why, for some taxa, the study of mitochondrial (mt) and nuclear (nu) genetic data results in discordant evolutionary patterns. Complex patterns of taxonomic diversity were recently revealed in earthworms for which distribution is largely the result of paleogeographical events. Here, we investigated reproductive isolation patterns in a complex of cryptic species of earthworms in which discordant patterns between mt and nu genetic lineages were previously revealed, the Allolobophora chlorotica aggregate. Using four nu microsatellite markers and a fragment of the cytochrome c oxidase subunit I mt gene, we carried out a parentage analysis to investigate the mating patterns (i) between individuals belonging to two divergent mt lineages that cannot be distinguished with nu markers and (ii) between individuals belonging to lineages that are differentiated both at the mt and nu levels. Amongst the 157 field-collected individuals, 66 adults were used in cross-breeding experiments to form 22 trios based on their assignment to a mt lineage, and 453 obtained juveniles were genotyped. We showed that adults that mated with both their potential mates in the trio produced significantly more juveniles. In crosses between lineages that diverged exclusively at the mt level, a sex-specific pattern of reproduction characteristic to each lineage was observed, suggesting a possible conflict of interest concerning the use of male/female function between mating partners. In crosses between lineages that diverged both at the mt and nu levels, a high production of cocoons was counterbalanced by a low hatching rate, suggesting a post-zygotic reproductive isolation. Different degrees of reproductive isolation, from differential sex allocation to post-zygotic isolation, were thus revealed. Lineages appear to be at different stages in the speciation process, which likely explain the observed opposite patterns of mitonuclear congruence

Neurological, Cognitive, and Psychological Findings Among Survivors of Ebola Virus Disease From the 1995 Ebola Outbreak in Kikwit, Democratic Republic of Congo: A Cross-sectional Study.

BackgroundClinical sequelae of Ebola virus disease (EVD) have not been described more than 3 years postoutbreak. We examined survivors and close contacts from the 1995 Ebola outbreak in Kikwit, Democratic Republic of Congo (DRC), and determined prevalence of abnormal neurological, cognitive, and psychological findings and their association with EVD survivorship.MethodsFrom August to September 2017, we conducted a cross-sectional study in Kikwit, DRC. Over 2 decades after the EVD outbreak, we recruited EVD survivors and close contacts from the outbreak to undergo physical examination and culturally adapted versions of the Folstein mini-mental status exam (MMSE) and Goldberg anxiety and depression scale (GADS). We estimated the strength of relationships between EVD survivorship and health outcomes using linear regression models by comparing survivors versus close contacts, adjusting for age, sex, educational level, marital status, and healthcare worker status.ResultsWe enrolled 20 EVD survivors and 187 close contacts. Among the 20 EVD survivors, 4 (20%) reported at least 1 abnormal neurological symptom, and 3 (15%) had an abnormal neurological examination. Among the 187 close contacts, 14 (11%) reported at least 1 abnormal neurologic symptom, and 9 (5%) had an abnormal neurological examination. EVD survivors had lower mean MMSE and higher mean GADS scores as compared to close contacts (MMSE: adjusted coefficient: -1.85; 95% confidence interval [CI]: -3.63, -0.07; GADS: adjusted coefficient: 3.91; 95% CI: 1.76, 6.04).ConclusionsEVD survivors can have lower cognitive scores and more symptoms of depression and anxiety than close contacts more than 2 decades after Ebola virus outbreaks

Forecasting the new case detection rate of leprosy in four states of Brazil : a comparison of modelling approaches

Background Brazil has the second highest annual number of new leprosy cases. The aim of this study is to formally compare predictions of future new case detection rate (NCDR) trends and the annual probability of NCDR falling below 10/100,000 of four different modelling approaches in four states of Brazil: Rio Grande do Norte, Amazonas, Ceará, Tocantins. Methods A linear mixed model, a back-calculation approach, a deterministic compartmental model and an individual-based model were used. All models were fitted to leprosy data obtained from the Brazilian national database (SINAN). First, models were fitted to the data up to 2011, and predictions were made for NCDR for 2012–2014. Second, data up to 2014 were considered and forecasts of NCDR were generated for each year from 2015 to 2040. The resulting distributions of NCDR and the probability of NCDR being below 10/100,000 of the population for each year were then compared between approaches. Results Each model performed well in model fitting and the short-term forecasting of future NCDR. Long-term forecasting of NCDR and the probability of NCDR falling below 10/100,000 differed between models. All agree that the trend of NCDR will continue to decrease in all states until 2040. Reaching a NCDR of less than 10/100,000 by 2020 was only likely in Rio Grande do Norte. Prediction until 2040 showed that the target was also achieved in Amazonas, while in Ceará and Tocantins the NCDR most likely remain (far) above 10/100,000. Conclusions All models agree that, while incidence is likely to decline, achieving a NCDR below 10/100,000 by 2020 is unlikely in some states. Long-term prediction showed a downward trend with more variation between models, but highlights the need for further control measures to reduce the incidence of new infections if leprosy is to be eliminated

Cuticular Compounds Bring New Insight in the Post-Glacial Recolonization of a Pyrenean Area: Deutonura deficiens Deharveng, 1979 Complex, a Case Study

Background: In most Arthropod groups, the study of systematics and evolution rely mostly on neutral characters, in this context cuticular compounds, as non-neutral characters, represent an underexplored but potentially informative type of characters at the infraspecific level as they have been routinely proven to be involved in sexual attraction. Methods and Findings: The collembolan species complex Deutonura deficiens was chosen as a model in order to test the utility of these characters for delineating four infraspecific entities of this group. Specimens were collected for three subspecies (D. d. deficiens, D. d. meridionalis, D. d. sylvatica) and two morphotypes (D. d. sylvatica morphoype A and B) of the complex; an additional species D. monticola was added. Cuticular compounds were extracted and separated by gas chromatography for each individual. Our results demonstrate that cuticular compounds succeeded in separating the different elements of this complex. Those data allowed also the reconstruction of the phylogenetic relationships among them. Conclusions: The discriminating power of cuticular compounds is directly related to their involvement in sexual attraction and mate recognition. These findings allowed a discussion on the potential involvement of intrinsic and paleoclimatic factors in the origin and the diversification of this complex in the Pyrenean zone. This character type brings the first advanc

Forecasting the new case detection rate of leprosy in four states of Brazil: A comparison of modelling approaches.

BACKGROUND: Brazil has the second highest annual number of new leprosy cases. The aim of this study is to formally compare predictions of future new case detection rate (NCDR) trends and the annual probability of NCDR falling below 10/100,000 of four different modelling approaches in four states of Brazil: Rio Grande do Norte, Amazonas, Ceará, Tocantins. METHODS: A linear mixed model, a back-calculation approach, a deterministic compartmental model and an individual-based model were used. All models were fitted to leprosy data obtained from the Brazilian national database (SINAN). First, models were fitted to the data up to 2011, and predictions were made for NCDR for 2012-2014. Second, data up to 2014 were considered and forecasts of NCDR were generated for each year from 2015 to 2040. The resulting distributions of NCDR and the probability of NCDR being below 10/100,000 of the population for each year were then compared between approaches. RESULTS: Each model performed well in model fitting and the short-term forecasting of future NCDR. Long-term forecasting of NCDR and the probability of NCDR falling below 10/100,000 differed between models. All agree that the trend of NCDR will continue to decrease in all states until 2040. Reaching a NCDR of less than 10/100,000 by 2020 was only likely in Rio Grande do Norte. Prediction until 2040 showed that the target was also achieved in Amazonas, while in Ceará and Tocantins the NCDR most likely remain (far) above 10/100,000. CONCLUSIONS: All models agree that, while incidence is likely to decline, achieving a NCDR below 10/100,000 by 2020 is unlikely in some states. Long-term prediction showed a downward trend with more variation between models, but highlights the need for further control measures to reduce the incidence of new infections if leprosy is to be eliminated

A Cluster-Randomized Trial to Assess the Efficacy of Targeting Trachoma Treatment to Children.

Background: The World Health Organization recommends annual treatment of entire trachoma-endemic communities, although children typically have a higher load, longer duration, and greater likelihood of infection. Methods: Forty-eight communities in Matameye, Niger, were randomized to annual oral azithromycin treatment of the entire community or biannual treatment of children aged 0-12 years only. Both children and adults were monitored for ocular chlamydial infection by polymerase chain reaction. Results: The prevalence of childhood infection was reduced in the annually treated arm from 21.2% (95% confidence interval [CI], 15.2%-28.0%) at baseline to 5.8% (95% CI, 3.2%-9.0%) at 36 months (P < .001) and in the biannual arm from 20.2% (95% CI, 15.5%-25.3%) to 3.8% (95% CI, 2.2%-6.0%; P < .001). Adult infection in the annual arm was reduced from 1.7% (95% CI, .9%-2.7%) to 0.3% (95% CI, .0%-.7%) and in the biannual arm from 1.2% (95% CI, .5%-2.2%) to 0.0% (95% CI, .0%-.7%; P = .005). The effect of biannual treatment of children compared with annual treatment of the entire community in both children (95% CI, -.04% to .02%) and adults (95% CI, .9%-2.7%) excluded the prespecified noninferiority threshold of 6% (P = .003 and P < .001, respectively). Conclusions: Periodic distribution of antibiotics to children in trachoma-endemic communities reduces chlamydial infection in both children and untreated adults, suggesting a form of herd protection. Biannual treatment of children was comparable to (specifically, noninferior to) annual treatment of the entire community, and may offer lower antibiotic use and other logistical advantages. Clinical Trials Registration: NCT00792922

Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control.

BACKGROUND: Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed. METHODS: Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms. RESULTS: No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms. CONCLUSIONS: Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status