Transcriptional responses of Biomphalaria pfeifferi and Schistosoma mansoni following exposure to niclosamide, with evidence for a synergistic effect on snails following exposure to both stressors.

BackgroundSchistosomiasis is one of the world's most common NTDs. Successful control operations often target snail vectors with the molluscicide niclosamide. Little is known about how niclosamide affects snails, including for Biomphalaria pfeifferi, the most important vector for Schistosoma mansoni in Africa. We used Illumina technology to explore how field-derived B. pfeifferi, either uninfected or harboring cercariae-producing S. mansoni sporocysts, respond to a sublethal treatment of niclosamide. This study afforded the opportunity to determine if snails respond differently to biotic or abiotic stressors, and if they reserve unique responses for when presented with both stressors in combination. We also examined how sporocysts respond when their snail host is treated with niclosamide.Principal findingsCercariae-producing sporocysts within snails treated with niclosamide express ~68% of the genes in the S. mansoni genome, as compared to 66% expressed by intramolluscan stages of S. mansoni in snails not treated with niclosamide. Niclosamide does not disable sporocysts nor does it seem to provoke from them distinctive responses associated with detoxifying a xenobiotic. For uninfected B. pfeifferi, niclosamide treatment alone increases expression of several features not up-regulated in infected snails including particular cytochrome p450s and heat shock proteins, glutathione-S-transferases, antimicrobial factors like LBP/BPI and protease inhibitors, and also provokes strong down regulation of proteases. Exposure of infected snails to niclosamide resulted in numerous up-regulated responses associated with apoptosis along with down-regulated ribosomal and defense functions, indicative of a distinctive, compromised state not achieved with either stimulus alone.Conclusions/significanceThis study helps define the transcriptomic responses of an important and under-studied schistosome vector to S. mansoni sporocysts, to niclosamide, and to both in combination. It suggests the response of S. mansoni sporocysts to niclosamide is minimal and not reflective of a distinct repertoire of genes to handle xenobiotics while in the snail host. It also offers new insights for how niclosamide affects snails

The in vivo transcriptome of Schistosoma mansoni in the prominent vector species Biomphalaria pfeifferi with supporting observations from Biomphalaria glabrata.

BackgroundThe full scope of the genes expressed by schistosomes during intramolluscan development has yet to be characterized. Understanding the gene products deployed by larval schistosomes in their snail hosts will provide insights into their establishment, maintenance, asexual reproduction, ability to castrate their hosts, and their prolific production of human-infective cercariae. Using the Illumina platform, the intramolluscan transcriptome of Schistosoma mansoni was investigated in field-derived specimens of the prominent vector species Biomphalaria pfeifferi at 1 and 3 days post infection (d) and from snails shedding cercariae. These S. mansoni samples were derived from the same snails used in our complementary B. pfeifferi transcriptomic study. We supplemented this view with microarray analyses of S. mansoni from B. glabrata at 2d, 4d, 8d, 16d, and 32d to highlight robust features of S. mansoni transcription, even when a different technique and vector species was used.Principal findingsTranscripts representing at least 7,740 (66%) of known S. mansoni genes were expressed during intramolluscan development, with the greatest number expressed in snails shedding cercariae. Many transcripts were constitutively expressed throughout development featuring membrane transporters, and metabolic enzymes involved in protein and nucleic acid synthesis and cell division. Several proteases and protease inhibitors were expressed at all stages, including some proteases usually associated with cercariae. Transcripts associated with G-protein coupled receptors, germ cell perpetuation, and stress responses and defense were well represented. We noted transcripts homologous to planarian anti-bacterial factors, several neural development or neuropeptide transcripts including neuropeptide Y, and receptors that may be associated with schistosome germinal cell maintenance that could also impact host reproduction. In at least one snail the presence of larvae of another digenean species (an amphistome) was associated with repressed S. mansoni transcriptional activity.Conclusions/significanceThis in vivo study, emphasizing field-derived snails and schistosomes, but supplemented with observations from a lab model, provides a distinct view from previous studies of development of cultured intramolluscan stages from lab-maintained organisms. We found many highly represented transcripts with suspected or unknown functions, with connection to intramolluscan development yet to be elucidated

Elucidating gene expression adaptation of phylogenetically divergent coral holobionts under heat stress

As coral reefs struggle to survive under climate change, it is crucial to know whether they have the capacity to withstand changing conditions, particularly increasing seawater temperatures. Thermal tolerance requires the integrative response of the different components of the coral holobiont (coral host, algal photosymbiont, and associated microbiome). Here, using a controlled thermal stress experiment across three divergent Caribbean coral species, we attempt to dissect holobiont member metatranscriptome responses from coral taxa with different sensitivities to heat stress and use phylogenetic ANOVA to study the evolution of gene expression adaptation. We show that coral response to heat stress is a complex trait derived from multiple interactions among holobiont members. We identify host and photosymbiont genes that exhibit lineage-specific expression level adaptation and uncover potential roles for bacterial associates in supplementing the metabolic needs of the coral-photosymbiont duo during heat stress. Our results stress the importance of integrative and comparative approaches across a wide range of species to better understand coral survival under the predicted rise in sea surface temperatures

Atrial Fibrillation Screen, Management And Guideline Recommended Therapy (AF SMART II) in the rural primary care setting: a cross-sectional study and cost-effectiveness analysis of eHealth tools to support all stages of screening

BackgroundInternationally, most atrial fibrillation (AF) management guidelines recommend opportunistic screening for AF in people aged ≥65 years, and oral anticoagulant (OAC) treatment for those at high stroke risk (CHA₂DS₂-VA ≥2). However, gaps remain in screening and treatment.Methods and ResultsGeneral practitioners/nurses at practices in rural Australia(n=8) screened eligible patients (aged ≥65 years without AF) using a smartphone electrocardiogram during practice visits. eHealth tools included electronic prompts, guideline-based electronic decision support, and regular data reports. Clinical audit tools extracted deidentified data. Results were compared to an earlier study in metropolitan practices(n=8) and non-randomised control practices(n=69). Cost-effectiveness analysis compared population-based screening to no screening and included screening, treatment and hospitalisation costs for stroke and serious bleeding events. Patients (n=3,103, 34%) were screened (mean age 75.1±6.8 years, 47% male) and 36(1.2%) new AF cases were confirmed (mean age 77.0 years, 64% male, mean CHA₂DS₂-VA=3.2). OAC treatment rates for patients with CHA₂DS₂-VA≥2 were 82% (screen-detected) versus 74% (pre-existing AF)(p=NS), similar to metropolitan and non-randomised control practices. The incremental cost-effectiveness ratio (ICER) for population-based screening was AU$16,578/quality adjusted life year gained and AU$84,383/stroke prevented compared to no screening. National implementation would prevent 147 strokes/year. Increasing the proportion screened to 75% would prevent 177 additional strokes/year.ConclusionsAn AF screening program in rural practices, supported by eHealth tools, screened 34% of eligible patients and was cost-effective. OAC treatment rates were relatively high at baseline, trending upwards during the study. Increasing the proportion screened would prevent many more strokes with minimal ICER change. eHealth tools, including data reports, may be a valuable addition to future programs

Comparative genomics explains the evolutionary success of reef-forming corals

Transcriptome and genome data from twenty stony coral species and a selection of reference bilaterians were studied to elucidate coral evolutionary history. We identified genes that encode the proteins responsible for the precipitation and aggregation of the aragonite skeleton on which the organisms live, and revealed a network of environmental sensors that coordinate responses of the host animals to temperature, light, and pH. Furthermore, we describe a variety of stress-related pathways, including apoptotic pathways that allow the host animals to detoxify reactive oxygen and nitrogen species that are generated by their intracellular photosynthetic symbionts, and determine the fate of corals under environmental stress. Some of these genes arose through horizontal gene transfer and comprise at least 0.2% of the animal gene inventory. Our analysis elucidates the evolutionary strategies that have allowed symbiotic corals to adapt and thrive for hundreds of millions of years.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by eLife Sciences Publications. The published article can be found at: https://elifesciences.org

The clinical pharmacokinetics and pharmacodynamics of febuxostat

Febuxostat lowers serum urate (SU) by inhibiting xanthine oxidoreductase. The data on the effect of renal function on the pharmacokinetics (PK) of febuxostat and the response of SU pharmacodynamics; PD) to febuxostat are limited and discordant. Febuxostat was reported to reduce the fractional clearance of urate (FCU) in healthy and gout subjects after chronic dosing, suggesting an unexpected mode of action. An HPLC method using fluorescence-detection was developed and validated in order to undertake PK-PD investigations. The new HPLC method is a modification and significant improvement of an existing method. The first study examined the PK-PD of a single dose of febuxostat (80 mg) in healthy subjects and the effect on FCU. The nadir of SU was achieved at 22 hours post-dose while the bulk of febuxostat (81%) was eliminated from plasma during the first 9 hours. Thus, the febuxostat-SU relationship over time exhibited a negative hysteresis as the time course of urate decline lagged behind that of febuxostat concentrations. There was no effect of febuxostat on FCU.The second study aimed mainly at examining the dose-concentration-response relationship of febuxostat and the covariates of the absolute reduction in urate in gout patients treated with febuxostat. Renal function was found to influence the trough concentrations of plasma febuxostat but had no effect on the reduction (absolute and percentage) in urate. Febuxostat 40 mg/day achieved a mean reduction in urate of 53%. Higher doses achieved small but clinically necessary additional hypouricaemic effects. Baseline urate and presence of tophi were significant covariates for the absolute reduction in urate. Finally, a population pharmacokinetic model was developed in order to examine the pharmacokinetics of febuxostat in subjects from the above two studies. Renal function had a significant but small effect on the apparent clearance of febuxostat. Body mass index was a significant covariate of the apparent central volume of distribution. Overall, the findings from this thesis provide a greater understanding of the PK-PD of febuxostat in patients with gout and across a range of renal function and confirm that there is no effect of a single dose of febuxostat (80 mg) on FCU in healthy subjects

The microbiome of a Pacific moon jellyfish Aurelia coerulea.

The impact of microbiome in animal physiology is well appreciated, but characterization of animal-microbe symbiosis in marine environments remains a growing need. This study characterizes the microbial communities associated with the moon jellyfish Aurelia coerulea, first isolated from the East Pacific Ocean and has since been utilized as an experimental system. We find that the microbiome of this Pacific Aurelia culture is dominated by two taxa, a Mollicutes and Rickettsiales. The microbiome is stable across life stages, although composition varies. Mining the host sequencing data, we assembled the bacterial metagenome-assembled genomes (MAGs). The bacterial MAGs are highly reduced, and predict a high metabolic dependence on the host. Analysis using multiple metrics suggest that both bacteria are likely new species. We therefore propose the names Ca. Mariplasma lunae (Mollicutes) and Ca. Marinirickettsia aquamalans (Rickettsiales). Finally, comparison with studies of Aurelia from other geographical populations suggests the association with Ca. Mariplasma lunae occurs in Aurelia from multiple geographical locations. The low-diversity microbiome of Aurelia provides a relatively simple system to study host-microbe interactions