Mining Bacillus subtilis chromosome heterogeneities using hidden Markov models

We present here the use of a new statistical segmentation method on the Bacillus subtilis chromosome sequence. Maximum likelihood parameter estimation of a hidden Markov model, based on the expectation-maximization algorithm, enables one to segment the DNA sequence according to its local composition. This approach is not based on sliding windows; it enables different compositional classes to be separated without prior knowledge of their content, size and localization. We compared these compositional classes, obtained from the sequence, with the annotated DNA physical map, sequence homologies and repeat regions. The first heterogeneity revealed discriminates between the two coding strands and the non-coding regions. Other main heterogeneities arise; some are related to horizontal gene transfer, some to t-enriched composition of hydrophobic protein coding strands, and others to the codon usage fitness of highly expressed genes. Concerning potential and established gene transfers, we found 9 of the 10 known prophages, plus 14 new regions of atypical composition. Some of them are surrounded by repeats, most of their genes have unknown function or possess homology to genes involved in secondary catabolism, metal and antibiotic resistance. Surprisingly, we notice that all of these detected regions are a + t-richer than the host genome, raising the question of their remote sources.     

A Multi-Marker Model for Detecting Chromosomal Segments Displaying Qtl Activity

A statistical method is presented for detecting quantitative trait loci (QTLs), based on the linear model. Unlike methods able to detect a few well separated QTLs and to estimate their effects and positions, this method considers the genome as a whole and enables the detection of chromosomal segments involved in the differences between two homozygous lines, and their backcross, doubled haploid, or F(2) progenies, for a quantitative trait. Genetic markers must be codominant, but missing markers are accepted, provided they are missing independently from the experiment. Asymptotic properties, which are of practical use, are developed. This method does not rely on strong genetic hypotheses, and thus does not permit any precise genetic analysis of the trait under study, but it does assess which regions of the genome are involved, whatever the complexity of the genetic determinism (number, effects and interactions among QTLs). Simultaneous use of several methods, including this one, should lead to better efficiency in QTL detection.     

Healthcare-Associated Infections Are Associated with Insufficient Dietary Intake: An Observational Cross-Sectional Study

Background

Indicators to predict healthcare-associated infections (HCAI) are scarce. Malnutrition is known to be associated with adverse outcomes in healthcare but its identification is time-consuming and rarely done in daily practice. This cross-sectional study assessed the association between dietary intake, nutritional risk, and the prevalence of HCAI, in a general hospital population.

Methods and findings

Dietary intake was assessed by dedicated dieticians on one day for all hospitalized patients receiving three meals per day. Nutritional risk was assessed using Nutritional Risk Screening (NRS)-2002, and defined as a NRS score ≥ 3. Energy needs were calculated using 110% of Harris-Benedict formula. HCAIs were diagnosed based on the Center for Disease Control criteria and their association with nutritional risk and measured energy intake was done using a multivariate logistic regression analysis. From 1689 hospitalised patients, 1024 and 1091 were eligible for the measurement of energy intake and nutritional risk, respectively. The prevalence of HCAI was 6.8%, and 30.1% of patients were at nutritional risk. Patients with HCAI were more likely identified with decreased energy intake (i.e. ≤ 70% of predicted energy needs) (30.3% vs. 14.5%, P = 0.002). The proportion of patients at nutritional risk was not significantly different between patients with and without HCAI (35.6% vs.29.7%, P = 0.28), respectively. Measured energy intake ≤ 70% of predicted energy needs (odds ratio: 2.26; 95% CI: 1.24 to 4.11, P = 0.008) and moderate severity of the disease (odds ratio: 3.38; 95% CI: 1.49 to 7.68, P = 0.004) were associated with HCAI in the multivariate analysis.

Conclusion

Measured energy intake ≤ 70% of predicted energy needs is associated with HCAI in hospitalised patients. This suggests that insufficient dietary intake could be a risk factor of HCAI, without excluding reverse causality. Randomized trials are needed to assess whether improving energy intake in patients identified with decreased dietary intake could be a novel strategy for HCAI prevention.     

Double-stranded RNA adenosine deaminase ADAR-1-induced hypermutated genomes among inactivated seasonal influenza and live attenuated measles virus vaccines

We sought to examine ADAR-1 editing of measles and influenza virus genomes derived from inactivated seasonal influenza and live attenuated measles virus vaccines grown on chicken cells as the culture substrate. Using highly sensitive 3DI-PCR (R. Suspène et al., Nucleic Acids Res. 36:e72, 2008), it was possible to show that ADAR-1 could hyperdeaminate adenosine residues in both measles virus and influenza virus A genomes. Detailed analysis of the dinucleotide editing context showed preferences for 5'ArA and 5'UrA, which is typical of editing in mammalian cells. The hyperedited mutant frequency, including genomes and antigenomes, was a log greater for influenza virus compared to measles virus, suggesting a greater sensitivity to restriction by ADAR-1.     

Restriction of foamy viruses by APOBEC cytidine deaminases

Foamy viruses (FVs) are nonpathogenic retroviruses infecting many species of mammals, notably primates, cattle, and cats. We have examined whether members of the apolipoprotein B-editing catalytic polypeptide-like subunit (APOBEC) family of antiviral cytidine deaminases restrict replication of simian FV. We show that human APOBEC3G is a potent inhibitor of FV infectivity in cell culture experiments. This antiviral activity is associated with cytidine editing of the viral genome. Both molecular FV clones and primary uncloned viruses were susceptible to APOBEC3G, and viral infectivity was also inhibited by murine and simian APOBEC3G homologues, as well as by human APOBEC3F. Wild-type and bet-deleted viruses were similarly sensitive to this antiviral activity, suggesting that Bet does not significantly counteract APOBEC proteins. Moreover, we did not detect FV sequences that may have been targeted by APOBEC in naturally infected macaques, but we observed a few G-to-A substitutions in humans that have been accidentally contaminated by simian FV. In infected hosts, the persistence strategy employed by FV might be based on low levels of replication, as well as avoidance of cells expressing large amounts of active cytidine deaminases.     

Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV,MVA-BN-Filo Ebola vaccination in healthy and HIV-infected adults: A randomised,placebo-controlled Phase II clinical trial in Africa

BackgroundWe investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations.Methods and findingsIn this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d’Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study.The first participant was enrolled on 9 November 2015, and the date of last participant’s last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response.Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants.ConclusionsAd26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02564523","term_id":"NCT02564523"}}NCT02564523

Houreratou Barry and co-workers report on safety and immunogenicity of an Ebola vaccine in adults across four African countries.     

How modeling can reconcile apparently discrepant experimental results: the case of pacemaking in dopaminergic neurons

Midbrain dopaminergic neurons are endowed with endogenous slow pacemaking properties. In recent years, many different groups have studied the basis for this phenomenon, often with conflicting conclusions. In particular, the role of a slowly-inactivating L-type calcium channel in the depolarizing phase between spikes is controversial, and the analysis of slow oscillatory potential (SOP) recordings during the blockade of sodium channels has led to conflicting conclusions. Based on a minimal model of a dopaminergic neuron, our analysis suggests that the same experimental protocol may lead to drastically different observations in almost identical neurons. For example, complete L-type calcium channel blockade eliminates spontaneous firing or has almost no effect in two neurons differing by less than 1% in their maximal sodium conductance. The same prediction can be reproduced in a state of the art detailed model of a dopaminergic neuron. Some of these predictions are confirmed experimentally using single-cell recordings in brain slices. Our minimal model exhibits SOPs when sodium channels are blocked, these SOPs being uncorrelated with the spiking activity, as has been shown experimentally. We also show that block of a specific conductance (in this case, the SK conductance) can have a different effect on these two oscillatory behaviors (pacemaking and SOPs), despite the fact that they have the same initiating mechanism. These results highlight the fact that computational approaches, besides their well known confirmatory and predictive interests in neurophysiology, may also be useful to resolve apparent discrepancies between experimental results.     

Diversity,distribution and conservation status assessment of Paraguayan palms (Arecaceae)

Indigenous palm species of Paraguay are presented with data on their diversity, distribution, threats and conservation status. The Paraguayan palm flora consists of 23 native species in 11 genera, representing two of the five subfamilies recognized in the group. The palm distribution in the country is strongly related to the different ecoregions present in Paraguay, with number of species by ecoregion being as follow: Cerrado (18), Upper Parana Atlantic forest (6), Wet Chaco (4), Pantanal (2), and Dry Chaco (1). Half of the species display an acaulescent habit reflecting an interesting ecological adaptation to natural fires in the Cerrado. The alarming rate of habitat modification that the country is undergoing since 1940s has put palms under a high risk of extinction in the wild. A GIS model was used to calculate the extent of occurrence and the area of occupancy of the species in order to assess their conservation status applying the IUCN Red List Categories and Criteria. This analysis shows that about 30% of the species are threatened; one species is Critically Endangered, three of them are Endangered, and three are Vulnerable. One species (Acrocomia hassleri) is considered Near Threatened, 13 are Least Concern whereas two species are insufficiently known and therefore unable to be assessed. Important areas for palm conservation in Paraguay were identified, revealing the importance of the Amambay department. Conservation measures for the threatened species identified are proposed.