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ABSTRACT Cellulose being the most abundant polysaccharide on earth, beta-glucosidases hydrolyzing cello-oligosaccharides are key enzymes to fuel glycolysis in microorganisms developing on plant material. In Streptomyces scabiei, the causative agent of common scab in root and tuber crops, a genetic compensation phenomenon safeguards the loss of the gene encoding the cello-oligosaccharide hydrolase BglC by awakening the expression of alternative beta-glucosidases. Here, we revealed that the BglC compensating enzyme BcpE2 was the GH3-family beta-glucosidase that displayed the highest reported substrate promiscuity and was able to release the glucose moiety of all tested types of plant-derived heterosides (aryl β-glucosides, monolignol glucosides, cyanogenic glucosides, anthocyanosides, and coumarin heterosides). BcpE2 structure analysis highlighted a large cavity in the PA14 domain that covered the active site, and the high flexibility of this domain would allow proper adjustment of this cavity for disparate heterosides. The exceptional substrate promiscuity of BcpE2 provides microorganisms a versatile tool for scavenging glucose from plant-derived nutrients that widely vary in size and structure. Importantly, scopolin was the only substrate commonly hydrolyzed by both BglC and BcpE2, thereby generating the potent virulence inhibitor scopoletin. Next to fueling glycolysis, both enzymes would also fine-tune the strength of virulence. IMPORTANCE Plant decaying biomass is the most abundant provider of carbon sources for soil-dwelling microorganisms. To optimally evolve in such environmental niches, microorganisms possess an arsenal of hydrolytic enzymatic complexes to feed on the various types of polysaccharides, oligosaccharides, and monosaccharides. In this work, structural, enzymatic, and expression studies revealed the existence of a “swiss-army knife” enzyme, BcpE2, that was able to retrieve the glucose moiety of a multitude of plant-derived substrates that vary in size, structure, and origin. This enzyme would provide the microorganisms with a tool that would allow them to find nutrients from any type of plant-derived material.

En este trabajo se estudian varios expedientes de la Comisión Agraria Mixta del Archivo General del Estado de Veracruz para conseguir información sobre la aplicación de la reforma agraria y la creación de ejidos (propiedad social) en el centro y el sureste del estado, durante las décadas veinte, treinta y cuarenta del siglo XX. Se busca en especial entender el papel que tuvieron los diferentes actores en el proceso de reparto: lo que representó la expropiación de sus propiedades para los hacendados y las distintas estrategias que adoptaron para quedarse con sus tierras; y por otra parte, lo que significó la atribución de una parcela para los ejidatarios, que hasta entonces siempre habían trabajado en tierras ajenas. Se estudia también la reconfiguración que se dio en los territorios después de la dotación, como resultado de la apropiación campesina y de los procesos físicos y simbólicos de cambio.

The definition of correlates of protection is critical for the development of next-generation SARS-CoV-2 vaccine platforms. Here, we propose a model-based approach for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication.

Summary: Background: There is an urgent need of a new generation of vaccine that are able to enhance protection against SARS-CoV-2 and related variants of concern (VOC) and emerging coronaviruses. Methods: We identified conserved T- and B-cell epitopes from Spike (S) and Nucleocapsid (N) highly homologous to 38 sarbecoviruses, including SARS-CoV-2 VOCs, to design a protein subunit vaccine targeting antigens to Dendritic Cells (DC) via CD40 surface receptor (CD40.CoV2). Findings: CD40.CoV2 immunization elicited high levels of cross-neutralizing antibodies against SARS-CoV-2, VOCs, and SARS-CoV-1 in K18-hACE2 transgenic mice, associated with viral control and survival after SARS-CoV-2 challenge. A direct comparison of CD40.CoV2 with the mRNA BNT162b2 vaccine showed that the two vaccines were equally immunogenic in mice. We demonstrated the potency of CD40.CoV2 to recall in vitro human multi-epitope, functional, and cytotoxic SARS-CoV-2 S- and N-specific T-cell responses that are unaffected by VOC mutations and cross-reactive with SARS-CoV-1 and, to a lesser extent, MERS epitopes. Interpretation: We report the immunogenicity and antiviral efficacy of the CD40.CoV2 vaccine in a preclinical model providing a framework for a pan-sarbecovirus vaccine. Fundings: This work was supported by INSERM and the Investissements d'Avenir program, Vaccine Research Institute (VRI), managed by the ANR and the CARE project funded from the Innovative Medicines Initiative 2 Joint Undertaking (JU).

Human papillomaviruses are common sexually transmitted infections, caused by a large diversity of genotypes. In the context of vaccination against a subgroup of genotypes, better understanding the role of genotype interactions and human sexual behavior on genotype dynamics is essential. Herein, we present an individual-based model that integrates realistic heterosexual partnership behaviors and simulates interactions between vaccine and non-vaccine genotypes. Genotype interactions were considered, assuming a previous vaccine-genotype infection shortened (competition) or extended (synergy) the duration of a secondary non-vaccine-genotype infection. Sexual behavior determined papillomavirus acquisition and transmission: only 19.5% of active individuals at most 1 partner r during the year, but > 80% of those with ≥ 2 partners, were infected before vaccine introduction. The pre-vaccination situation was consistent with all genotype interaction scenarios. These genotype interactions, despite being undetectable during the pre-vaccination era, markedly impacted genotype prevalence after vaccination started, with a significant increase/decrease of non-vaccine genotypes prevalence for respectively competitive/synergistic interactions. These prevalence changes were more pronounced in individuals with ≤ 3 partners per year (up to 30% of prevalence modification assuming 65% vaccine coverage) but barely visible for individuals with > 3 partners per year (at most 0.30%). Results suggest the presence of genotype interaction, which is consistent with the pre-vaccine situation, may impact the dynamics of non-vaccine genotypes, particularly in less active individuals.

Abstract High‐throughput sequencing of amplicons (HTSA) has been proposed as an effective approach to evaluate taxonomic and genetic diversity at the same time. However, there are still uncertainties as to how the results produced by different bioinformatics treatments impact the conclusions drawn on biodiversity and population genetics indices. We evaluated the ability of six bioinformatics pipelines to recover taxonomic and genetic diversity from HTSA data obtained from controlled assemblages. To that end, 20 assemblages were produced using 354 colonies of Botrylloides spp., sampled in the wild in ten marinas around Brittany (France). We used DNA extracted from preservative ethanol (ebDNA) after various time of storage (3, 6, and 12 months), and from a bulk of preserved specimens (bulkDNA). DNA was amplified with primers designed for targeting this ascidian genus. Results obtained from HTSA data were compared with Sanger sequencing on individual zooids (i.e., individual barcoding). Species identification and relative abundance determined with HTSA data from either ebDNA or bulkDNA were similar to those obtained with traditional individual barcoding. However, after 12 months of storage, the correlation between HTSA and individual‐based data was lower than after shorter durations. The six bioinformatics pipelines were able to depict accurately the genetic diversity using standard population genetics indices (HS and FST), despite producing false positives and missing rare haplotypes. However, they did not perform equally and dada2 was the only pipeline able to retrieve all expected haplotypes. This study showed that ebDNA is a nondestructive alternative for both species identification and haplotype recovery, providing storage does not last more than 6 months before DNA extraction. Choosing the bioinformatics pipeline is a matter of compromise, aiming to retrieve all true haplotypes while avoiding false positives. We here recommend to process HTSA data using dada2, including a chimera‐removal step. Even if the possibility to use multiplexed primer sets deserves further investigation to expand the taxonomic coverage in future similar studies, we showed that primers targeting a particular genus allowed to reliably analyze this genus within a complex community.

Abstract Background Weight gain (mainly gain of fat mass) occurs quickly after successful kidney transplantation and is associated with metabolic complications (alterations of glycaemic control, hyperlipidaemia). Determinants of weight gain are multifactorial and are mainly related to the transplant procedure itself (glucocorticoid use, increased appetite). In the modern era of transplantation, one challenge is to limit these metabolic alterations by promoting gain of muscle mass rather than fat mass. This prospective study was performed to assess determinants of fat mass, fat-free mass and body cell mass changes after kidney transplantation with a focus on physical activity and nutritional behaviour before and after transplantation. Methods Patients were included at the time of listing for deceased donor kidney transplantation. Body composition was determined using dual X-ray absorptiometry and bioimpedance spectroscopy to assess fat mass, fat-free mass and body cell mass (= fat-free mass − extracellular water) at the time of inclusion, 12 months later, and 1, 6, 12 and 24 months after transplantation. Recall dietary data and physical activity level were also collected. Results Eighty patients were included between 2007 and 2010. Sixty-five had a complete 24-month follow-up after kidney transplantation. Fat mass, fat-free mass and body cell mass decreased during the waiting period and early after kidney transplantation. The nadirs of body cell mass and fat-free mass occurred at 1 month and the nadir for fat mass occurred at 6 months. Maximum levels of all parameters of body composition were seen at 12 months, after which body cell mass and fat-free mass decreased, while fat mass remained stable. In multivariate analysis, male recipients, higher physical activity level and lower corticosteroid dose were significantly associated with better body cell mass recovery after kidney transplantation. Conclusions Lifestyle factors, such as physical activity level, together with low dose of corticosteroids seem to influence body composition evolution following kidney transplantation with recovery of body cell mass. Specific strategies to promote physical activity in kidney transplant recipients should be provided before and after kidney transplantation.

Abstract Natural killer (NK) cells are implicated among immune effectors after vaccination against viral pathogens, including Ebola virus. The two-dose heterologous Ebola virus vaccine regimen, adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo (EBOVAC2 consortium, EU Innovative Medicines Initiative), induces NK cell activation and anti-Ebola glycoprotein (GP) antibody-dependent NK cell activation post-dose 1, which is further elevated post-dose 2. Here, in a multicentre, phase 2 clinical trial (EBL2001), we demonstrate durable ex vivo NK cell activation 180 days after dose 2, with responses enriched in CD56bright NK cells. In vitro antibody-dependent responses to immobilised Ebola GP increased after dose 1, and remained elevated compared to pre-vaccination levels in serum collected 180 days later. Peak NK cell responses were observed post-dose 2 and NK cell IFN-γ responses remained significantly elevated at 180 days post-dose 2. Individual variation in NK cell responses were influenced by both anti-Ebola GP antibody concentrations and intrinsic interindividual differences in NK cell functional capacity. In summary, this study demonstrates durable NK cell responses after Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccination and could inform the immunological evaluation of future iterations of the vaccine regimen and vaccination schedules.

BackgroundFamilies with young children have faced serious challenges during the first lockdown as a result of the COVID-19 pandemic. In addition to remote working, parents have had to monitor their children’s schoolwork and manage their daily lives. When one of the children also has neuro-developmental disorders, this results in an increased burden. We can therefore wonder how these families with one or more young children (under 6 years old) with special needs have experienced and dealt with this lockdown.Aim of the StudyIn this context, the “COVJEUNENFANT” study focused more specifically on the subjective experience, as a parent, of those who cared for children with special needs (i.e., with developmental disorders, neurodevelopmental disorders, proven disabilities or chronic health conditions) compared to the general population. We wished to see if the consequences of the health crisis were significantly different from those perceived by respondents in the general population (n = 490) and if the sociodemographic structure of these families differed from those of other respondents.MethodsNinety three French families with at least one child under 6 years old and one with developmental difficulties or a chronic illness, from a cohort of 490 control families, participated in a web-based survey during the first lockdown, from the 28th April 2020 to 29th May 2020.ResultsAfter presenting the participants’ sociodemographic characteristics, the results show that these French families (n = 93) are less wealthy than the control population “without special needs” (n = 397), have felt more pressures originating from their environment (families, friends, colleagues, media, social networks…), have suffered from more health issues (other than COVID-19), have taken more measures to protect themselves (social-distancing), and were less likely to feel happy. A significantly larger number of them lamented the lack of free time and voiced a larger need for information regarding children’s education. However, their parental role was felt as being more satisfying and their family relations strengthened more than in the general population of participants.ConclusionIt is apparent that urgent prioritisation is needed in order to support and care for these families by continuing to provide care for their children in one way or another, and by ensuring that their need to adapt again does not exceed their own abilities and resources, especially as young children, who have high levels of requirements, are present in the home.

The stalked barnacle Pollicipes pollicipes inhabits rocky shores from the Atlantic coasts of Brittany (France) to Senegal. Because of the culinary traditions of southern Europe, stalked barnacles represent an important target species for local fisheries on the Iberian Peninsula. To manage this fishery sustainably, it is therefore important to assess the dynamics of local populations over the Iberian coast, and how they are interconnected at a wider scale using finely tuned genetic markers. In this work, a new enriched library of GT microsatellites for P. pollicipes was prepared and sequenced using Ion Torrent™ Next Gen-Sequencing Technology. 1,423 adults and juveniles were sampled in 15 localities of three geographic regions: southern Portugal, Galicia and Asturias (both in northern Spain). Twenty polymorphic loci arranged in five multiplex PCRs were then tested and validated as new molecular tools to address the spatial and temporal genetic patterns of P. pollicipes. Our results revealed high genetic diversity among adults. However, juveniles were genetically more structured than their adult counterparts, which alternatively displayed much more connectivity among the three studied regions. The lack of spatial genetic heterogeneity in adults may be due to the overlapping of several generations of settlers coming from different geographic origins, which mainly depends on the orientation of residual currents along the coast during reproduction. The genetic differentiation of juveniles may indeed be congruent with Iberian Peninsula hydrodynamics, which can produce chaotic genetic patchiness (CGP) at small temporal scales due to sweepstake reproductive success, collective dispersal and/or self-recruitment. Remarkably, most of the genetic heterogeneity of juveniles found in this work was located in Galicia, which could represent an admixture between distinct metapopulations or an old refuge for the most northern populations. To conclude, high genetic variation in P. pollicipes can lead to the false impression of population panmixia at the Iberian scale by masking more restricted and current-driven larval exchanges between regions. This possibility should be taken into consideration for further specific management and conservation plans for the species over the Iberian Peninsula.

Patients who have recovered from Ebola virus can have ongoing health problems. Here, the authors show that 35 Guinean survivors of the last West African Ebola epidemic have a chronic disease with high inflammatory cytokine expression and other markers of immune activation as well as evidence of intestinal tissue damage nearly two years after their release from hospital.

Abstract Twenty years of genetic studies of marine invaders have shown that successful invaders are often characterized by native and introduced populations displaying similar levels of genetic diversity. This pattern is presumably due to high propagule pressure and repeated introductions. The opposite pattern is reported in this study of the brown seaweed, Sargassum muticum, an emblematic species for circumglobal invasions. Albeit demonstrating polymorphism in the native range, microsatellites failed to detect any genetic variation over 1,269 individuals sampled from 46 locations over the Pacific–Atlantic introduction range. Single‐nucleotide polymorphisms (SNPs) obtained from ddRAD sequencing revealed some genetic variation, but confirmed severe founder events in both the Pacific and Atlantic introduction ranges. Our study thus exemplifies the need for extreme caution in interpreting neutral genetic diversity as a proxy for invasive potential. Our results confirm a previously hypothesized transoceanic secondary introduction from NE Pacific to Europe. However, the SNP panel unexpectedly revealed two additional distinct genetic origins of introductions. Also, conversely to scenarios based on historical records, southern rather than northern NE Pacific populations could have seeded most of the European populations. Finally, the most recently introduced populations showed the lowest selfing rates, suggesting higher levels of recombination might be beneficial at the early stage of the introduction process (i.e., facilitating evolutionary novelties), whereas uniparental reproduction might be favored later in sustainably established populations (i.e., sustaining local adaptation).

Introduction: Access in France to early diagnosis and care for the most severe, but infrequent, Neurodevelopmental Disorders (NDD), autism spectrum disorder and global developmental delay, in children aged 0–7 was improved through measures implemented in 2019. However, there are no such measures for specific learning disorders (SLD), attention, motricity and language disorders (SLDD), despite their annual incidence of between 5 and 8%.Method: We describe the design of a new type of organization and financing of care for SLDD including evaluation procedure, as well as other factors, mainly at the prevention level that will contribute to local and national policy for this frequent health problem. This in response to a national call for projects, commonly called Article 51, targeted innovation in healthcare delivery and funding in the context of medium-term national reform. This provides project stakeholders with the opportunity to set up and implement “bottom-up” projects, mainly using local professionals. A joint initiative by the regional Health Authorities of the Occitanie region, the French Social Security system and a non-profit Association (Occitadys) proposed an experimental new structure of NDD care and funding.Discussion: We here discuss the design of this experiment that aims, over two to three years, to alleviate families' financial burden of care and establish a regional three-tier care system with respect to evaluation, re-education and rehabilitation care. Our approach may benefit SLDD health-care planning, and addresses the questions of prevention, early detection and care-design for families, taking local and socioeconomic disparities into account.

Background Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa. Methods and findings In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc. Conclusions The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU. Trial registration ClinicalTrials.govNCT02564523. Zacchaeus Anywaine and co-workers study safety and immunogenicity of an Ebola vaccine among children and adolescents across four African countries. Author summary Why was the study done? There have been larger and more extensive Ebola virus disease (EVD) outbreaks in Africa in the past decade with no licenced treatments available. As such, there is an unmet medical need for prophylactic Ebola vaccines. This study was performed to evaluate whether a 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination was safe and immunogenic in healthy African children. What did the researchers do and find? In this randomised, placebo-controlled, Phase II clinical trial, the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination regimen was administered to African participants in 2 age cohorts (12 to 17 and 4 to 11 years). No vaccine-related serious adverse events were reported, and robust immune responses were induced in both adolescents and children after receiving the active 2-dose regimen. What do these findings mean? These data support the use of the Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in African adolescents and children at risk of Ebola infection. Although vaccination according to a 28-day regimen may lead to protection against EVD in a shorter time frame, vaccination according to a 56-day regimen results in higher EBOV GP binding and neutralising antibody responses. The observation that Ad26 preexisting immunity in the majority of participants does not affect the EBOV GP-specific antibody responses postvaccination augurs well for the use of this vaccine regimen even in regions with a high prevalence of preexisting Ad26 seropositivity.

The linear polarization of thermal dust emission provides a powerful tool to probe interstellar and circumstellar magnetic fields, because aspherical grains tend to align themselves with magnetic field lines. While the Radiative Alignment Torque (RAT) mechanism provides a theoretical framework for this phenomenon, some aspects of this alignment mechanism still need to be quantitatively tested. One such aspect is the possibility that the reference alignment direction changes from the magnetic field (“ B -RAT”) to the radiation field k-vector (“ k -RAT”) in areas of strong radiation fields. We investigate this transition toward the Orion Bar PDR, using multiwavelength SOFIA HAWC+ dust polarization observations. The polarization angle maps show that the radiation field direction is on average not the preferred grain alignment axis. We constrain the grain sizes for which the transition from B -RAT to k -RAT occurs in the Orion Bar (grains ≥ 0.1 μ m toward the most irradiated locations), and explore the radiatively driven rotational disruption that may take place in the high-radiation environment of the Bar for large grains. While the grains susceptible to rotational disruption should be in suprathermal rotation and aligned with the magnetic field, k -RAT aligned grains would rotate at thermal velocities. We find that the grain size at which the alignment shifts from B -RAT to k -RAT corresponds to grains too large to survive the rotational disruption. Therefore, we expect a large fraction of grains to be aligned at suprathermal rotation with the magnetic field, and to potentially be subject to rotational disruption, depending on their tensile strength.

Extreme adaptive optics (XAO) has severe difficulties meeting the high speed (>1kHz), accuracy and photon efficiency requirements for future extremely large telescopes. An innovative high order adaptive optics system using a self-referenced Mach-Zehnder wavefront sensor (MZWFS) allows counteracting these limitations. In addition to its very high accuracy, this WFS is the most robust alternative to segments gaps and telescope spiders which can result in strong wavefront artifacts. In particular in XAO systems when the size of these gaps in the wavefront measurement is comparable to the sub aperture size, loss in performance can be very high. The MZWFS estimates the wavefront phase by measuring intensity differences between two outputs, with a λ/4 path length difference between its two legs, but is limited in dynamic range. During the past few years, such an XAO system has been studied by our team in the framework of 8-meter class telescopes. In this paper, we report on our latest results with the XAO testbed recently installed in CRAL laboratory, and dedicated to high contrast imaging with 30m-class telescopes (such as the E-ELT or the TMT). A woofer-tweeter architecture is used in order to deliver the required high Strehl ratio (>95%). It consists of a 12x12 deformable mirror (DM) and a 512x512 Spatial Light Modulator (SLM) characterized both using monochromatic and polychromatic light. We present our latest experimental results, including components characterization, close loop performances and sensitivity to calibration errors. This work is carried out in synergy with the validation of fast iterative wavefront reconstruction algorithms and the optimal treatment of phase ambiguities in order to mitigate the dynamical range limitation of such a wavefront sensor.

© 2015 The Authors.Clinical and population research on dementia and related neurologic conditions, including Alzheimer's disease, faces several unique methodological challenges. Progress to identify preventive and therapeutic strategies rests on valid and

The CCAAT-binding complex (CBC) is a conserved heterotrimeric transcription factor which, in fungi, requires additional regulatory subunits to act on transcription. In the pathogenic yeast Candida glabrata, CBC has a dual role. Together with the Hap4 regulatory subunit, it activates the expression of genes involved in respiration upon growth with non-fermentable carbon sources, while its association with the Yap5 regulatory subunit is required for the activation of iron tolerance genes in response to iron excess. In the present work, we investigated further the interplay between CBC, Hap4 and Yap5. We showed that Yap5 regulation requires a specific Yap Response Element in the promoter of its target gene GRX4 and that the presence of Yap5 considerably strengthens the binding of CBC to the promoters of iron tolerance genes. Chromatin immunoprecipitation (ChIP) and transcriptome experiments showed that Hap4 can also bind these promoters but has no impact on the expression of those genes when Yap5 is present. In the absence of Yap5 however, GRX4 is constitutively regulated by Hap4, similarly to the genes involved in respiration. Our results suggest that the distinction between the two types of CBC targets in C. glabrata is mainly due to the dependency of Yap5 for very specific DNA sequences and to the competition between Hap4 and Yap5 at the promoter of the iron tolerance genes.

Background: Learning disabilities (LDs) are a major public health issue, affecting cognitive functions and academic performance for 8% of children. If LDs are not detected early and addressed through appropriate interventions, they have a heavy impact on these children in the social, educational, and professional spheres, at great cost to society. The BMT-i (Batterie Modulable de Tests informatisée, or “computerized Adaptable Test Battery”) enables fast, easy, reliable assessments for each cognitive domain. It has previously been validated in children ages 4–13 who had no prior complaints. The present study demonstrates the sensitivity of the BMT-i, relative to reference test batteries, for 191 children with cognitive difficulties.Materials and Methods: These 191 subjects were included in the study by the 14 pediatricians treating them for complaints in five cognitive domains: written language [60 (cases)]; mathematical cognition (40); oral language (60); handwriting, drawing, and visuospatial construction (45); and attention and executive functioning (45). In accordance with a predefined protocol, the children were administered BMT-i tests first, by their pediatricians, and reference tests later, by specialists to whom the BMT-i test results were not disclosed. Comparison of BMT-i and reference test results made it possible to evaluate sensitivity and agreement between tests.Results: For each of the five domains, the BMT-i was very sensitive (0.91–1), and normal BMT-i results were highly predictive of normal results for specialized reference tests [negative likelihood ratio (LR–): 0–0.16]. There was close agreement between BMT-i and reference tests in all domains except attention and executive functioning, for which only moderate agreement was observed.Conclusion: The BMT-i offers rapid, reliable, simple computerized assessments whose sensitivity and agreement with reference test batteries make it a suitable first-line instrument for LD screening in children 4–13 years old.

Background We 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 findings In 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. Conclusions Ad26.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 registration ClinicalTrials.govNCT02564523 Houreratou Barry and co-workers report on safety and immunogenicity of an Ebola vaccine in adults across four African countries. Author summary Why was this study done? With Ebola outbreaks increasing, there is an unmet medical need for a prophylactic vaccine to prevent and mitigate Ebola outbreaks. To address the urgent medical need during the 2014 to 2016 outbreak, the clinical development of the 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo was accelerated. This Phase II study was part of this accelerated program, evaluating the safety and immunogenicity of the 2-dose vaccine regimen in healthy and HIV-infected African adults, with 28-, 56-, and 84-day intervals between doses. The study was amended to evaluate safety and immunogenicity of a booster vaccination with Ad26.ZEBOV, administered approximately 1 year after the first vaccination, in healthy adults. What did the researchers do and find? We conducted a randomised trial to assess the safety and the immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in 3 different vaccination intervals in healthy and HIV-infected adults. The vaccine regimen was well tolerated and induced marked immune responses; the highest humoral responses were observed after vaccination with 56-day and 84-day intervals. Anamnestic responses were observed in all healthy participants receiving Ad26.ZEBOV as booster at 1 year after the first dose. What do these findings mean? Our results demonstrate that the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen is safe and immunogenic in healthy and HIV-infected adults and induces immune memory that can rapidly be reactivated. Our findings support the prophylactic use of the 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against Ebola infection in African adult populations. The 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo has received marketing authorisation under exceptional circumstances for prophylactic use against EVD in adults and children ≥1 year old within the European Union.

Over the last few years, the development of micro-distilleries producing diverse spirits with various flavors has been observed. Versatile analytical techniques for the characterization of aroma compounds in such alcoholic beverages are therefore required. A model mixture embodying a theoretical distilled spirit was made according to the data found in literature to compare usual extraction techniques. When it was applied to the model liquor, the headspace solid phase microextraction (HS-SPME) extraction method was preferred to the liquid-liquid extraction (LLE), solid phase extraction (SPE) and stir bar/headspace sorptive extraction (SBSE/HSSE) methods according to efficiency, cost, and environmental criteria. An optimization study using the model mixture showed that the extraction was optimal with a divinylbenzene/carboxen/poly(dimethylsiloxane) DVB/CAR/PDMS fiber, during 60 min, at 35 °C and with the addition of 10% NaCl. This method was successfully applied to three different commercial liquors and led to the identification of 188 flavor compounds, including alcohols, esters, lactones, carbonyls, acetals, fatty acids, phenols, furans, aromatics, terpenoids, alkenes, and alkanes.

The aim of this paper is to describe a protocol that simulates the spinal surgery undergone by adolescents with idiopathic scoliosis (AIS) by using a 3D-printed spine model. Patients with AIS underwent pre- and postoperative bi-planar low-dose X-rays from which a numerical 3D model of their spine was generated. The preoperative numerical spine model was subsequently 3D printed to virtually reproduce the spine surgery. Special consideration was given to the printing materials for the 3D-printed elements in order to reflect the radiopaque and mechanical properties of typical bones most accurately. Two patients with AIS were recruited and operated. During the virtual surgery, both pre- and postoperative images of the 3D-printed spine model were acquired. The proposed 3D-printing workflow used to create a realistic 3D-printed spine suitable for virtual surgery appears to be feasible and reliable. This method could be used for virtual-reality scoliosis surgery training incorporating 3D-printed models, and to test surgical instruments and implants.