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Purpose An increasing number of anomia treatment studies have coupled traditional word retrieval accuracy outcome measures with more fine-grained analysis of word retrieval errors to allow for more comprehensive measurement of treatment-induced changes in word retrieval. The aim of this study was to examine changes in picture naming errors after phonomotor treatment. Method Twenty-eight individuals with aphasia received 60 hr of phonomotor treatment, an intensive, phoneme-based therapy for anomia. Confrontation naming was assessed pretreatment, immediately posttreatment, and 3 months posttreatment for trained and untrained nouns. Responses were scored for accuracy and coded for error type, and error proportions of each error type (e.g., semantic, phonological, omission) were compared: pre- versus posttreatment and pretreatment versus 3 months posttreatment. Results The group of treatment participants improved in whole-word naming accuracy on trained items and maintained their improvement. Treatment effects also generalized to untrained nouns at the maintenance testing phase. Additionally, participants demonstrated a decrease in proportions of omission and description errors on trained items immediately posttreatment. Conclusions Along with generalized improved whole-word naming accuracy, results of the error analysis suggest that a global (i.e., both lexical–semantic and phonological) change in lexical knowledge underlies the observed changes in confrontation naming accuracy following phonomotor treatment.

Mayaro (MAYV) is an emerging arthropod-borne virus belonging to the Alphavirus genus of the Togaviridae family. Although forest-dwelling Haemagogus mosquitoes have been considered as its main vector, the virus has also been detected in circulating Aedes ssp mosquitoes. Here we assess the susceptibility of Aedes aegypti and Aedes albopictus to infection with MAYV and their innate immune response at an early stage of infection. Aedes albopictus was more susceptible to infection with MAYV than Ae. aegypti. Analysis of transcript levels of twenty immunity-related genes by real-time PCR in the midgut of both mosquitoes infected with MAYV revealed increased expression of several immune genes, including CLIP-domain serine proteases, the anti-microbial peptides defensin A, E, cecropin E, and the virus inducible gene. The regulation of certain genes appeared to be Aedes species-dependent. Infection of Ae. aegypti with MAYV resulted in increased levels of myeloid differentiation2-related lipid recognition protein (ML26A) transcripts, as compared to Ae. albopictus. Increased expression levels of thio-ester-containing protein 22 (TEP22) and Niemann&ndash, Pick type C1 (NPC1) gene transcripts were observed in infected Ae. albopictus, but not Ae. aegypti. The differences in these gene expression levels during MAYV infection could explain the variation in susceptibility observed in both mosquito species.

The case-fatality rate of yellow fever virus (YFV) is one of the highest among arthropod-borne viruses (arboviruses). Although historically, the Asia-Pacific region has remained free of YFV, the risk of introduction has never been higher due to the increasing influx of people from endemic regions and the recent outbreaks in Africa and South America. Singapore is a global hub for trade and tourism and therefore at high risk for YFV introduction. Effective control of the main domestic mosquito vector Aedes aegypti in Singapore has failed to prevent re-emergence of dengue, chikungunya and Zika viruses in the last two decades, raising suspicions that peridomestic mosquito species untargeted by domestic vector control measures may contribute to arbovirus transmission. Here, we provide empirical evidence that the peridomestic mosquito Aedes malayensis found in Singapore can transmit YFV. Our laboratory mosquito colony recently derived from wild Ae. malayensis in Singapore was experimentally competent for YFV to a similar level as Ae. aegypti controls. In addition, we captured Ae. malayensis females in one human-baited trap during three days of collection, providing preliminary evidence that host-vector contact may occur in field conditions. Finally, we detected Ae. malayensis eggs in traps deployed in high-rise building areas of Singapore. We conclude that Ae. malayensis is a competent vector of YFV and re-emphasize that vector control methods should be extended to target peridomestic vector species., Author summary Yellow fever is a dreadful disease caused by a mosquito-borne virus circulating in Africa and South America. Historically, the Asia-Pacific region has remained free of yellow fever but the ever increasing influx of travelers puts places such as Singapore at unprecedented risk of yellow fever virus introduction. The present study characterized the potential contribution of a mosquito species called Aedes malayensis to yellow fever virus transmission in Singapore. Aedes malayensis breeds in urban parks of Singapore and is suspected to have participated in the resurgence of other mosquito-borne diseases such as dengue because it is not targeted by current mosquito control measures. Not only was Ae. malayensis able to experimentally acquire and transmit yellow fever virus, but it was also found to engage in contact with humans in a field situation. This empirical evidence indicates that Ae. malayensis is a competent vector of yellow fever virus and should be targeted by mosquito control programs.

International audience; Dengue fever is caused by dengue viruses (DENV) from the Flavivirus genus and is the most prevalent arboviral disease. DENV exists in four immunogenically distinct and genetically related serotypes (DENV-1 to 4), each subdivided in genotypes. Despite the endemic-ity of all four DENV serotypes in Thailand, no prior study has characterized the circulation of DENV in the southern provinces of the country. To determine the genetic diversity of DENV circulating in Southern Thailand in 2015 and 2016, we investigated 46 viruses from 182 patients' sera confirmed positive for DENV by serological and Nested RT-PCR tests. Our dataset included 2 DENV-1, 20 DENV-2, 9 DENV-3 and 15 DENV-4. Phylogenetic analysis was performed on viral envelop sequences. This revealed that part of the identified genotypes from DENV-1 and DENV-4 had been predominant in Asia (genotype I for both sero-types), while genotype II for DENV-4 and the Cosmopolitan genotype DENV-2 were also circulating. Whereas DENV-3 genotype II had been predominantly detected in South East Asia during the previous decades, we found genotype III and genotype I in Southern Thai-land. All DENV genotype identified in this study were closely related to contemporary strains circulating in Southeast Asian countries, emphasizing the regional circulation of DENV. These results provide new insights into the co-circulation of all four DENV serotypes in Southern Thailand, confirming the hyperendemicity of DENV in the region. These findings also suggest a new trend of dissemination for some DENV serotypes with a possible shift in genotype distribution; as recently observed in other Asian countries.

Malaria, a major cause of child mortality in Africa, is engendered by Plasmodium parasites that are transmitted by anopheline mosquitoes. Fitness of Plasmodium parasites is closely linked to the ecology and evolution of its anopheline vector. However, whether the genetic structure of vector populations impacts malaria transmission remains unknown. Here, we describe a partitioning of the African malaria vectors into generalists and specialists that evolve along ecological boundaries. We next identify the contribution of mosquito species to Plasmodium abundance using Granger causality tests for time-series data collected over two rainy seasons in Mali. We find that mosquito microevolution, defined by changes in the genetic structure of a population over short ecological timescales, drives Plasmodium dynamics in nature, whereas vector abundance, infection prevalence, temperature and rain have low predictive values. Our study demonstrates the power of time-series approaches in vector biology and highlights the importance of focusing local vector control strategies on mosquito species that drive malaria dynamics. A combination of genetic analyses of Anopheles species across sub-Saharan Africa, time-series quantification of Plasmodium falciparum prevalence in mosquitoes and Granger causality statistical testing reveals that changes in the genetic structure of a population over short ecological timescales drive Plasmodium dynamics in nature.

More than half of the world population is at risk of dengue virus (DENV) infection because of the global distribution of its mosquito vectors. DENV is an envelope virus that relies on host lipid membranes for its life-cycle. Here, we characterized how DENV hijacks the mosquito lipidome to identify targets for novel transmission-blocking interventions. To describe metabolic changes throughout the mosquito DENV cycle, we deployed a Liquid chromatography–high resolution mass spectrometry (LC-HRMS) workflow including spectral similarity annotation in cells, midguts and whole mosquitoes at different times post infection. We revealed a major aminophospholipid reconfiguration with an overall early increase, followed by a reduction later in the cycle. We phylogenetically characterized acylglycerolphosphate acyltransferase (AGPAT) enzyme isoforms to identify those that catalyze a rate-limiting step in phospholipid biogenesis, the acylation of lysophosphatidate to phosphatidate. We showed that DENV infection decreased AGPAT1, but did not alter AGPAT2 expression in cells, midguts and mosquitoes. Depletion of either AGPAT1 or AGPAT2 increased aminophospholipids and partially recapitulated DENV-induced reconfiguration before infection in vitro. However, only AGPAT1 depletion promoted infection by maintaining high aminophospholipid concentrations. In mosquitoes, AGPAT1 depletion also partially recapitulated DENV-induced aminophospholipid increase before infection and enhanced infection by maintaining high aminophospholipid concentrations. These results indicate that DENV inhibition of AGPAT1 expression promotes infection by increasing aminophospholipids, as observed in the mosquito’s early DENV cycle. Furthermore, in AGPAT1-depleted mosquitoes, we showed that enhanced infection was associated with increased consumption/redirection of aminophospholipids. Our study suggests that DENV regulates aminophospholipids, especially phosphatidylcholine and phosphatidylethanolamine, by inhibiting AGPAT1 expression to increase aminophospholipid availability for virus multiplication., Author summary Dengue is endemic in tropical and subtropical regions, and has now encroached onto temperate regions because of the geographic expansion of its vector, Aedes aegypti. In the absence of effective vaccine and curative drug, the sole intervention relies on containment strategies using insecticide. However, occurrence of insecticide resistance diminishes vector control efficacy. Here, we explore the nascent field of mosquito metabolomics as part of our discovery effort for new transmission-blocking targets. Dengue virus (DENV) relies on host metabolome, specifically the lipid membrane to complete its life-cycle. However, little is known about how DENV subverts the mosquito physiology. Using high-resolution mass spectrometry, we described metabolic changes incurred by DENV throughout the mosquito cycle, from cellular replication onset to systemic infection. Membrane phospholipids were highly reconfigured and were associated with reduced expression of AGPAT1, an enzyme involved in their biogenesis. AGPAT1 depletion partially recapitulated DENV-induced metabolic reconfiguration and enhanced infection by maintaining high phospholipid concentrations. These phospholipids were then consumed/redirected later in the mosquito DENV cycle. Our work comprehensively describes metabolic changes associated with DENV infection. In addition, we reveal how DENV subdues the lipidome for its benefit by demonstrating the role of phospholipids in mosquito infection.

BACKGROUND: Aphasia is an acquired language disorder that makes it difficult for people to produce and comprehend language, with every person with aphasia (PWA) demonstrating difficulty accessing and selecting words (anomia). While aphasia treatments typically focus on a single aspect of language, such as word retrieval, the ultimate goal of aphasia therapy is to improve communication, which is best seen at the level of discourse. AIMS: This retrospective study investigated the effects of one effective anomia therapy, Phonomotor Treatment, on discourse production. METHODS & PROCEDURES: Twenty-six PWA participated in 60 hours of Phonomotor Treatment, which focuses on building a person’s ability to recognise, produce, and manipulate phonemes in progressively longer non-word and real-word contexts. Language samples were collected prior to, immediately after, and three months after the treatment program. Percent Correct Information Units (CIUs) and CIUs per minute were calculated. OUTCOMES & RESULTS: Overall, PWA showed significantly improved CIUs per minute, relative to baseline, immediately after treatment and three months later, as well as significantly improved percent CIUs, relative to baseline, three months following treatment. CONCLUSIONS: Phonomotor Treatment, which focuses on phonological processing, can lead to widespread improvement throughout the language system, including to the functionally critical level of discourse production.

The case-fatality rate of yellow fever virus (YFV) is one of the highest among arthropod-borne viruses (arboviruses). Although historically, the Asia-Pacific region has remained free of YFV, the risk of introduction has never been higher due to the increasing influx of people from endemic regions and the recent outbreaks in Africa and South America. Singapore is a global hub for trade and tourism and therefore at high risk for YFV introduction. Effective control of the main domestic mosquito vector Aedes aegypti in Singapore has failed to prevent re-emergence of dengue, chikungunya and Zika viruses in the last two decades, raising suspicions that peridomestic mosquito species untargeted by domestic vector control measures may contribute to arbovirus transmission. Here, we provide empirical evidence that the peridomestic mosquito Aedes malayensis found in Singapore can transmit YFV. Our laboratory mosquito colony recently derived from wild Ae. malayensis in Singapore was experimentally competent for YFV to a similar level as Ae. aegypti controls. In addition, we captured Ae. malayensis females in one human-baited trap during three days of collection, providing preliminary evidence that host-vector contact may occur in field conditions. Finally, we detected Ae. malayensis eggs in traps deployed in high-rise building areas of Singapore. We conclude that Ae. malayensis is a competent vector of YFV and re-emphasize that vector control methods should be extended to target peridomestic vector species.

The MYRRHA project aims at coupling a cw 600 MeV, 4 mA proton linac with a sub-critical reactor as the very first prototype nuclear reactor to be driven by a particle accelerator (ADS). Among several applications, MYRRHA main objective is to demonstrate the principle of partitioning and transmutation (P&T) as a viable solution to drastically reduce the radiotoxicity of long-life nuclear waste. For this purpose, the linac needs an unprecedented level of reliability in terms of allowable beam trips. The normal conducting injector delivers 16.6 MeV protons to the superconducting main linac. The first section of the injector (up to 5.9 MeV) consists of an ECR source, a 4-Rod-RFQ and a rebunching line followed by 7 individual CH-type cavities. This entire section will be set up and operated by SCK·CEN in Louvain-la-Neuve, Belgium, for ample performance and reliability testing. The first CH cavity has been sent for power tests to IAP Frankfurt, Germany. The most recent status of all cavities, couplers and the beam diagnostics of the MYRRHA injector is presented in this paper.

Mayaro (MAYV) is an emerging arthropod-borne virus belonging to the Alphavirus genus of the Togaviridae family. Although forest-dwelling Haemagogus mosquitoes have been considered as its main vector, the virus has also been detected in circulating Aedes ssp mosquitoes. Here we assess the susceptibility of Aedes aegypti and Aedes albopictus to infection with MAYV and their innate immune response at an early stage of infection. Aedes albopictus was more susceptible to infection with MAYV than Ae. aegypti. Analysis of transcript levels of twenty immunity-related genes by real-time PCR in the midgut of both mosquitoes infected with MAYV revealed increased expression of several immune genes, including CLIP-domain serine proteases, the anti-microbial peptides defensin A, E, cecropin E, and the virus inducible gene. The regulation of certain genes appeared to be Aedes species-dependent. Infection of Ae. aegypti with MAYV resulted in increased levels of myeloid differentiation2-related lipid recognition protein (ML26A) transcripts, as compared to Ae. albopictus. Increased expression levels of thio-ester-containing protein 22 (TEP22) and Niemann-Pick type C1 (NPC1) gene transcripts were observed in infected Ae. albopictus, but not Ae. aegypti. The differences in these gene expression levels during MAYV infection could explain the variation in susceptibility observed in both mosquito species.

Deciphering the impact of dengue pathogenesis on vector transmission is critical for understanding virulence evolution, epidemiology and developing transmission-blocking tools. Dengue infection can alter blood coagulation and fibrinolysis pathways, resulting in severe hemorrhage and death. Here, we demonstrate that when plasmin, the human fibrinolytic factor, is added to blood meal, it enhances DENV infection in mosquito midgut, resulting in higher dissemination in mosquitoes. In addition, the mosquito midgut-expressed AaTI, a plasmin-selective mosquito Kazal-type inhibitor, reverted this enhanced infection by inhibiting plasmin proteolysis in the midgut lumen. Using bio-layer interferometry, we showed that DENV, plasmin and AaTI interact to form a tripartite complex. Eventually, plasmin supplementation in infectious blood meal increased midgut internalization of dextran molecules and this was reverted by AaTI. Our study demonstrates that: (a) DENV recruits plasmin to increase local proteolytic activity in the midgut, thus degrading the glyocalyx and enhancing DENV infection onset, and (b) AaTI can act as a transmission-blocking agent by inhibiting plasmin proteolysis. Our results indicate that dengue pathogenesis enhances DENV fitness by increasing its infectivity to mosquitoes.

The MYRRHA Project (Multi-purpose hYbrid Research Reactor for High-tech Applications) in Mol, Belgium, is an upcoming accelerator driven system (ADS) for the transmutation of long-living radioactive waste. In the injector section of the accelerator, consisting of a 4-rod RFQ and a normal conducting CH-cavity section, the protons will be accelerated up to 17 MeV before entering the superconducting gap-spoke cavity section with an output energy of 600 MeV. A shortened test-injector with an output energy of 5.9 MeV is currently being installed at the SCK. CEN in Louvein-la- Neuve, Belgium. This test-injector serves the purpose of testing the reliability of the planned injector. When commissioning a cavity, it first has to be fed very little power to avoid damage to the structure by flashovers, discharges and multipacting. The power is then slowly increased up to full operation level. In this process, the surfaces are cleaned by heating/outgasing so that the effects disturbing operation described above do no longer occur. This paper will report on the status of the conditioning of the 176.1 MHz 4-rod RFQ up to 120 kW of the MYRRHA-injector and additional measurements concerning the gap voltage which are currently being performed at the SCK. CEN., Proceedings of the 10th Int. Particle Accelerator Conf., IPAC2019, Melbourne, Australia

Quaking (QKI) is an RNA-binding protein (RBP) involved in multiple aspects of RNA metabolism and many biological processes. Despite a known immune function in regulating monocyte differentiation and inflammatory responses, the degree to which QKI regulates the host interferon (IFN) response remains poorly characterized. Here we show that QKI ablation enhances poly(I:C) and viral infection-induced IFN beta transcription. Characterization of IFN-related signalling cascades reveals that QKI knockout results in higher levels of IRF3 phosphorylation. Interestingly, complementation with QKI-5 isoform alone is sufficient to rescue this phenotype and reduce IRF3 phosphorylation. Further analysis shows that MAVS, but not RIG-I or MDA5, is robustly upregulated in the absence of QKI, suggesting that QKI downregulates MAVS and thus represses the host IFN response. As expected, MAVS depletion reduces IFN beta activation and knockout of MAVS in the QKI knockout cells completely abolishes IFN beta induction. Consistently, ectopic expression of RIG-I activates stronger IFN beta induction via MAVS-IRF3 pathway in the absence of QKI. Collectively, these findings demonstrate a novel role for QKI in negatively regulating host IFN response by reducing MAVS levels.

Proceedings of the North American Particle Accelerator Conference, NAPAC2019, Lansing, MI, USA North American Particle Accelerator Conference, NAPAC2019, Michigan, USA, 2 Sep 2019 - 6 Sep 2019; JACoW Publishing, Geneva, Switzerland 6 pages (2019). doi:10.18429/JACOW-NAPAC2019-THZBA2, The main objective of the MYRRHA project at SCK•CEN, the Belgian Nuclear Research Centre, is to demonstrate the feasibility of nuclear waste transmutation using an Accelerator Driven System (ADS). It is based on a High Power CW operated 600 MeV proton Linac with an average beam power of 2.4 MW. Due to the coupling of the accelerator with a subcritical reactor, a major concern is reliability and availability of the accelerator. The MYRRHA Linac consists of a room temperature 17 MeV Injector based on CH-cavities and the superconducting main Linac using different RF structures as Single Spokes, Double-Spokes and elliptical cavities. In 2017, it has been decided to stage the project and to start with the construction of a 100 MeV Linac (Injector and Single Spoke section) including a 400 kW proton target station. This facility (MINERVA) will be operational in 2026 aiming to evaluate the reliability potential of the 600 MeV Linac. The Front-End consisting of an ECR source, LEBT and 1.5 MeV RFQ is already operational while the first 7 CH-cavities are under construction. The presentation gives an overview about the MYRRHA Project, its challenges and the status of construction and testing., Published by JACoW Publishing, Geneva, Switzerland

International audience; Very recently, Zika virus (ZIKV) has gained a medical importance following the large-scale epidemics in South Pacific and Latin America.This paper reviews information on the epidemiology and clinical features of Zika disease with a particular emphasis on the host-virus in-teractions that contribute to the pathogenicity of ZIKV in humans

International audience; Quantitative structure-activity relationships may bring invaluable information on structural elements of both enzymes and substrates that, together, govern substrate specificity. Buried active sites in cytochrome P450 enzymes are connected to the solvent by a network of channels exiting at the distal surface of the protein. This review presents different in silico tools that were developed to uncover such channels in P450 crystal structures. It also lists some of the experimental evidence that actually suggest that these predicted channels might indeed play a critical role in modulating P450 functions. Amino acid residues at the entrance of the channels may participate to a first global ligand recognition of ligands by P450 enzymes before they reach the buried active site. Moreover, different P450 enzymes show different networks of predicted channels. The plasticity of P450 structures is also important to take into account when looking at how channels might play their role.

Purpose Chronic stress is likely a common experience among people with the language impairment of aphasia. Importantly, chronic stress reportedly alters the neural networks central to learning and memory—essential ingredients of aphasia rehabilitation. Before we can explore the influence of chronic stress on rehabilitation outcomes, we must be able to measure chronic stress in this population. The purpose of this study was to (a) modify a widely used measure of chronic stress (Perceived Stress Scale [PSS]; Cohen & Janicki-Deverts, 2012) to fit the communication needs of people with aphasia (PWA) and (b) validate the modified PSS (mPSS) with PWA. Method Following systematic modification of the PSS (with permission), 72 PWA completed the validation portion of the study. Each participant completed the mPSS, measures of depression, anxiety, and resilience, and provided a sample of the stress hormone cortisol extracted from the hair. Pearson's product–moment correlations were used to examine associations between mPSS scores and these measures. Approximately 30% of participants completed the mPSS 1 week later to establish test–retest reliability, analyzed using an interclass correlation coefficient. Results Significant positive correlations were evident between the reports of chronic stress and depression and anxiety. In addition, a significant inverse correlation was found between reports of chronic stress and resilience. The mPSS also showed evidence of test–retest reliability. No association was found between mPSS score and cortisol level. Conclusion Although questions remain about the biological correlates of chronic stress in people with poststroke aphasia, significant associations between chronic stress and several psychosocial variables provide evidence of validity of this emerging measure of chronic stress.

International audience; The MYRRHA project borne by SCK•CEN, the Belgian Nuclear Research Centre, aims at realizing a pre-industrial Accelerator Driven System (ADS) for exploring the transmutation of long lived nuclear waste. The linac for this ADS will be a High Power Proton Accelerator delivering 2.4 MW CW beam at 600 MeV. It has to satisfy stringent requirements for reliability and availability: a beam-MTBF of 250h is targeted. The reliability goal is pursued through a phased approach. During Phase 1, expected till 2024, the MYRRHA linac up to 100 MeV will be constructed. It will allow to evaluate the reliability potential of the 600 MeV linac. It will also feed a Proton Target Facility in which radioisotopes of interest will be collected through an ISOL system. This contribution will focus on the transition to integrated prototyping, which will emphasize (i) a test platform consisting of the initial section of the normal conducting injector (5.9 MeV), (ii) the realization of a complete cryomodule for the superconducting linac and of its cryogenic valve box. The cryomodule will house two 352 MHz single spoke cavities operated at 2K.

International audience; Flaviviruses, such as dengue, Japanese encephalitis, tick-borne encephalitis, West Nile, yellow fever, and Zika viruses, are critically important human pathogens that sicken a staggeringly high number of humans every year. Most of these pathogens are transmitted by mosquitos, and not surprisingly, as the earth warms and human populations grow and move, their geographic reach is increasing. Flaviviruses are simple RNA–protein machines that carry out protein synthesis, genome replication, and virion packaging in close association with cellular lipid membranes. In this review, we examine the molecular biology of flaviviruses touching on the structure and function of viral components and how these interact with host factors. The latter are functionally divided into pro-viral and antiviral factors, both of which, not surprisingly, include many RNA binding proteins. In the interface between the virus and the hosts we highlight the role of a noncoding RNA produced by flaviviruses to impair antiviral host immune responses. Throughout the review, we highlight areas of intense investigation, or a need for it, and potential targets and tools to consider in the important battle against pathogenic flaviviruses.

Dengue viruses cause severe and sudden human epidemics worldwide. The secreted form of the nonstructural protein 1 (sNS1) of dengue virus causes vascular leakage, a hallmark of severe dengue disease. Here, we reverse engineered the T164S mutation of NS1, associated with the severity of dengue epidemics in the Americas, into a dengue virus serotype 2 mildly infectious strain. The T164S mutant virus decreased infectious virus production and increased sNS1 production in mammalian cell lines and human peripheral blood mononuclear cells (PBMCs) without affecting viral RNA replication. Gene expression profiling of 268 inflammation-associated human genes revealed up-regulation of genes induced in response to vascular leakage. Infection of the mosquito vector Aedes aegypti with the T164S mutant virus resulted in increased viral load in the mosquito midgut and higher sNS1 production compared to wild-type virus infection. Infection of type 1 and 2 interferon receptor-deficient AG129 mice with the T164S mutant virus resulted in severe disease coupled with increased complement activation, tissue inflammation, and more rapid mortality compared to AG129 mice infected with wild-type virus. Molecular dynamics simulations predicted that mutant sNS1 formed stable dimers similar to the wild-type protein, whereas the hexameric mutant sNS1 was predicted to be unstable. Immunoaffinity-purified sNS1 from T164S mutant virus-infected mammalian cells was associated with different lipid classes compared to wild-type sNS1. Treatment of human PBMCs with sNS1 purified from T164S mutant virus resulted in a twofold higher production of proinflammatory cytokines, suggesting a mechanism for how mutant sNS1 may cause more severe dengue disease.

International audience; 11 Application of droplet-based microfluidics for the screening of microbial libraries is one of the 12 important ongoing development in functional genomics/metagenomics. In this article, we propose a 13 new method that can be employed for the high-throughput profiling of cell growth. It consists in light-14 driven labelling droplets that contain growing cells directly in microfluidics observation chamber, 15 followed by recovery of the labelled cells. This method is based on intracellular expression of green to 16 red switchable fluorescent proteins. The proof of concept is established here for two commonly used 17 biological models, E.coli and S.cerevisiae. Growth of cells in droplets was monitored under a 18 microscope and, depending on the targeted phenotype, the fluorescence of selected droplets was 19 switched from a "green" to a "red" state. Red fluorescent cells from labelled droplets were then 20 successfully detected, sorted with the Fluorescence Activated Cell Sorting machine and recovered. 21 Finally, the application of this method for different kind of screenings, in particular of metagenomic 22 libraries, is discussed and this idea is validated by the analysis of a model mini-library. 23

OBJECTIVE: The purpose of this study was to examine the unique contribution of psychosocial factors including perceived social support, depression, and resilience to communicative participation in adult survivors of head and neck cancer (HNC). STUDY DESIGN: Cross-sectional SETTING: University-based laboratory and speech clinic SUBJECTS AND METHODS: Adult survivors of HNC who were at least 2 years posttreatment for HNC completed patient-reported outcome measures including those related to communicative participation and psychosocial function. Multiple linear regression analysis was conducted to predict communicative participation. Self-rated speech severity, cognitive function, laryngectomy status, and time since diagnosis were entered first as a block of variables (block 1), and psychosocial factors were entered second (block 2). RESULTS: 88 adults who were on average 12.2 years post HNC diagnosis participated. The final regression model predicted 58.2% of the variance in communicative participation (full model R(2) = 0.58, P < .001). Self-rated speech severity, cognitive function, laryngectomy status, and time since diagnosis together significantly predicted 46.1% of the variance in block 1. Perceived social support, depression, resilience and interactions significantly and uniquely predicted 12.1% of the additional variance in block 2. CONCLUSION: Psychosocial factors such as perceived depression warrant consideration when counseling HNC patients about communication outcomes and when designing future studies related to rehabilitation.

Flaviviruses, such as dengue, Japanese encephalitis, tick-borne encephalitis, West Nile, yellow fever, and Zika viruses, are critically important human pathogens that sicken a staggeringly high number of humans every year. Most of these pathogens are transmitted by mosquitos, and not surprisingly, as the earth warms and human populations grow and move, their geographic reach is increasing. Flaviviruses are simple RNA-protein machines that carry out protein synthesis, genome replication, and virion packaging in close association with cellular lipid membranes. In this review, we examine the molecular biology of flaviviruses touching on the structure and function of viral components and how these interact with host factors. The latter are functionally divided into pro-viral and antiviral factors, both of which, not surprisingly, include many RNA binding proteins. In the interface between the virus and the hosts we highlight the role of a noncoding RNA produced by flaviviruses to impair antiviral host immune responses. Throughout the review, we highlight areas of intense investigation, or a need for it, and potential targets and tools to consider in the important battle against pathogenic flaviviruses.

The four dengue viruses (DENV1-4) are rapidly reemerging infectious RNA viruses. These positive-strand viral genomes contain structured 3' untranslated regions (UTRs) that interact with various host RNA binding proteins (RBPs). These RBPs are functionally important in viral replication, pathogenesis, and defense against host immune mechanisms. Here, we combined RNA chromatography and quantitative mass spectrometry to identify proteins interacting with DENV1-4 3' UTRs. As expected, RBPs displayed distinct binding specificity. Among them, we focused on quaking (QKI) because of its preference for the DENV4 3' UTR (DENV-4/SG/06K2270DK1/2005). RNA immunoprecipitation experiments demonstrated that QKI interacted with DENV4 genomes in infected cells. Moreover, QKI depletion enhanced infectious particle production of DENV4. On the contrary, QKI did not interact with DENV2 3' UTR, and DENV2 replication was not affected consistently by QKI depletion. Next, we mapped the QKI interaction site and identified a QKI response element (QRE) in DENV4 3' UTR. Interestingly, removal of QRE from DENV4 3' UTR abolished this interaction and increased DENV4 viral particle production. Introduction of the QRE to DENV2 3' UTR led to QKI binding and reduced DENV2 infectious particle production. Finally, reporter assays suggest that QKI reduced translation efficiency of viral RNA. Our work describes a novel function of QKI in restricting viral replication.

Zika virus (ZIKV) is a flavivirus that can cause congenital disease and requires development of an effective long-term preventative strategy. A replicative ZIKV vaccine with properties similar to the yellow fever 17D (YF17D) live-attenuated vaccine (LAV) would be advantageous, as a single dose of YF17D produces lifelong immunity. However, a replicative ZIKV vaccine must also be safe from causing persistent organ infections. Here we report an approach to ZIKV LAV development. We identify a ZIKV variant that produces small plaques due to interferon (IFN)-restricted viral propagation and displays attenuated infection of endothelial cells. We show that these properties collectively reduce the risk of organ infections and vertical transmission in a mouse model but remain sufficiently immunogenic to prevent wild-type ZIKV infection. Our findings suggest a strategy for the development of a safe but efficacious ZIKV LAV.

International audience; Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family. Although infection with ZIKV generally leads to mild disease, its recent emergence in the Americas has been associated with an increase in the development of the Guillain-Barré syndrome in adults, as well as with neurological complications, in particular congenital microcephaly, in new-borns. To date, little information is available on neuroinflammation induced by ZIKV, notably in micro-glial cells in the context of their metabolic activity, a series of chemical transformations that are essential for their growth, reproduction, structural maintenance and environmental responses. Therefore, in the present study we investigated the metabolomic profile of ZIKV-infected microglia. Microglial cells were exposed to ZIKV at different time points and were analyzed by a Liquid Chromatography-High Resolution mass spectrometry-based metabo-lomic approach. The results show that ZIKV infection in microglia leads to modulation of the expression of numerous metabolites, including lysophospholipids, particulary Lysophospha-tidylcholine, and phospholipids such as Phosphatidylcholine, Phosphatidylserine, Ceramide and Sphingomyelin, and carboxylicic acids as Undecanedioic and Dodecanedioic acid. Some of these metabolites are involved in neuronal differentiation, regulation of apoptosis, virion architecture and viral replication. ZIKV infection was associated with concomitant secretion of inflammatory mediators linked with central nervous system inflammation such as IL-6, TNF-α, IL-1β, iNOS and NO. It also resulted in the upregulation of the expression of the gene encoding CX3CR1, a chemokine receptor known to regulate functional synapse plasticity and signaling between microglial cells. These findings highlight an important role for microglia and their metabolites in the process of neuroinflammation that occurs during ZIKV pathogenesis.

The MYRRHA project aims at coupling a cw 600 MeV, 4 mA proton linac with a sub-critical reactor as the very first prototype nuclear reactor to be driven by a particle accelerator (ADS). Among several applications, MYRRHA main objective is to demonstrate the principle of partitioning and transmutation (P&T) as a viable solution to drastically reduce the radiotoxicity of long-life nuclear waste. For this purpose, the linac needs an unprecedented level of reliability in terms of allowable beam trips. The normal conducting injector delivers 16.6 MeV protons to the superconducting main linac. The first section of the injector (up to 5.9 MeV) consists of an ECR source, a 4-Rod-RFQ and a rebunching line followed by 7 individual CH-type cavities. This entire section will be set up and operated by SCK·CEN in Louvain-la-Neuve, Belgium, for ample performance and reliability testing. The first CH cavity has been sent for power tests to IAP Frankfurt, Germany. The most recent status of all cavities, couplers and the beam diagnostics of the MYRRHA injector is presented in this paper., Proceedings of the 9th Int. Particle Accelerator Conf., IPAC2018, Vancouver, BC, Canada