131 research outputs found
Recommended from our members
Development of Vitrification Process and Glass Formulation for Nuclear Waste Conditioning
The vitrification of high-level waste is the internationally recognized standard to minimize the impact to the environment resulting from waste disposal as well as to minimize the volume of conditioned waste to be disposed of. COGEMA has been vitrifying high-level waste industrially for over 20 years and is currently operating three commercial vitrification facilities based on a hot metal crucible technology, with outstanding records of safety, reliability and product quality. To further increase the performance of vitrification facilities, CEA and COGEMA have been developing the cold crucible melter technology since the beginning of the 1980s. This type of melter is characterized by a virtually unlimited equipment service life and a great flexibility in dealing with various types of waste and allowing development of high temperature matrices. In complement of and in parallel with the vitrification process, a glass formulation methodology has been developed by the CEA in order to tailor matrices for the wastes to be conditioned while providing the best adaptation to the processing technology. The development of a glass formulation is a trade-off between material properties and qualities, technical feasibility, and disposal safety criteria. It involves non-radioactive and radioactive laboratories in order to achieve a comprehensive matrix qualification. Several glasses and glass ceramics have thus been studied by the CEA to be compliant with industrial needs and waste characteristics: glasses or other matrices for a large spectrum of fission products, or for high contents of specifics elements such as sodium, phosphate, iron, molybdenum, or actinides. New glasses or glass-ceramics designed to minimize the final wasteform volume for solutions produced during the reprocessing of high burnup fuels or to treat legacy wastes are now under development and take benefit from the latest CEA hot-laboratories and technology development. The paper presents the CEA state-of-the-art in developing matrices or glasses and provides several examples
DNA-PK Is Targeted by Multiple Vaccinia Virus Proteins to Inhibit DNA Sensing
Virus infection is sensed by pattern recognition receptors (PRRs) detecting virus nucleic acids and initiating an innate immune response. DNA-dependent protein kinase (DNA-PK) is a PRR that binds cytosolic DNA and is antagonized by vaccinia virus (VACV) protein C16. Here, VACV protein C4 is also shown to antagonize DNA-PK by binding to Ku and blocking Ku binding to DNA, leading to a reduced production of cytokines and chemokines in vivo and a diminished recruitment of inflammatory cells. C4 and C16 share redundancy in that a double deletion virus has reduced virulence not seen with single deletion viruses following intradermal infection. However, non-redundant functions exist because both single deletion viruses display attenuated virulence compared to wild-type VACV after intranasal infection. It is notable that VACV expresses two proteins to antagonize DNA-PK, but it is not known to target other DNA sensors, emphasizing the importance of this PRR in the response to infection in vivo
More rapid blood interferon α2 decline in fatal versus surviving COVID-19 patients
BackgroundThe clinical outcome of COVID-19 pneumonia is highly variable. Few biological predictive factors have been identified. Genetic and immunological studies suggest that type 1 interferons (IFN) are essential to control SARS-CoV-2 infection.ObjectiveTo study the link between change in blood IFN-α2 level and plasma SARS-Cov2 viral load over time and subsequent death in patients with severe and critical COVID-19.MethodsOne hundred and forty patients from the CORIMUNO-19 cohort hospitalized with severe or critical COVID-19 pneumonia, all requiring oxygen or ventilation, were prospectively studied. Blood IFN-α2 was evaluated using the Single Molecule Array technology. Anti-IFN-α2 auto-Abs were determined with a reporter luciferase activity. Plasma SARS-Cov2 viral load was measured using droplet digital PCR targeting the Nucleocapsid gene of the SARS-CoV-2 positive-strand RNA genome.ResultsAlthough the percentage of plasmacytoid dendritic cells was low, the blood IFN-α2 level was higher in patients than in healthy controls and was correlated to SARS-CoV-2 plasma viral load at entry. Neutralizing anti-IFN-α2 auto-antibodies were detected in 5% of patients, associated with a lower baseline level of blood IFN-α2. A longitudinal analysis found that a more rapid decline of blood IFN-α2 was observed in fatal versus surviving patients: mortality HR=3.15 (95% CI 1.14â8.66) in rapid versus slow decliners. Likewise, a high level of plasma SARS-CoV-2 RNA was associated with death risk in patients with severe COVID-19.ConclusionThese findings could suggest an interest in evaluating type 1 IFN treatment in patients with severe COVID-19 and type 1 IFN decline, eventually combined with anti-inflammatory drugs.Clinical trial registrationhttps://clinicaltrials.gov, identifiers NCT04324073, NCT04331808, NCT04341584
Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies
Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 lineages has led to the
emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariants
BA.2.75.2 and BQ.1.1 are expected to become predominant in many countries in November 2022. They
carry an additional and often redundant set of mutations in the spike, likely responsible for increased
transmissibility and immune evasion. Here, we established a viral amplification procedure to easily
isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs)
and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5
breakthrough infection. Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and
Tixagevimab) lost any antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab)
remained weakly active. BQ.1.1 was also resistant to Bebtelovimab. Neutralizing titers in triply
vaccinated individuals were low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after
boosting. A BA.1/BA.2 breakthrough infection increased these titers, which remained about 18-fold
lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infection
increased more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the
evolution trajectory of novel Omicron subvariants facilitated their spread in immunized populations
and raises concerns about the efficacy of most currently available mAbs.N
Comparaison des propriĂ©tĂ©s antiapoptotiques de quatre protĂ©ines du virus de la vaccine en isolement et au cours de lâinfection virale.
Apoptosis, which occurs following activation of effector caspases, can restrict the replication of intracellular pathogens, especially viruses. Vaccinia virus (VACV) is a large dsDNA virus encoding approximately 200 proteins, several of which inhibit apoptosis. This redundancy of viral anti-apoptotic proteins complicates the study of these proteins in the context of viral infection. Here a comparative study of the anti-apoptotic proteins B13, F1, GAAP and N1 with and without virus infection is presented. Firstly, using lentiviral constructs, we generated transduced cell lines expressing the anti-apoptotic proteins in isolation and we analysed their ability to protect against extrinsic and intrinsic apoptosis induced by different drugs. In that context B13 was the most potent inhibitor of intrinsic apoptosis and the only protein to inhibit both extrinsic and intrinsic apoptosis. We then used a deficient VACV strain, vv811, that lacks the genes coding for the four anti-apoptotic proteins. Infection with vv811 can induce apoptosis without the need for any other stimulus. After vv811 infection of cell lines expressing the anti-apoptotic proteins in trans, B13 and to a lesser extent F1, inhibited apoptosis. Finally, we introduced each gene separately into vv811 by genetic recombination. Using these recombinant viruses to induce apoptosis, B13 and F1 were very potent inhibitors. The protection conferred by GAAP was cell type dependant and N1 failed to protect any of the tested cells from the virus induced apoptosis. Using these different approaches, we have been able to overcome the redundancy issue to compare 4 anti-apoptotic proteins from VACV, including in the context of viral infection. The results illustrate that vv811 is a useful tool to determine the role of VACV anti-apoptotic proteins during infection and that whilst all of these proteins have some anti-apoptotic activity, B13 is most potent.Lâapoptose, mort cellulaire observĂ©e suite Ă lâactivation des caspases effectrices, est un moyen de dĂ©fense contre les pathogĂšnes, en particulier les virus. Le virus de la vaccine (VACV) est un virus contenant un grand gĂ©nome Ă ADN codant pour environ 200 protĂ©ines, dont plusieurs inhibent lâapoptose. Cette apparente redondance fonctionnelle complique lâĂ©tude des protĂ©ines antiapoptotiques du virus dans un contexte dâinfection virale. Dans ce travail, nous comparerons les propriĂ©tĂ©s antiapoptotiques des protĂ©ines B13, F1, GAAP et N1 de VACV. Cette comparaison sera Ă©tablie dans un premier temps en dehors de toute infection virale. En utilisant des vecteurs lentiviraux, nous avons obtenu des lignĂ©es cellulaires stables (U2-OS) exprimant ces protĂ©ines en isolation. Nous avons alors pu tester les capacitĂ©s antiapoptotiques de ces protĂ©ines en rĂ©ponse Ă des stimuli provoquant lâapoptose extrinsĂšque et intrinsĂšque. Les rĂ©sultats ont montrĂ© que B13 Ă©tait la plus puissante molĂ©cule inhibitrice de lâapoptose intrinsĂšque et quâelle Ă©tait la seule Ă inhiber lâapoptose extrinsĂšque. Ensuite nous avons tirĂ© avantage dâun virus de la vaccine dĂ©ficient (vv811) qui ne possĂšde aucune de ces protĂ©ines antiapoptotiques, capable Ă lui seul dâinduire lâapoptose, en lâabsence de toute autre stimulus. En infectant nos lignĂ©es cellulaires exprimant les molĂ©cules in trans avec vv811, nous avons pu montrer que B13 inhibait cette apoptose induite par le virus beaucoup plus efficacement que F1. GAAP et N1 dans ce contexte nâont pas dĂ©montrĂ© de propriĂ©tĂ©s antiapoptotiques. Enfin, nous avons construit par mutagĂ©nĂšse des virus vv811 recombinants exprimant les molĂ©cules Ă©tudiĂ©es in cis. Suite Ă lâinfection par ces virus de cellules U2-OS et Hela, B13, de nouveau, et F1 ont montrĂ© des capacitĂ©s dâinhibition importantes de lâapoptose. Lâaction de GAAP sâest rĂ©vĂ©lĂ©e dĂ©pendante du type cellulaire et N1 nâa pas pu inhiber lâapoptose induite par ce virus dĂ©ficient dans aucune des cellules testĂ©es. En utilisant ces diffĂ©rentes approches, nous avons pu nous affranchir des problĂšmes de redondance et comparer 4 molĂ©cules antiapoptotiques du virus de la vaccine, y compris dans un contexte dâinfection virale. Les rĂ©sultats ont confirmĂ© que toutes les protĂ©ines Ă©tudiĂ©es possĂ©daient des propriĂ©tĂ©s antiapoptiques et ont clairement montrĂ© que B13 Ă©tait la plus puissant
Comparison of the anti-apoptotic properties of 4 vaccinia virus proteins in isolation and during viral infection
Lâapoptose, mort cellulaire observĂ©e suite Ă lâactivation des caspases effectrices, est un moyen de dĂ©fense contre les pathogĂšnes, en particulier les virus. Le virus de la vaccine (VACV) est un virus contenant un grand gĂ©nome Ă ADN codant pour environ 200 protĂ©ines, dont plusieurs inhibent lâapoptose. Cette apparente redondance fonctionnelle complique lâĂ©tude des protĂ©ines antiapoptotiques du virus dans un contexte dâinfection virale. Dans ce travail, nous comparerons les propriĂ©tĂ©s antiapoptotiques des protĂ©ines B13, F1, GAAP et N1 de VACV. Cette comparaison sera Ă©tablie dans un premier temps en dehors de toute infection virale. En utilisant des vecteurs lentiviraux, nous avons obtenu des lignĂ©es cellulaires stables (U2-OS) exprimant ces protĂ©ines en isolation. Nous avons alors pu tester les capacitĂ©s antiapoptotiques de ces protĂ©ines en rĂ©ponse Ă des stimuli provoquant lâapoptose extrinsĂšque et intrinsĂšque. Les rĂ©sultats ont montrĂ© que B13 Ă©tait la plus puissante molĂ©cule inhibitrice de lâapoptose intrinsĂšque et quâelle Ă©tait la seule Ă inhiber lâapoptose extrinsĂšque. Ensuite nous avons tirĂ© avantage dâun virus de la vaccine dĂ©ficient (vv811) qui ne possĂšde aucune de ces protĂ©ines antiapoptotiques, capable Ă lui seul dâinduire lâapoptose, en lâabsence de toute autre stimulus. En infectant nos lignĂ©es cellulaires exprimant les molĂ©cules in trans avec vv811, nous avons pu montrer que B13 inhibait cette apoptose induite par le virus beaucoup plus efficacement que F1. GAAP et N1 dans ce contexte nâont pas dĂ©montrĂ© de propriĂ©tĂ©s antiapoptotiques. Enfin, nous avons construit par mutagĂ©nĂšse des virus vv811 recombinants exprimant les molĂ©cules Ă©tudiĂ©es in cis. Suite Ă lâinfection par ces virus de cellules U2-OS et Hela, B13, de nouveau, et F1 ont montrĂ© des capacitĂ©s dâinhibition importantes de lâapoptose. Lâaction de GAAP sâest rĂ©vĂ©lĂ©e dĂ©pendante du type cellulaire et N1 nâa pas pu inhiber lâapoptose induite par ce virus dĂ©ficient dans aucune des cellules testĂ©es. En utilisant ces diffĂ©rentes approches, nous avons pu nous affranchir des problĂšmes de redondance et comparer 4 molĂ©cules antiapoptotiques du virus de la vaccine, y compris dans un contexte dâinfection virale. Les rĂ©sultats ont confirmĂ© que toutes les protĂ©ines Ă©tudiĂ©es possĂ©daient des propriĂ©tĂ©s antiapoptiques et ont clairement montrĂ© que B13 Ă©tait la plus puissanteApoptosis, which occurs following activation of effector caspases, can restrict the replication of intracellular pathogens, especially viruses. Vaccinia virus (VACV) is a large dsDNA virus encoding approximately 200 proteins, several of which inhibit apoptosis. This redundancy of viral anti-apoptotic proteins complicates the study of these proteins in the context of viral infection. Here a comparative study of the anti-apoptotic proteins B13, F1, GAAP and N1 with and without virus infection is presented. Firstly, using lentiviral constructs, we generated transduced cell lines expressing the anti-apoptotic proteins in isolation and we analysed their ability to protect against extrinsic and intrinsic apoptosis induced by different drugs. In that context B13 was the most potent inhibitor of intrinsic apoptosis and the only protein to inhibit both extrinsic and intrinsic apoptosis. We then used a deficient VACV strain, vv811, that lacks the genes coding for the four anti-apoptotic proteins. Infection with vv811 can induce apoptosis without the need for any other stimulus. After vv811 infection of cell lines expressing the anti-apoptotic proteins in trans, B13 and to a lesser extent F1, inhibited apoptosis. Finally, we introduced each gene separately into vv811 by genetic recombination. Using these recombinant viruses to induce apoptosis, B13 and F1 were very potent inhibitors. The protection conferred by GAAP was cell type dependant and N1 failed to protect any of the tested cells from the virus induced apoptosis. Using these different approaches, we have been able to overcome the redundancy issue to compare 4 anti-apoptotic proteins from VACV, including in the context of viral infection. The results illustrate that vv811 is a useful tool to determine the role of VACV anti-apoptotic proteins during infection and that whilst all of these proteins have some anti-apoptotic activity, B13 is most potent
Nihilismo y metafĂsica en Danilo Cruz VĂ©lez
El propĂłsito de este escrito es estudiar las investigaciones de Danilo Cruz VĂ©lez sobre el nihilismo nietzscheano en relaciĂłn con la metafĂsica. Para la consecuciĂłn de este objetivo, se requieren parĂĄmetros para la comparaciĂłn entre los trabajos y escritos del pensador colombiano con los estudios e investigaciones de Martin Heidegger, con el fin de establecer los nexos e influencias del pensador alemĂĄn en nuestro eximio filĂłsofo colombiano. Lo anterior nos permite concluir, con la autoridad y el rigor de los textos mismos, que las tesis de Cruz VĂ©lez a este respecto no son mĂĄs que la traducciĂłn del alemĂĄn al español de los estudios de Heidegger sobre Nietzsche, cosa que se produce como consecuencia de los seminarios impartidos por Heidegger en  la universidad de Friburgo, a los cuales asistiĂł Danilo Cruz VĂ©lez en calidad de estudiante.Â
Pharmacie clinique basĂ©e sur les preuves Ă lâofficine : Ă©valuation et perspectives
Evidence Based Medecine (EBM) is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient. This practice should be used in order to optimize patient care. The goal of this study was to evaluate the level of Evidence Based Practice (EBP) of the community pharmacists of France, and to investigate the factors linked to this practice. We created and broadcasted an online questionary to evaluate the level of EBP of the french pharmacists on 4 typical clinical cases, related to conventional medicine and alternative and complementary medicine. We then analysed these data using descriptive and inferential statistics (univariate and multivariate analysis). We collected 595 pharmacist answers. The EBP level of our sample is mixed, with only 11% of respondants getting the maximal score on every case. The explicative factors were the quality and quantity of information sources used by the pharmacist, as well as the type of the continuous training he get. This highlighted the importance of learning to recognize the best sources and how to use them, as soon as the university training. The students must learn to develop their critical mind to be able to face the conflicts of interest existing in the healthcare system. The profile of the owner-pharmacist is linked to a lower score, compared to the other profiles (non-owner pharmacists and 6th grade community pharmacy students). The pharmacists must be encouraged to a more evidence based practice, to be recognized as scientific and reliable healthcare providers, thus legitimate to an important role in the patient system care.LâEvidence Based Medicine est dĂ©finie comme lâutilisation consciencieuse, explicite et judicieuse des meilleures preuves mĂ©dicales actuelles dans toute prise de dĂ©cision concernant la prise en charge personnalisĂ©e de chaque patient. Le but de cette Ă©tude Ă©tait de connaĂźtre le niveau de pratique basĂ©e sur les preuves (EBP) des pharmaciens dâofficine en France et les facteurs lâinfluençant. Nous avons construit puis diffusĂ© un questionnaire en ligne pour tester le niveau dâEBP du pharmacien dâofficine sur la base de 4 cas cliniques. Les donnĂ©es rĂ©coltĂ©es ont Ă©tĂ© analysĂ©es de maniĂšre descriptive puis explicative (analyses univariĂ©es et multivariĂ©es). 595 rĂ©ponses ont Ă©tĂ© rĂ©coltĂ©es. Le niveau dâEBP de notre population apparaĂźt mitigĂ©, avec 11% de score optimal sur les cas cliniques. La qualitĂ© et la quantitĂ© des sources dâinformations utilisĂ©es par le pharmacien et le type de formation continue pratiquĂ©e influencent le niveau dâEBP, dâoĂč la nĂ©cessitĂ© dâapprendre Ă distinguer et Ă utiliser les meilleures sources dĂšs la formation initiale. Les Ă©tudiants doivent apprendre Ă dĂ©velopper leur esprit critique, pour faire face aux conflits dâintĂ©rĂȘts existant dans le monde de la santĂ©. Le profil « titulaire » est associĂ© Ă un score final plus faible comparĂ© aux autres profils de pharmaciens exerçants au sein de lâofficine (adjoints, remplaçants, Ă©tudiants en 6Ăšme annĂ©e dâofficine). Les pharmaciens doivent ĂȘtre encouragĂ©s Ă avoir une pratique basĂ©e sur les preuves, afin dâĂȘtre reconnus comme des professionnels scientifiques, responsables, et donc lĂ©gitimes Ă une place importante dans la prise en charge des patients
Histoire et renouveau de l'absinthe
CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF
- âŠ