Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production

Secondary bacterial infections often complicate viral respiratory infections. We hypothesize that perturbation of the gut microbiota during influenza A virus (IAV) infection might favor respiratory bacterial superinfection. Sublethal infection with influenza transiently alters the composition and fermentative activity of the gut microbiota in mice. These changes are attributed in part to reduced food consumption. Fecal transfer experiments demonstrate that the IAV-conditioned microbiota compromises lung defenses against pneumococcal infection. In mechanistic terms, reduced production of the predominant short-chain fatty acid (SCFA) acetate affects the bactericidal activity of alveolar macrophages. Following treatment with acetate, mice colonized with the IAV-conditioned microbiota display reduced bacterial loads. In the context of influenza infection, acetate supplementation reduces, in a free fatty acid receptor 2 (FFAR2)-dependent manner, local and systemic bacterial loads. This translates into reduced lung pathology and improved survival rates of double-infected mice. Lastly, pharmacological activation of the SCFA receptor FFAR2 during influenza reduces bacterial superinfection

1,4-addition of TMSCCl3to nitroalkenes: efficient reaction conditions and mechanistic understanding

Improved synthetic conditions allow preparation of TMSCCl3 in good yield (70 %) and excellent purity. Compounds of the type NBu4X [X=Ph3SiF2 (TBAT), F (tetrabutylammonium fluoride, TBAF), OAc, Cl and Br] act as catalytic promoters for 1,4-additions to a range of cyclic and acyclic nitroalkenes, in THF at 0–25 °C, typically in moderate to excellent yields (37–95 %). TBAT is the most effective promoter and bromide the least effective. Multinuclear NMR studies (1H, 19F, 13C and 29Si) under anaerobic conditions indicate that addition of TMSCCl3 to TBAT (both 0.13 M) at −20 °C, in the absence of nitroalkene, leads immediately to mixtures of Me3SiF, Ph3SiF and NBu4CCl3. The latter is stable to at least 0 °C and does not add nitroalkene from −20 to 0 °C, even after extended periods. Nitroalkene, in the presence of TMSCCl3 (both 0.13 M at −20 °C), when treated with TBAT, leads to immediate formation of the 1,4-addition product, suggesting the reaction proceeds via a transient [Me3Si(alkene)CCl3] species, in which (alkene) indicates an Si⋅⋅⋅O coordinated nitroalkene. The anaerobic catalytic chain is propagated through the kinetic nitronate anion resulting from 1,4 CCl3− addition to the nitroalkene. This is demonstrated by the fact that isolated NBu4[CH2[DOUBLE BOND]NO2] is an efficient promoter. Use of H2C[DOUBLE BOND]CH(CH2)2CH[DOUBLE BOND]CHNO2 in air affords radical-derived bicyclic products arising from aerobic oxidation

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Performance of scintillation materials at cryogenic temperatures

An increasing number of applications of scintillators at low temperatures, particularly in cryogenic experiments searching for rare events, has motivated the investigation of scintillation properties of materials over a wide temperature range. This paper provides an overview of the latest results on the study of luminescence, absorption and scintillation properties of materials selected for rare event searches so far. These include CaWO4, ZnWO4, CdWO4, MgWO4, CaMoO4, CdMoO4, Bi4Ge3O12, CaF2, MgF2, ZnSe and AL2O3-Ti. We discuss the progress achieved in research and development of these scintillators, both in material preparation and in the understanding of scintillation mechanisms, as well as the underlying physics. To understand the origin of the performance limitation of self-activated scintillators we employed a semi-empirical model of conversion of high energy radiation into light and made appropriate provision for effects of temperature and energy transfer. We conclude that the low-temperature value of the light yield of some modern scintillators, namely CaWO4, CdWO4 and Bi4Ge3O12, is close to the theoretical limit. Finally, we discuss the advantages and limitations of different materials with emphasis on their application as cryogenic phonon-scintillation detectors (CPSD) in rare event search experiments

Postoperative acute kidney injury in adult non-cardiac surgery:joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research

Coxiella burnetii employs the Dot/Icm type IV secretion system to modulate host NF-KB/RelA activation

Coxiella burnetii is the causative agent of Q fever and an obligate intracellular pathogen in nature that survives and grows in a parasitophorous vacuole (PV) within eukaryotic host cells. C. burnetii promotes intracellular survival by subverting apoptotic and pro-inflammatory signaling pathways that are typically regulated by nuclear transcription factor-κB (NF-κB). We and others have demonstrated that C. burnetii NMII proteins inhibit expression of pro-inflammatory cytokines and induce expression of anti-apoptotic genes during infection. Here, we demonstrate that C. burnetii promotes intracellular survival by modulating NF-κB subunit p65 (RelA) phosphorylation, and thus activation, in a Type Four B Secretion System (T4BSS)-dependent manner. Immunoblot analysis of RelA phosphorylated at serine-536 demonstrated that C. burnetii increases NF-κB activation via the canonical pathway. However, RelA phosphorylation levels were even higher in infected cells where bacterial protein or mRNA synthesis was inhibited. Importantly, we demonstrate that inhibition of RelA phosphorylation impairs PV formation and C. burnetii growth. We found that a T4BSS-defective mutant (CbΔdotA) elicited phosphorylated RelA levels similar to those of wild type C. burnetii infection treated with Chloramphenicol. Moreover, cells infected with CbΔdotA or wild type C. burnetii treated with Chloramphenicol showed similar levels of GFP-RelA nuclear localization, and significantly increased localization compared to wild type C. burnetii infection. These data indicate that without de novo protein synthesis and a functional T4BSS, C. burnetii is unable to modulate NF-κB activation, which is crucial for optimal intracellular growth.Peer reviewedMicrobiology and Molecular Genetic

The macrophage in HIV-1 infection: From activation to deactivation?

Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-γ display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

A new palladium-catalysed domino reaction : alcoxycarbonylation / allylation for the synthesis of α-allylated esters

L’objectif de ce travail est la mise au point d’une nouvelle réaction domino combinant deux réactions pallado-catalysées d’alcoxycarbonylation et d’alkylation allylique pour la synthèse d’esters allylés. Dans un premier temps, l’étude individuelle de chaque réaction mise en jeu dans la réaction domino a permis de mettre en avant l’incompatibilité des deux réactions lorsque le réactif est un halogénure de benzyle. Les [Alpha]-chlorocétones, conduisant par alcoxycarbonylation à des β-cétoesters plus réactifs en alkylation allylique, ont, par contre, permis de montrer la faisabilité de ce type de transformation. L’optimisation de la réaction d’alcoxycarbonylation d’α-chlorocétones a mis en avant l’importance de l’utilisation de la Xantphos comme ligand phosphoré associé au palladium pour la préparation de β-cétoesters avec de très bons rendements. Dans un deuxième temps, l’alcoxycarbonylation d’α-chlorocétones et la réaction d’alkylation allylique ont pu être combinées de façon efficace dans une nouvelle réaction pseudo-domino de type I, impliquant un seul catalyseur au palladium capable de promouvoir les deux étapes, à des charges catalytiques tout à fait modérées. Le choix du phénate d’allyle comme substrat allylique, moins réactif vis-à-vis du palladium que d’autres dérivés allyliques, et l’utilisation de Xantphos se sont avérés les paramètres clé permettant d’obtenir les β-cétoesters allylés avec de bons rendements et une bonne sélectivité.La généralisation de cette nouvelle réaction à différents substrats laisse entrevoir des perspectives intéressantes d’application de la réaction domino en version intramoléculaire pour la synthèse d’hétérocycles hautement fonctionnalisés.The aim of this work was to develop a new domino reaction combining two different pallado-catalysed transformations: alcoxycarbonylation and allylic alkylation for the synthesis of α-allylated esters.First of all, each elementary reaction involved in the domino reaction was studied individually. When benzyl halide was used as the starting material, the incompatibility of the reactions conditions was clearly demonstrated, whereas the use of [Alpha]-chloroketones, leading to intermediate β-ketoesters, more reactive in allylic alkylation showed us the feasibility of this kind of transformation. Alcoxycarbonylation of α-chloroketones was optimized and the use of Xantphos as an ancillary ligand allowed us to get β-ketoesters with very good yields.Then, [Alpha]-chloroketones alcoxycarbonylation and subsequent allylation could be efficiently combined to provide a new pseudo-domino type I sequence wherein the same catalytic system drives the two concatenated cycles at moderate catalyst loadings. The use of allylic phenyl ether, less reactive to the metal than other allylic substrates, turned out to be the key factor, along with the use of Xantphos, to get allylated ketoesters with good yields and selectivity.This new domino reaction has been extended to several substrates which precludes interesting perspectives for the synthesis of highly functionalized cyclic structures via its intramolecular version

Nouvelle réaction domino pallado-catalysée (alcoxycarbonylation / allylation pour la synthèse d'esters alpha-allylés)

L objectif de ce travail est la mise au point d une nouvelle réaction domino combinant deux réactions pallado-catalysées d alcoxycarbonylation et d alkylation allylique pour la synthèse d esters allylés. Dans un premier temps, l étude individuelle de chaque réaction mise en jeu dans la réaction domino a permis de mettre en avant l incompatibilité des deux réactions lorsque le réactif est un halogénure de benzyle. Les [Alpha]-chlorocétones, conduisant par alcoxycarbonylation à des b-cétoesters plus réactifs en alkylation allylique, ont, par contre, permis de montrer la faisabilité de ce type de transformation. L optimisation de la réaction d alcoxycarbonylation d a-chlorocétones a mis en avant l importance de l utilisation de la Xantphos comme ligand phosphoré associé au palladium pour la préparation de b-cétoesters avec de très bons rendements. Dans un deuxième temps, l alcoxycarbonylation d a-chlorocétones et la réaction d alkylation allylique ont pu être combinées de façon efficace dans une nouvelle réaction pseudo-domino de type I, impliquant un seul catalyseur au palladium capable de promouvoir les deux étapes, à des charges catalytiques tout à fait modérées. Le choix du phénate d allyle comme substrat allylique, moins réactif vis-à-vis du palladium que d autres dérivés allyliques, et l utilisation de Xantphos se sont avérés les paramètres clé permettant d obtenir les b-cétoesters allylés avec de bons rendements et une bonne sélectivité.La généralisation de cette nouvelle réaction à différents substrats laisse entrevoir des perspectives intéressantes d application de la réaction domino en version intramoléculaire pour la synthèse d hétérocycles hautement fonctionnalisés.The aim of this work was to develop a new domino reaction combining two different pallado-catalysed transformations: alcoxycarbonylation and allylic alkylation for the synthesis of a-allylated esters.First of all, each elementary reaction involved in the domino reaction was studied individually. When benzyl halide was used as the starting material, the incompatibility of the reactions conditions was clearly demonstrated, whereas the use of [Alpha]-chloroketones, leading to intermediate b-ketoesters, more reactive in allylic alkylation showed us the feasibility of this kind of transformation. Alcoxycarbonylation of a-chloroketones was optimized and the use of Xantphos as an ancillary ligand allowed us to get b-ketoesters with very good yields.Then, [Alpha]-chloroketones alcoxycarbonylation and subsequent allylation could be efficiently combined to provide a new pseudo-domino type I sequence wherein the same catalytic system drives the two concatenated cycles at moderate catalyst loadings. The use of allylic phenyl ether, less reactive to the metal than other allylic substrates, turned out to be the key factor, along with the use of Xantphos, to get allylated ketoesters with good yields and selectivity.This new domino reaction has been extended to several substrates which precludes interesting perspectives for the synthesis of highly functionalized cyclic structures via its intramolecular version.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF