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We would like to acknowledge and thank Pascale Cossart for her valuable insight and support throughout the project and for her contribution towards the acquisition of financial support. We also thank Michael G. Connor for his help in the quantification and analysis of microscopy data.; International audience; The NAD-dependent deacetylase Sirtuin-2 (SIRT2) functions in diverse cellular processes including the cell cycle, metabolism, and has important roles in tumorigenesis and bacterial infection. SIRT2 predominantly resides in the cytoplasm but can also function in the nucleus. Consequently, SIRT2 localisation and its interacting partners may greatly impact its function and need to be defined more clearly. In this study we used mass spectrometry to determine the interactomes of SIRT2 in whole cells and in specific cellular fractions; cytoplasm, nucleus and chromatin. Using this approach, we identified novel interacting partners of SIRT2. These included a number of proteins that function in nuclear import. We show that multiple importins interact with and contribute to the basal nuclear shuttling of SIRT2 and that one of these, IPO7 is required for SIRT2 mediated H3K18 deacetylation in response to bacterial infection. Furthermore, we reveal that the unstructured C-terminus of SIRT2 negatively regulates importin-binding and nuclear transport. This study demonstrates that SIRT2 is actively transported into the nucleus via a process regulated by its C-terminus and provides a resource of SIRT2 interacting partners.

International audience; Treatment of the iron hydride [Cp*(dppe)FeH] (1) with methyl triflate (CH3OSO2CF3) yielded the iron triflate adduct [Cp*(dppe)FeOSO2CF3] (4, 85 %). In the solid state, the triflate is coordinated at the iron center as shown by XRD (d(Fe-O) = 2.118(4) angstrom) and IR spectroscopy (nu(SO) = 1305 cm(-1)). In solution, 4 is in equilibrium with the 16-electron species [Cp*(dppe)Fe]OSO2CF3 (5(OSO2CF3)), 4/5(OSO2CF3) = 21). The CV of 4 displays two waves (E-1 = -0.74 V, E-2 = 0.24 V vs. SCE) assigned to the [Cp*(dppe)Fe(I)]/[Cp*(dppe)Fe(II)](+) and [Cp*(dppe)Fe(II)](+)/[Cp*(dppe)Fe(III)](2+) redox couples. Reduction of 4 with Cp2Co provided the complex [Cp*(dppe)Fe(I)] (6, 95 %) and oxidation of 6 with [Cp2Fe]PF6 gave [Cp*(dppe)Fe]PF6 (5(PF6), 98 %). XRD established the pseudo-trigonal bipyramidal geometry for the five-coordinated cation 5(+). The reactivity of 5(PF6) and 6 toward small molecules (CH2Cl2, H2O, CO, H-2, N-2) is reported.

The growing interest in regulating flavored E-liquids must incorporate understanding of the “flavoring profile” of each E-liquid—which flavorings (flavoring chemicals) are present and at what concentrations not just focusing on the flavor on the label. We investigated the flavoring profile of 10 different flavored E-liquids. We assessed bronchial epithelial cell viability and apoptosis, phagocytosis of bacteria and apoptotic cells by macrophages after exposure to E-cigarette vapor extract (EVE). We validated our data in normal human bronchial epithelial cells (NHBE) and alveolar macrophages (AM) from healthy donors. We also assessed cytokine release and validated in the saliva from E-cigarette users. Increased necrosis/apoptosis (16.1–64.5% apoptosis) in 16HBE cells was flavor dependent, and NHBEs showed an increased susceptibility to flavors. In THP-1 differentiated macrophages phagocytosis was also flavor dependent, with AM also showing increased susceptibility to flavors. Further, Banana and Chocolate were shown to reduce surface expression of phagocytic target recognition receptors on alveolar macrophages. Banana and Chocolate increased IL-8 secretion by NHBE, whereas all 4 flavors reduced AM IL-1β secretion, which was also reduced in the saliva of E-cigarette users compared with healthy controls. Flavorant profiles of E-liquids varied from simple 2 compound mixtures to complex mixtures containing over a dozen flavorants. E-liquids with high benzene content, complex flavoring profiles, high chemical concentration had the greatest impacts. The Flavorant profile of E-liquids is key to disruption of the airway status quo by increasing bronchial epithelial cell apoptosis, causing alveolar macrophage phagocytic dysfunction, and altering airway cytokines.

Caffeine is the most consumed alkaloid stimulant in the world. It is synthesized through the activity of three known N-methyltransferase proteins. Here we are reporting on the 422-Mb chromosome-level assembly of the Coffea humblotiana genome, a wild and endangered, naturally caffeine-free, species from the Comoro archipelago. We predicted 32,874 genes and anchored 88.7% of the sequence onto the 11 chromosomes. Comparative analyses with the African Robusta coffee genome (C. canephora) revealed an extensive genome conservation, despite an estimated 11 million years of divergence and a broad diversity of genome sizes within the Coffea genus. In this genome, the absence of caffeine is likely due to the absence of the caffeine synthase gene which converts theobromine into caffeine through an illegitimate recombination mechanism. These findings pave the way for further characterization of caffeine-free species in the Coffea genus and will guide research towards naturally-decaffeinated coffee drinks for consumers.

International audience; New “all-in-one” theranostic systems, combining a magnetic resonance imaging (MRI) contrast agent with a biphotonic photodynamic therapy (2P-PDT) photosensitiser generating cytotoxic singlet oxygen, were envisaged and synthesised. They are based on azamacrocycles, regiospecifically functionalised by two-photon PDT π-conjugated dibromobenzene–picolinate photosensitisers and acetate, able to complex gadolinium(III) and allow an MRI signal. Our approach was to use two different macrocyclic platforms, tacn and pyclen, for modulating simultaneously the structures, properties and solubility of the complexes. Photophysical properties of the ligands and their gadolinium(III) complexes were fully investigated. The Gd3+–pyclen derivative showed the best water solubility and the greatest value of singlet oxygen generation of the series with ΦΔ = 0.53 enabling in vitro studies. The biological PDT activity under mono and biphotonic excitation was evaluated in human breast cancer cells (MCF-7). While a very low dark toxicity was observed, an almost total cell death was induced after only 3 successive irradiations of 1.57 s. Finally, its relaxivity was measured in a DMSO/H2O solvent mixture with r1p = 11.21 and r2p = 24.60 mM−1 s−1 at 3.0 T and T1- and T2-weighted phantom MR images were obtained highlighting a first generation of “all-in-one” PDT/MRI theranostic agents.

Nuclear Magnetic Resonance (NMR) is an analytical technique extensively used in almost every chemical laboratory for structural identification. This technique provides statistically equivalent signals in spite of using spectrometer with different hardware features and is successfully used for the traceability and quantification of analytes in food samples. Nevertheless, to date only a few internationally agreed guidelines have been reported on the use of NMR for quantitative analysis. The main goal of the present study is to provide a methodological pipeline to assess the reproducibility of NMR data produced for a given matrix by spectrometers from different manufacturers, with different magnetic field strengths, age and hardware configurations. The results have been analyzed through a sequence of chemometric tests to generate a community-built calibration system which was used to verify the performance of the spectrometers and the reproducibility of the predicted sample concentrations.

Purpose To determine the changes of corneal thickness and curvature of human corneal grafts in organ culture medium II, containing dextran T500 6%, before keratoplasty. Methods We examined the tomography of 24 corneas from our eye bank transferred from medium I into medium II. Images were repeated hourly during 24 hours using an anterior segment optical coherence tomography. The central corneal thickness (CCT) was measured with the manual measurement tool of the anterior segment optical coherence tomography. The radii of curvature (anterior flat and steep and posterior flat and steep) were measured with a MATLAB self-programmed software for "sterile donor tomography." Results The mean CCT (±SD) at baseline (T0) was 727 ± 156 μm. It reached 581 ± 103, 506 ± 84, 472 ± 79, and 456±7 μm after 6, 12, 18, and 24 hours, respectively. After 12 hours, 83% of the final deswelling was achieved. The radii of curvature (±SD) at baseline (T0) were (posterior flat, posterior steep, anterior flat, and anterior steep) 6.6 ± 0.5, 6.2 ± 0.5, 7.7 ± 0.4, and 7.4 ± 0.4 mm, respectively. After 24 hours, the radii of curvature reached 6.8 ± 0.1, 6.6 ± 0.3, 7.6 ± 0.1, and 7.4 ± 0.2 mm, respectively. Conclusions The kinetics of the deswelling process in medium II follow a hyperbolic curve. Considering a CCT of 506 μm at T12, we assume that a time interval of 12 hours in medium II might be enough for clinical purposes. This result might help to keep storage in medium II as short as possible to escape potential toxic effects of dextran in medium II. The radius of curvature does not seem to change within 24 hours for all measured surfaces.

Hypothesis Confinement causes a change in the amount of surfactant adsorbed and in the adsorption morphology. Experiments Two cationic surfactants, tetradecyltrimethylammonium bromide (TTAB) and cetylpyridinium chloride (CPC) were adsorbed at the silica-water interface. Atomic force microscopy (AFM) force curves were measured on 50 nm and 80 nm wide trenches. Force curves were also measured on silica pillars, and the results were quantified based on distance from the edge. Findings Trenches: Adsorbed surfactants films in 50 nm and 80 nm trenches showed the same break-through values. However, compared to unconfined values, TTAB in trenches had decreased break-through and adhesion forces while CPC in trenches had increased break-through and adhesion forces, indicating that surfactant identity varies the confinement effect. Pillars: Near the edge, few surfactants adsorb, and those that do extend in the direction normal to the surface. While the experimental data agree qualitatively with previous coarse-grained molecular dynamic simulations, the length scales at which the phenomena are detected differ by ~ half-order of magnitude. Specifically, experimental data show measurable effects on adsorbed surfactant morphology at a distance from the edge 10–20 times the length of a surfactant molecule after accounting for the ~8 nm size of the probe.

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3's novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

International audience; In addition to the already described ligand L4a, two pyclen-based lanthanide chelators, L4b and L4c, bearing two specific picolinate two-photon antennas (tailor-made for each targeted metal) and one acetate arm arranged in a dissymmetrical manner, have been synthesized, to form a complete family of lanthanide luminescent bioprobes: [EuL4a], [SmL4a], [YbL4b], [TbL4c], and [DyL4c]. Additionally, the symmetrically arranged regioisomer L4a′ was also synthesized as well as its [EuL4a′] complex to highlight the astonishing positive impact of the dissymmetrical N-distribution of the functional chelating arms. The investigation clearly shows the high performance of each bioprobe, which, depending on the complexed lanthanide, could be used in various applications. Each presents high brightness, quantum yields, and lifetimes. Staining of the complexes into living human breast cancer cells was observed. In addition, in vivo two-photon microscopy was performed for the first time on a living zebrafish model with [EuL4a]. No apparent toxicity was detected on the growth of the zebrafish, and images of high quality were obtained.

Summary: Pathogenic bacteria can alter host gene expression through post-translational modifications of histones. We show that a natural colonizer, Streptococcus pneumoniae, induces specific histone modifications, including robust dephosphorylation of histone H3 on serine 10 (H3S10), during infection of respiratory epithelial cells. The bacterial pore-forming toxin pneumolysin (PLY), along with the pyruvate oxidase SpxB responsible for H2O2 production, play important roles in the induction of this modification. The combined effects of PLY and H2O2 trigger host signaling that culminates in H3S10 dephosphorylation, which is mediated by the host cell phosphatase PP1. Strikingly, S. pneumoniae infection induces dephosphorylation and subsequent activation of PP1 catalytic activity. Colonization of PP1 catalytically deficient cells results in impaired intracellular S. pneumoniae survival and infection. Interestingly, PP1 activation and H3S10 dephosphorylation are not restricted to S. pneumoniae and appear to be general epigenomic mechanisms favoring intracellular survival of pathogenic bacteria. : Dong et al. show that Streptococcus pneumoniae infection induces histone H3 dephosphorylation in lung epithelial cells, through two bacterial factors, PLY and SpxB. Infection-triggered activation of the host phosphatase PP1 is required for this histone modification and efficient intracellular infection. Keywords: histone modification, Streptococcus pneumoniae, H3S10 dephosphorylation, protein phosphatase 1, bacterial infection, pneumolysin, SpxB

Significance Learning depends on synaptic plasticity. The signaling mechanisms that control induction of plasticity determine the learning rules at the specific synapse involved. Moreover, the relationship between the activity patterns of synaptic inputs and the type, direction, and level of plasticity induced may evolve during development. Here, we establish a key link between receptor activation presynaptic to cerebellar Purkinje cells, downstream signaling mechanisms, and the ability of adult animals to learn a cerebellar motor task., Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional plasticity is shaped by the balance between transcellular nitric oxide (NO) driven by presynaptic N-methyl-D-aspartate receptor (NMDAR) activation and postsynaptic calcium dynamics. However, the role and the location of NMDAR activation in these pathways is still debated in mature animals. Here, we show in adult rodents that NMDARs are present and functional in presynaptic terminals where their activation triggers NO signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at parallel fiber-PC (PF-PC) synapses. Consistent with this finding, the selective deletion of GC NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning.

We have recently reported a series of neutral square planar tridentate Schiff base (L) complexes of the general formula [(L)M(py)], showing relatively high first-order hyperpolarizabilities and NLO redox switching behavior. In the present study, new members of this family of compounds have been prepared with the objective to investigate their potential as building blocks in the on-demand construction of D-π-A push–pull systems. Namely, ternary nickel(II) building blocks of general formula [(LA/D)Ni(4-pyX)] (4–7), where LA/D stands for an electron accepting or donating dianionic O,N,O-tridentate Schiff base ligand resulting from the monocondensation of 2-aminophenol or its 4-substituted nitro derivative and β-diketones R-C(=O)CH2C(=O)CH3 (R = methyl, anisyl, ferrocenyl), and 4-pyX is 4-iodopyridine or 4-ethynylpyridine, were synthesized and isolated in 60–78% yields. Unexpectedly, the Sonogashira cross-coupling reaction between the 4-iodopyridine derivative 6 and 4-ethynylpyridine led to the formation of the bis(4-pyridyl) acetylene bridged centrosymmetric dimer [{(LD)Ni}2(µ2-py-C≡C-py)] (8). Complexes 4–8 were characterized by elemental analysis, FT-IR and NMR spectroscopy, single crystal X-ray diffraction and computational methods. In each compound, the four-coordinate Ni(II) metal ion adopts a square planar geometry with two nitrogen and two oxygen atoms as donors occupying trans positions. In 8, the Ni…Ni separation is of 13.62(14) Å. Experimental results were proved and explained theoretically exploiting Density Functional Theory calculations.

International audience; The bis(ironvinylidene) complex [1,4-{Cp*(dppe)Fe=C=CH}(2)-2,5-(C equivalent to CH)(2)-C6H2](PF6)(2) ([2-2H](PF6)(2)) was prepared from 1,2,4,5-tetraethynylbenzene and two equiv. of Cp*(dppe)FeCl in 87 % yield. The reaction is very selective and [2-2H](PF6)(2) is the unique organoiron species to be formed. Deprotonation of [2-2H](PF6)(2) provided the target complex 2 (66 % yield) and subsequent oxidation gave the monocationic and dicationic complexes 2(PF6) and 2(PF6)(2). The new complexes were characterized by ESI-mass spectrometry, IR, multinuclear NMR, ESR and Mossbauer spectroscopy, and XRD analyses on single crystals for [2-2H](PF6)(2) and 2(PF6)(2). The magnetic properties of 2(PF6)(2) were investigated by VT H-1 NMR. The data were analyzed with the support of quantum chemistry calculations. The terminal ethynyl groups on the aromatic ring of the bridge modify the population of the bridge-oxidized state, weaken the electronic communication (H-ab approximate to 601 cm(-1)) and strengthen magnetic coupling interactions (J = -530 cm(-1)) compared to the unsubstituted species (H-ab = 1700 cm(-1) and J = -340 cm(-1), respectively).

International audience; The unprecedented tetrairon dication [{Cp*(dppe)FeC≡C-} -μ-(1,2,4,5-C H )](PF ) (1) was obtained through a sequence of three reactions from 1,2,4,5-tetraethynylbenzene, Cp*(dppe)FeCl (Cp*=C Me , dppe=1,2-bis(diphenylphosphino)-ethane), KOtBu, and ferrocenium hexafluorophosphate. The cyclic voltammogram of the target molecule, isolated in 77 % yield, exhibits four well separated and reversible redox events showing that 1 is thermodynamically stable with respect to disproportionation (Kc>10 ). The tetranuclear dication 1 was characterized by XRD on single crystal, IR and NMR spectroscopies and Mössbauer spectrometry. The experimental data show that 1 behaves as a class II mixed-valence complex with the positive charges preferentially disposed on antipodal positions. This new molecule can be regarded as a potential molecular prototype of quantum dot cellular automata.

International audience; Dendrimers have already been successfully used in nanoparticle (NP) catalysis for many years, particularly for Pd NP protection towards carbon-carbon coupling reactions. In this paper, assemblies between Pd nanoparticles and two generations of "click" dendrimers, with 27 (dendrimer-1) and 81 (dendrimer-2) triethylene glycol (TEG) termini, respectively, are examined for catalytic peroxidase-like oxidative activity. This catalysis is investigated with o-phenylenediamine (OPD) and H2O2 as the substrates in water, displaying different colours. The dendritic effect is negative upon increasing generation, i.e., dendrimer 1-Pd nanoparticles show the best results, providing values with a V-max of 1.49 x 10(-9) M s(-1) and K-m of 3.02 mM as obtained with the Michaelis-Menten model. The detection limit is 0.5 mu M of H2O2 detection with dendrimer-1-PdNPs, and both dendrimer-Pd nanocatalysts exhibit excellent robustness of catalytic activity, with a water-dispersive state being stable for at least 2 months, thus showing promise as a mimic for peroxidase catalysts.

Background: Peripheral neuropathic pain (PNP) is frequent in patients with breast cancer (BC) and BC survivors (BCSs). Data supporting the use of high-concentration (179 mg) capsaicin patches (HCCP) in PNP in oncology are limited. This observational study evaluated the effectiveness and safety of HCCP applications in BCSs/BC patients with PNP. Methods: The study took place in the Anaesthesiology and Pain Medicine department of a French comprehensive cancer centre (Angers, France). For all patients treated with HCCP from 01-Jan-2014 to 18-Dec-2018 data have been collected retrospectively over this period, and for those continuing to receive HCCP after 18-Dec-2018 data collection continued prospectively until 14-Oct-2020. Treatment with HCCP was at the entire discretion of the treating pain specialists. Independent pain specialists completed the Clinical Global Impression of Change (CGIC) for each included patient based on data extracted from patient’s electronic medical record completed by the treating pain specialist after each HCCP application. Results: This study included 279 patients (1141 HCCP applications). Patients were on average 59.2 years old; 54.5% had received at least one medication for their PNP before entering the study. PNP was most frequently caused by surgery (62.4%) followed by chemotherapy (11.8%) and radiotherapy (6.5%). Patients received on average 4.1 repeated HCCP applications; 68.8% received HCCP as an add-on to systemic therapy and 27.9% as first-line therapy. A complete/important analgesic effect was reported at least once by 82.3% of patients; 6.0% of patients reported no effect at all. Complete/important effect was observed in 70.7% and 56.0% of applications in post-surgical PNP existing for 10 years, and 52.7% and 52.3% of applications in chemotherapy- or radiotherapy-induced PNP respectively. HCCP application was associated with application site reactions in 54.4% of patients with burning sensation or pain (45.9%) and erythema (30.8%) being the most frequently reported. High blood pressure was reported in 7.2% and frostbite, likely due to local cooling, in 1.4% of patients. Conclusions: This real-world chart review evaluating HCCP under usual practice conditions in a large cohort of patients provides important effectiveness and safety information to clinicians when considering topical options to treat PNP in BCSs/BC patients. Trial registration: Not applicable

International audience; Extensive studies showed the crucial role of ATP binding cassette (ABC) transporter ABCA1 in organizing the lipid microenvironment at the plasma membrane (PM) of living cells. However, the exact role of this protein in terms of lipid redistribution and lateral reorganization of the PM is still being discussed. Here, we took advantage of the spot variation fluorescence correlation spectroscopy (svFCS) to investigate the molecular dynamics of the ABCA1 expressed at the PM of Chinese hamster ovary cells (CHO-K1). We confirmed that this protein is strongly confined into the raft nanodomains. Next, in agreement with our previous observations, we showed that amphotericin B does not affect the diffusion properties of an active ABCA1 in contrary to inactive mutant ABCA1MM. We also evidenced that ApoA1 influences the molecular diffusion properties of ABCA1. Finally, we showed that the molecular confinement of ABCA1 depends on the cholesterol content in the PM, but presumably, this is not the only factor responsible for that. We concluded that the molecular dynamics of ABCA1 strongly depends on its activity and the PM composition. We hypothesize that other factors than lipids (i.e., proteins) are responsible for the strong confinement of ABCA1 in PM nanodomains which possibility has to be elucidated.

Carbonate formations are characterized by multiscale heterogeneities that control their acoustic response and flow properties. At the laboratory scale, carbonate rocks do not indicate a strong correlation between P- and S-wave velocities and porosity. The velocity disparities between carbonates of similar mineralogy and porosity result from different microstructures derived from their sedimentary facies and subsequent diagenetic transformations. The still-discussed applicability of Biot-Gassmann’s equation for fluid substitution in carbonate rocks remains another key issue. We have developed an integrated experimental workflow that allows a consistent checking of the applicability of Biot-Gassmann’s equation and provides key geologic and microstructural information to understand the petroacoustic signature of carbonate rocks. The defined approach is based on the phase-velocity measurements performed in liquid-saturated conditions using polar and nonpolar fluids. It allows the identification of the whole set of parameters required by Biot-Gassmann’s equation including the bulk modulus of the solid matrix. This approach is implemented on samples representative of two different carbonate formations deposited in lacustrine and marine environments, respectively. The obtained results demonstrate the applicability of Biot-Gassmann’s equation for the two studied carbonate families and indicate the link between their petroacoustic signature and diagenetic history.

Amphotericin B (AmB) belongs to a group of polyene antibiotics commonly used in the treatment of systemic mycotic infections. A widely accepted mechanism of action of AmB is based on the formation of an oligomeric pore structure within the plasma membrane (PM) by interaction with membrane sterols. Although AmB binds preferentially to ergosterol, it can also bind to cholesterol in the mammalian PM and cause severe cellular toxicity. The lipid content and its lateral organization at the cell PM appear to be significant for AmB binding. Several ATP-binding cassette (ABC) transporters, including ABCA1, play a crucial role in lipid translocation, cholesterol redistribution and efflux. Here, we demonstrate that cells expressing ABCA1 are more resistant to AmB treatment, while cells lacking ABCA1 expression or expressing non-active ABCA1MM mutant display increased sensitivity. Further, a FLIM analysis of AmB-treated cells reveals a fraction of the antibiotic molecules, characterized by relatively high fluorescence lifetimes (> 6 ns), involved in formation of bulk cholesterol–AmB structures at the surface of ABCA1-expressing cells. Finally, lowering the cellular cholesterol content abolishes resistance of ABCA1-expressing cells to AmB. Therefore, we propose that ABCA1-mediated cholesterol efflux from cells induces formation of bulk cholesterol–AmB structures at the cell surface, preventing AmB cytotoxicity. Electronic supplementary material The online version of this article (10.1007/s00018-019-03154-w) contains supplementary material, which is available to authorized users.

International audience; Upon crystallization from DMF/diethyl ether or CH 2 Cl 2 /pyridine of tetracoordinated Zn(II) complexes containing either 4-fluorophenyl or 4-anisyl substituted O,N,O-tridentate Schiff base ligands and pyridine as auxiliary ligand, three new doubly phenoxide-bridged dimeric Zn(II) complexes were isolated and their catalytic properties for the ring opening polymerization (ROP) of rac-lactide were explored. The single-crystal XRD analysis allowed to corroborate the molecular structures of the binuclear complexes, showing that the pentacoordinated Zn(II) metal ion adopts a slightly distorted square pyramidal geometry. The basal plane Is formed by the O,N,O-donor set of the tridentate Schiff base ligand and a phenoxo bridging oxygen, while a pyridine or a DMF molecule is located at the apex of the pyramid. The binuclear complexes were employed as catalysts in the ROP of rac-lactide for polylactide (PLA) synthesis. Polymerization conditions such as reaction time, catalyst concentration and use of benzyl alcohol as cocatalyst were studied, as well as their influence on the conversion rate, average molecular weight and polydispersity of the obtained PLA. The catalyst substituted with fluorine was more reactive, but with a lower control on the molecular weight compared to the methoxy-substituted catalyst. On the other hand, the presence of pyridine as an auxiliary ligand generates an improvement in the polydispersity of PLA.

International audience; Roasting of Coffea arabica L. seeds gives rise to chemical reactions that produce more than 800 compounds, some being responsible for the desired organoleptic properties for which the beverage called “coffee” is known. In the industry, the “roasting profile,” that is, the times and temperatures applied, is key to influence the composition of roasted coffee beans and the flavour of the beverage made from them. The impact of roasting on the chemical composition of coffee has been the subject of numerous studies, including by nuclear magnetic resonance (NMR) spectroscopy. However, the roasting equipment and profiles applied in these studies are often far from real industrial conditions. In this work, the effects of two critical technological parameters of the roasting process, namely, the “development time” (the period of time after the “first crack,” a characteristic noise due to seed disruption) and the final roasting temperature on coffee extracts, were investigated. Seeds were roasted at pilot scale according to 13 industrial roasting profiles and extracted in D2O. The extracts were analysed by 1H NMR experiments. The NMR spectra were compared using (a) quantitative analysis of main signals by successive orders of magnitude and (b) chemometric tools (principal component analysis, partial least squares and sparse‐orthogonal partial least squares analysis). This allowed to identify compounds, which may serve as markers of roasting and showed that changes in chemical composition can be detected even for slight change in final temperature (~1°C) or in total roasting time (~25 s).

International audience; Four new ternary Ni(ii) and Cu(ii) complexes of ONO tridentate Schiff base and pyridylmethylenepyran (PyMP) ligands [(R-ONO)M(PyMP)] (R = anisyl = An M = Ni 1, Cu 2; R = ferrocenyl = Fc M = Ni 3, Cu 4) have been synthesized under facile reaction conditions starting from R-ONOH2, metal(ii) nitrate salts, and PyMP; R-ONOH2 stands for the Schiff base ligand precursors obtained by condensation of either 1-anisyl- or 1-ferrocenyl-butan-1,3-dione and 2-aminophenol. They have been thoroughly characterized with the help of various physicochemical tools, such as CHN analyses, IR and UV-vis spectra, H-1 NMR for diamagnetic Ni(ii) derivatives 1 and 3, and HRMS for paramagnetic Cu(ii) species 2 and 4. The molecular structures of 1-3 were authenticated by single-crystal X-ray diffraction methods, along with that of the doubly phenoxide-bridged dimer [Cu-2(mu-ONO-Fc)(2)(PyMp)(2)] (4 '), resulting from the recrystallization of 4. In 1-3, the four-coordinate nickel and copper atoms adopt a square planar geometry, whereas in 4 ' the Cu-II metal ion is five-coordinated in a square pyramidal environment with the pyridyl nitrogen occupying the apex. Electrochemical studies reveal two well-separated redox waves. The spin density distribution analyses reveal that the initial oxidation process is associated with a ligand-based level, with some ferrocenyl participation for the heterobimetallic compounds 3 and 4. Reversible redox switching can be established for 1 and 3 by time-resolved spectroelectrochemistry under thin-layer conditions where electrochemical cycling is associated with a significant modification of the UV-vis spectra of the chromophores. The second-order nonlinear optical responses of 1-4 along with those of assumed bispyrylium dimeric species 5 and 6, generated by chemical oxidation of 1 and 3, respectively, have been determined by harmonic light scattering measurements in dichloromethane solutions at 1.91 mu m incident wavelength. Rather high beta values ranging from 270-530 x 10(-30) esu were determined for 1-4. The beta value of 5 (800 x 10(-30) esu) was found to be almost twice that of its monomeric precursor 1, whereas the beta value of 6 (160 x 10(-30) esu) is reduced by half with respect to that of 3. In 5 the anisyl retains its donor ability whereas in 6 the electron-donating character of the oxidized ferrocenyl moiety is cancelled. Optimized geometries of the four compounds 1-4 as well as their electronic structures and that of their respective cations 1(+)-4(+) have been analyzed through DFT calculations, while TD-DFT computation has been used to interpret the major features of the UV-vis spectra.

SUMMARYThe photomorphogenic remodelling of seedling growth upon exposure to light is a key developmental transition in the plant life cycle. The α/β-hydrolase signalling protein KARRIKIN-INSENSITIVE2 (KAI2), a close homologue of the strigolactone receptor DWARF14 (D14), is involved in this process, and kai2 mutants have strongly altered seedling growth as a result1. KAI2 and D14 both act through the MAX2 (MORE AXILLARY BRANCHING2) F-box protein to target proteins of the SMAX1-LIKE (SUPPRESSOR OF MAX2 1) (SMXL) family for degradation, but the signalling events downstream of this step are unclear in both pathways2. Here, we show that kai2 phenotypes arise because of a failure to downregulate auxin transport from the seedling shoot apex towards the root system, rather than a failure to respond to light per se. We demonstrate that KAI2 controls the light-induced remodelling of the PIN-mediated auxin transport system in seedlings, promoting the reduction of PIN3, PIN4, and PIN7 abundance in older tissues, and the increase of PIN1, PIN2, PIN3, and PIN7 abundance in the root meristem, consistent with transition from elongation-mediated growth in the dark to meristematically-mediated growth in the light. We show that removing PIN3, PIN4 and PIN7 from kai2 mutants, or pharmacological inhibition of auxin transport and synthesis, is sufficient to suppress most kai2 seedling phenotypes. KAI2 is not required for the light-mediated changes in PIN gene expression but is required for the changes in PIN protein abundance at the plasma membrane; we thus propose that KAI2 acts to promote vesicle trafficking, consistent with previous suggestions about D14-mediated signalling in the shoot3.

The protection of current collectors against anodic dissolution at high potential has been identified as crucial for next generation of high energy and safe lithium-ion batteries. Herein, a systematic study of the electrochemical behavior of two grades of aluminum current collectors has been performed in five representative liquid electrolytes. Analysis of electrochemical data and microscopy images have notably shown that aluminum current collectors appear to be stable up to 5 V vs. Li+/Li in the presence of the reactive LiPF6 salt whereas imide salts trigger the aluminum anodic dissolution except in ionic liquid medium. It was also observed that the grade of the tested aluminum current collectors had little impact. To support the robustness of this study dedicated to practical developments of the “5 V” Li-ion battery technology, a statistical analysis has been performed for the most corrosive electrolyte formulation (1 M LiTFSI/[EC/DMC]). These data show the anodic dissolution systematically occurs in a reproducible way whatever the sampling area of the aluminum foil.

We designed a strategy, based on a careful examination of the activation capabilities of proteins and antibodies used as substrates for adhering T cells, coupled to protein microstamping to control at the same time the position, shape, spreading, mechanics and activation state of T cells. Once adhered on patterns, we examined the capacities of T cells to be activated with soluble anti CD3, in comparison to T cells adhered to a continuously decorated substrate with the same density of ligands. We show that, in our hand, adhering onto an anti CD45 antibody decorated surface was not affecting T cell calcium fluxes, even adhered on variable size micro-patterns. Aside, we analyzed the T cell mechanics, when spread on pattern or not, using Atomic Force Microscopy indentation. By expressing MEGF10 as a non immune adhesion receptor in T cells we measured the very same spreading area on PLL substrates and Young modulus than non modified cells, immobilized on anti CD45 antibodies, while retaining similar activation capabilities using soluble anti CD3 antibodies or through model APC contacts. We propose that our system is a way to test activation or anergy of T cells with defined adhesion and mechanical characteristics, and may allow to dissect fine details of these mechanisms since it allows to observe homogenized populations in standardized T cell activation assays.

International audience; This article presents an integrated approach based on stratigraphic forward modeling and reactive transport modeling to adequately represent the development of a mixed siliciclastic-carbonate sedimentary system and its diagenesis. This work was realized on a realistic case study, the Oligo-Miocene series of Carry-le-Rouet, South-East of France, characterized by a complex pattern of bioclastic, bioconstructed and siliciclastic deposits, and affected by several exposure surfaces and associated meteoric diagenesis. A first phase consisted in building a stratigraphic forward model (SFM), using the software DionisosFlow. The construction of the model was based on sensitivity tests on the two main parameters controlling basin sedimentation: 1) competition between carbonate production and siliciclastic supply; 2) subsidence. The results of the simulations, especially the facies distribution, the thickness of the deposits and the sedimentary architectures were compared with the observed data to validate the model. A second phase consisted in focusing on a specific stratigraphic event and performing reactive transport modeling (RTM) on a 2D section extracted from the DionisosFlow model to evaluate the mineralogical transformations and resulting petrophysical evolutions created by early diagenesis. The calculation results show the occurrence of two domains of salinity, that were associated with two distinct diagenetic environments: marine and meteoric phreatic. Globally, the simulated diagenetic trends are qualitatively consistent with the petrographic observations, except for the replacement of aragonite by a calcite cement, that systematically occurred in the model and is not always observed in thin sections. This preliminary study emphasizes the issues associated with the application of RTM to diagenetic phenomena, linked with the uncertainties inherent to specific parameters, such as minerals kinetic properties, and the mismatch between the space and time scales of the modeled processes and the upscaled description of each SFM cell. These results argue in favor of an alternative solution, that could conciliate the different processes. The combination of the various SFM output properties with simplified chemical reactions whose rates have been tuned for specific diagenetic processes of interest could provide diagenetic risk maps that would constitute useful guides for exploration at basin scale.

Alternaria brassicicola causes black spot disease in Brassicaceae. During host infection, this necrotrophic fungus is exposed to various antimicrobial compounds, such as the phytoalexin brassinin which is produced by many cultivated Brassica species. To investigate the cellular mechanisms by which this compound causes toxicity and the corresponding fungal adaptive strategies, we first analyzed fungal transcriptional responses to short-term exposure to brassinin and then used additional functional approaches. This study supports the hypothesis that indolic phytoalexin primarily targets mitochondrial functions in fungal cells. Indeed, we notably observed that phytoalexin treatment of A. brassicicola disrupted the mitochondrial membrane potential and resulted in a significant and rapid decrease in the oxygen consumption rates. Secondary effects, such as Reactive oxygen species production, changes in lipid and endoplasmic reticulum homeostasis were then found to be induced. Consequently, the fungus has to adapt its metabolism to protect itself against the toxic effects of these molecules, especially via the activation of high osmolarity glycerol and cell wall integrity signaling pathways and by induction of the unfolded protein response.

International audience; Mass graves are usually key historical markers with strong incentive for archeological investigations. The identification of individuals buried in mass graves has long benefitted from traditional historical, archaeological, anthropological and paleopathological techniques. The addition of novel methods including genetic, genomic and isotopic geochemistry have renewed interest in solving unidentified mass graves. In this study, we demonstrate that the combined use of these techniques allows the identification of the individuals found in two Breton historical mass graves, where one method alone would not have revealed the importance of this discovery. The skeletons likely belong to soldiers from the two enemy armies who fought during a major event of Breton history: the siege of Rennes in 1491, which ended by the wedding of the Duchess of Brittany with the King of France and signaled the end of the independence of the region. Our study highlights the value of interdisciplinary approaches with a particular emphasis on increasingly accurate isotopic markers. The development of the sulfur isoscape and testing of the triple isotope geographic assignment are detailed in a companion paper [13].

International audience; The glass transition temperature (Tg) is a key parameter to investigate for application in nuclear waste immobilization in borosilicate glasses. Tg for several glasses containing iodine (I) has been measured in order to determine the I effect on Tg. Two series of glass composition (ISG and NH) containing up to 2.5 mol% I and synthesized under high pressure (0.5 to 1.5 GPa) have been investigated using differential scanning calorimetry (DSC). The I local environment in glasses has been determined using X‐ray photoelectron spectroscopy and revealed that I is dissolved under its iodide form (I−). Results show that Tg is decreased with the I addition in the glass in agreement with previous results. We also observed that this Tg decrease is a strong function of glass composition. For NH, 2.5 mol% I induces a decrease of 24°C in Tg, whereas for ISG, 1.2 mol% decreases the Tg by 64°C. We interpret this difference as the result of the I dissolution mechanism and its effect on the polymerization of the boron network. The I dissolution in ISG is accompanied by a depolymerization of the boron network, whereas it is the opposite in NH. Although ISG corresponds to a standardized glass, for the particular case of I immobilization it appears less adequate than NH considering that the decrease in Tg for NH is small in comparison to ISG.

International audience; • Iodine is dissolved as iodide (I − ) in high pressure borosilicate glasses. • Both alkali and alkaline-earth cations act as a charge compensator to I − species. • The absence of iodate (I 5+ ) suggests that there is a complex interplay between I − species and oxygen species within the glass structure.

Macrophages (MΦ) form a highly heterogenous compartment within tumor lesions. Using lineage tracing, we recently established that advanced NSCLC lesions in both mice and humans are depleted of tissue-resident macrophages (TRM) and are mainly populated by monocyte-derived MΦ (MoMΦ). Here, we show that TREM2+ MoMΦ dominate murine and human NSCLC lesions. Importantly, using mice reconstituted with mixed TREM2-deficient and -proficient bone marrow cells, we identified a cell-intrinsic ability for TREM2 to drive an efferocytosis-associated molecular program that profoundly reduced the expression of immunogenic molecules in tumor-infiltrating MoMΦ. Trem2 deletion significantly dampened this program, reversed MoMΦ immunosuppression, and significantly enhanced the accumulation of activated NK cells and cDC1 in tumor lesions. Notably, Trem2 deletion reduced lung cancer progression in an NK cell-dependent manner. Taken together, our results underscore the potential for therapeutic inhibition of TREM2 to mount a potent anti-tumor immune response by unleashing cooperative NK/cDC1 cell function.

International audience; Engineering symmetry breaking in seed-mediated growth is a fundamental challenge to produce colloidal nanocrystals with controlled morphologies and properties. In this work, we show a simple, aqueous approach to breaking the inversion symmetry of silver nanorods by restricting growth to one end of the pentatwinned gold bipyramid seed. Controlled addition of dimethyl sulfoxide (DMSO) allows us to tune both the symmetry and the length and width of the objects. Simulations and experiments demonstrate the adsorption of DMSO, which displaces interfacial water, reduces binding of surfactant and chloride ions at the gold surface, and slows down the deposition kinetics of silver. Besides showing the potential of DMSO for controlling the synthesis of complex nanostructures, this work opens new perspectives for the study of the physical properties of non-centrosymmetric nanoparticles, e.g. by controlling their plasmon modes and their second-harmonic generation efficiency.

International audience; The new complexes [1,3-{Cp*(dppe)Fe−C≡C-}2-5-(X)-(C6H3)] (X=CH3, [m-1 b]; X=C(O)OCH3, [m-1 c]; X=C≡C-4-C6H4-C(O)OCH3, [m-1 d]; X=C≡C-4-C6H4-NO2, [m-1 e]) were prepared by reaction of the iron chloride Cp*(dppe)FeCl (4) and the proligands 3 b-e obtained by a cross coupling reaction between the suitable aryl dibromides and trimethylsylilacethylene. After purification the complexes [m-1 b–e] were isolated in yields ranging from 14 to 37 % and characterized by elemental analysis, high-resolution, ESI-mass spectra, multinuclear NMR, cyclic voltammetry, and IR spectroscopy. The complexes [m-1 b], [m-1 d], and [m-1 e] were also characterized by XRD analyses on single crystals. The doubly oxidized complexes [m-1 b–e](PF6)2 were prepared (in ca. 64–87 % yields) by treatment of a CH2Cl2 solution of the corresponding neutral complexes [m-1 b–e] with two equiv. of [(C5H5)2Fe](PF6). The mixed-valence complexes (MV) [m-1 b–e](PF6) were obtained by comproportionation between one equiv. of [m-1 b–e] and one equiv. of [m-1 b–e](PF6)2. CV, IR and NIR data led to the conclusion that the MV [m-1 b–e](PF6) complexes are weakly coupled Class II MV derivatives and the distribution of the charge between the alkynyl iron centers and the phenyl ring might be tuned by the X-substituents in a limited extend. © 2021 Wiley-VCH GmbH.

International audience; We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms at either positions 3,6 (3,6-PC2A) or 3,9 (3,9-PC2A) of the macrocyclic fragment. The 3,6-PC2A ligand was synthesized in five steps from pyclen oxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with 3,9-PC2A is characterized by a higher thermodynamic stability [log KMnL = 17.09(2)] than the 3,6-PC2A analogue [log KMnL = 15.53(1); 0.15 M NaCl]. Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high 1H relaxivities (r1p = 2.72 and 2.91 mM–1 s–1 for the complexes with 3,6-PC2A and 3,9-PC2A, respectively, at 25 °C and 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (kex298) are 140 × 106 and 126 × 106 s–1 for [Mn(3,6-PC2A)(H2O)] and [Mn(3,9-PC2A)(H2O)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with half-lives of 63 and 21 h, respectively, at pH = 7.4 in the presence of excess Cu(II). The r1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)(H2O)]2– (H4EDTA = ethylenediaminetetraacetic acid) and [Mn(PhDTA)(H2O)]2– (H4PhDTA = phenylenediamine-N,N,N′,N′-tetraacetic acid), indicating that the PC2A complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/p-nitro blue tetrazolium chloride assay at pH = 7.8. The Mn(II) complexes of 3,6-PC2A and 3,9-PC2A are capable of assisting decomposition of the superoxide anion radical. The kinetic rate constant of the complex of 3,9-PC2A is smaller by 1 order of magnitude than that of 3,6-PC2A.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Treatment of the triflate complex [Cp*(dppe)FeOTf] ₅; Cp* = η5-C5(CH3)5, dppe = 1,2-bis(diphenylphosphanyl)ethane, OTf = CF3SO3_ with an excess of HC≡C–[Si(CH3)2]2–1,4-C6H4X (6a–e) in a mixture of THF and triethylamine (NEt3) provides the new complexes ₁a: X = H; 1b: X = CH3; 1c: X = N(CH3)2; 1d: X = CF3; 1e: X = Br_, which were isolated in 64 to 81 % yields as orange powders. The cyclic voltammetry, and multinuclear NMR, IR, and UV/Vis spectroscopic data obtained for 1a–e, as well as the X-ray crystal structures determined for 1a, 1c, and 1e, reveal the importance of the σ–π conjugation (hyperconjugation) between the Si–Si σ-bond and the vicinal C≡C π-orbitals in the description of the electronic structure of the ground state of these complexes. When compounds 1a–e are reacted with [(C5H5)2Fe](PF6) (1 equiv.) at 20 °C, they provide [1a–e](PF6), which partially decompose in solution during the reaction process. They were isolated as mixtures with the mononuclear [Cp*(dppe)Fe=C=CH2](PF6) (7) and binuclear [Cp*(dppe)Fe=C=CH–CH=C=Fe(dppe)Cp*](PF6)2 (8) vinylidenes. Reduction of these mixtures with cobaltocene affords the parent neutral compounds 1a–e in analytically pure forms. The iron(III) complexes were characterized by IR and Mossbauer spectroscopy, which clearly showed that the iron(III) nucleus sensed the electronic effect of the X substituents. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim