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International audience; A systematic comparison of lipophilicity modulations upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl substituents, at a single carbon atom, is provided using directly comparable, and easily accessible model compounds. In addition, comparison with relevant linear chain derivatives is provided, as well as lipophilicity changes occurring upon chain extension of acyclic precursors to give cyclopropyl containing compounds. For the compounds investigated, fluorination of the isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent.

International audience; Efficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation–activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformer-specific lipophilicities (logp) is much less explored. Here we show how conformer-specific logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer 19F NMR signals as a facile, direct method to obtain logp values. The difference between logp and logP optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery.

Summary Background Salmonella spp are a major cause of food-borne outbreaks in Europe. We investigated a large multi-country outbreak of Salmonella enterica serotype Enteritidis in the EU and European Economic Area (EEA). Methods A confirmed case was defined as a laboratory-confirmed infection with the outbreak strains of S Enteritidis based on whole-genome sequencing (WGS), occurring between May 1, 2015, and Oct 31, 2018. A probable case was defined as laboratory-confirmed infection with S Enteritidis with the multiple-locus variable-number tandem repeat analysis outbreak profile. Multi-country epidemiological, trace-back, trace-forward, and environmental investigations were done. We did a case-control study including confirmed and probable cases and controls randomly sampled from the population registry (frequency matched by age, sex, and postal code). Odds ratios (ORs) for exposure rates between cases and controls were calculated with unmatched univariable and multivariable logistic regression. Findings 18 EU and EEA countries reported 838 confirmed and 371 probable cases. 509 (42%) cases were reported in 2016, after which the number of cases steadily increased. The case-control study results showed that cases more often ate in food establishments than did controls (OR 3·4 [95% CI 1·6–7·3]), but no specific food item was identified. Recipe-based food trace-back investigations among cases who ate in food establishments identified eggs from Poland as the vehicle of infection in October, 2016. Phylogenetic analysis identified two strains of S Enteritidis in human cases that were subsequently identified in salmonella-positive eggs and primary production premises in Poland, confirming the source of the outbreak. After control measures were implemented, the number of cases decreased, but increased again in March, 2017, and the increase continued into 2018. Interpretation This outbreak highlights the public health value of multi-country sharing of epidemiological, trace-back, and microbiological data. The re-emergence of cases suggests that outbreak strains have continued to enter the food chain, although changes in strain population dynamics and fewer cases indicate that control measures had some effect. Routine use of WGS in salmonella surveillance and outbreak response promises to identify and stop outbreaks in the future. Funding European Centre for Disease Prevention and Control; Directorate General for Health and Food Safety, European Commission; and National Public Health and Food Safety Institutes of the authors' countries (see Acknowledgments for full list).

Identifying non-contaminated sample of high-redshift galaxies with escaping Lyman continuum (LyC) flux is important for understanding the sources and evolution of cosmic reionization. We present CLAUDS $u$-band photometry of the COSMOS field to probe LyC radiation from spectroscopically confirmed galaxies at $z\geq3.5$ and outside the standard Lyman-break galaxy colour selection expectations. Complementary to the CLAUDS data, we use Subaru multi-filter photometry, \textit {Hubble Space Telescope} ($HST$) multi-filter imaging, and the spectroscopic surveys D10K, VUDS and 3D-HST. We present a sample of Lyman continuum galaxy (LCG) candidates in the redshift range $3.5\lesssim z\lesssim5.1$. Here, we introduce 5 LCG candidates, where two are flagged quality 1 and three quality 2. The estimated $f_{\rm esc}^{\rm abs}$ for quality 1 candidates are in the range $\sim5\% - 73\%$ and $\sim30\% - 93\%$. These estimates are based on our derived parameters from individual galaxies as inputs to a range of BPASS models as well as mean intergalactic medium (IGM) and maximal intergalactic and circumgalactic media (IGM+CGM) transmission. We conclude that our search for LCGs is most likely biased to lines of sight with low HI densities or free from Lyman limit systems. Our two best LCG candidates have EW (Ly$\alpha)\leq50$\AA\ and we find no correlation or anti-correlation between EW (Ly$\alpha$), $f_{\rm esc}^{\rm abs}$, and $R_{\rm obs}$, the ratio of ionizing to non-ionizing observed flux in the measured passbands. Stacking candidates without solid LyC detections ($S/N, Comment: 22 pages, 12 figures, accepted for publication 30/3/2020

An electric field–induced, symmetry-breaking, transition from NTB to NSB nematics reveals the importance of local biaxiality., Although the existence of the twist-bend (NTB) and splay-bend (NSB) nematic phases was predicted long ago, only the former has as yet been observed experimentally, whereas the latter remains elusive. This is especially disappointing because the NSB nematic is promising for applications in electro-optic devices. By applying an electric field to a planar cell filled with the compound CB7CB, we have found an NTB-NSB phase transition using birefringence measurements. This field-induced transition to the biaxial NSB occurred, although the field was applied along the symmetry axis of the macroscopically uniaxial NTB. Therefore, this transition is a counterintuitive example of breaking of the macroscopic uniaxial symmetry. We show by theoretical modeling that the transition cannot be explained without considering explicitly the biaxiality of both phases at the microscopic scale. This strongly suggests that molecular biaxiality should be a key factor favoring the stability of the NSB phase.

International audience; Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic log P values, are involved in discussing various lipophilicity trends. As well as confirming known trends, a number of novel lipophilicity-reducing motifs are introduced. Tactics to reduce lipophilicity are discussed, such as "motif extensions" and "motif rearrangements", including with concomitant extension of the carbon chain, as well as one- and two-fluorine 'deletions' within perfluoroalkyl groups. Quantum chemical log P calculations (SMD-MN15) based on solvent-dependent three-dimensional (3D) conformational analysis gave excellent correlations with experimental values, superior to Clog P predictions based on 2D structural motifs. The availability of a systematic collection of data based on a small number of parent molecules illustrates the relative lipophilicity modulations of aliphatic fluorination motifs.

The authors thank Lyndon Emsley for making means available.; International audience; We have induced hyperpolarized long-lived states in compounds containing C-13-bearing methyl groups by dynamic nuclear polarization (DNP) at cryogenic temperatures, followed by dissolution with a warm solvent. The hyper polarized methyl long-lived states give rise to enhanced antiphase C-13 NMR signals in solution, which often persist for times much longer than the C-13 and H-1 spin-lattice relaxation times under the same conditions. The DNP-induced effects are similar to quantum-rotor-induced polarization (QRIP) but are observed in a wider range of compounds because they do not depend critically on the height of the rotational barrier. We interpret our observations with a model in which nuclear Zeeman and methyl tunnelling reservoirs adopt an approximately uniform temperature, under DNP conditions. The generation of hyperpolarized NMR signals that persist for relatively long times in a range of methyl-bearing substances may be important for applications such as investigations of metabolism, enzymatic reactions, protein ligand binding, drug screening, and molecular imaging.

International audience; Fluorinated proline derivatives have found diverse applications in areas ranging from medicinal chemistry over structural biochemistry to organocatalysis. Depending on the stereochemistry of monofluorination at the proline 3- or 4-position, different effects on the conformational properties of proline (ring pucker, cis/ trans isomerization) are introduced. With fluorination at both 3- and 4-positions, matching or mismatching effects can occur depending on the relative stereochemistry. Here we report, in full, the syntheses and conformational properties of three out of the four possible 3,4-difluoro-l-proline diastereoisomers. The yet unreported conformational properties are described for (3 S,4 S)- and (3 R,4 R)-difluoro-l-proline, which are shown to bias ring pucker and cis/ trans ratios on the same order of magnitude as their respective monofluorinated progenitors, although with significantly faster amide cis/ trans isomerization rates. The reported analogues thus expand the scope of available fluorinated proline analogues as tools to tailor proline's distinct conformational and dynamical properties, allowing for the interrogation of its role in, for instance, protein stability or folding.

In this work we extended the generic approach for the site-directed immobilization of enzymes based on maleimide\thiol coupling of engineered enzymes to the oriented immobilization of variants of bilirubin oxidase from Magnaporthe oryzae (MoBOD) to electrodes. We show that this approach leads to the stable attachment of the enzyme to the electrode surface and that the immobilised MoBOD variants are active for bioelectrocatalytic reduction of di-oxygen through direct (unmediated) electron transfer (DET) from the electrode. For the three MoBOD variants studied significant differences are observed in the kinetics of DET that relate to the orientation of the enzyme and the distance of the T1 site from the electrode surface. The stability of the immobilized enzymes allows us to compare the DET and mediated electron transfer (MET) pathways and to investigate the effects of pH and Cl‾. Our studies show a change in the slope of pH dependence at pH 6.0 and highlight the effect of Cl‾ on the direct oxygen reduction by MoBOD as a function of pH for the immobilized enzyme and the interconversion of the resting oxidized (RO) form of the immobilized enzyme and the alternative resting (AR) state formed in the presence of Cl‾.

International audience; We have studied a mixture of the twist-bend nemogenic dimer CB7CB with rod-like nematic molecules, which exhibits nematic (N) and twist-bend nematic (NTB) phases and a very large biphasic coexistence range. At the N-NTB transition, we observe the nucleation of highly anisometric NTB droplets which are very similar to the classic smectic A (SmA) bâtonnets. These observations confirm the recently proposed close analogy between the NTB and SmA phases, on the basis of their identical macroscopic symmetry. As for their smectic analogues, the NTB bâtonnets are fluid in two dimensions; they easily merge when brought into contact and they are solid-like in that they did not flow along their optic axis. The observed fluidity and low viscosity show that the NTB phase is indeed a nematic phase, i.e. an anisotropic fluid, rather than a soft crystal or glassy state. Unlike their smectic analogues, the NTB bâtonnets have almost perfect symmetry of revolution and the axis of the NTB helix is uniformly aligned parallel to the long axis of the bâtonnet. The large aspect ratio of the bâtonnets, typically ≈ 10-30, indicates a very strong anisotropy of the N-NTB interfacial energy, W2/W0 ≈ 200-2000, and suggests that the anchoring energy differs from the usual Rapini-Papoular form.

International audience; The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received 12 million s funding under the European Union Framework Programme 7 from 1st June 2008 to 30th November 2012. The 19 project partners from both academia and industry from in total 7 countries had a project budget of 16 Ms with which they have discovered, created and developed a huge body of insights into nucleic acid analysis. Results have been presented widely in publications and in innumerous public presentations. Results have been moved to spin-offs such as the Olink enrichment kits (now sold by Agilent as Haloplex) and are findingtheir way to the market, such as the Oxford Nanopore MinIon sequencer that was first released to early-access user sites in 2014.

A range of nuclear magnetic resonance spectroscopy and imaging applications are limited by the short lifetimes of magnetisation in solution. Long-lived states, which are slowly relaxing configurations of nuclear spins, have been shown to alleviate this limitation. Long-lived states have decay lifetimes TLLS significantly exceeding the longitudinal relaxation time T1, in some cases by an order of magnitude. Here we present an experimental case of a long-lived state for a 15N labelled molecular system in solution. We observe a strongly biexponential decay for the long-lived state, with the lifetime of the slowly relaxing component exceeding 40 minutes, ∼21 times longer than the spin-lattice relaxation time T1. The lifetime of the long-lived state was revealed by using a dedicated two-field NMR spectrometer capable of fast sample shuttling between high and low magnetic fields, and the application of a resonant radiofrequency field at low magnetic field. The relaxation characteristics of the long-lived state are examined.

In the recently discovered Twist-Bend Nematic (NTB) phase, the nematic director is spontaneously distorted and twisted along a conical helix with an extremely short pitch, ~10 nm. We have investigated the behavior of the NTB phase subject to an electric-field. We show that, due to the periodic NTB structure, the electro-optic effects are not nematic-like but are close analogs to those in the smectic and cholesteric phases. In particular, we have studied the fast (sub-microsecond) flexoelectrically- induced rotation of the optic axis, which is similar to the electroclinic effect in the SmA* phase and the flexoelectric response of short-pitch cholesterics. We discuss the possible applications of the fast NTB electro-optic effects.

Dissolution-dynamic nuclear polarization is implemented to hyperpolarize long-lived nuclear spin states in monodeuterated methyl groups., Monodeuterated methyl groups may support a long-lived nuclear spin state, with a relaxation time exceeding the conventional spin–lattice relaxation time T1. Dissolution-DNP (dynamic nuclear polarization) may be used to hyperpolarize such a long-lived spin state. This is demonstrated for the CH2D groups of a piperidine derivative. The polarized sample is manipulated in the ambient magnetic field of the laboratory, without destruction of the hyperpolarized singlet order. Strongly enhanced CH2D signals are observed more than one minute after dissolution, even in the presence of paramagnetic radicals, by which time the NMR signal from the hyperpolarized proton magnetization has completely disappeared.

Highly branched polyamidoamine (PAMAM) dendrimers presenting biological activities have been envisaged as non-viral gene delivery vectors. They are known to associate with nucleic acid (DNA) in non-covalent complexes via electrostatic interactions. Although their transfection efficiency has been proved, PAMAMs present a significant cytotoxicity due to their cationic surface. To overcome such a drawback, different chemical modifications of the PAMAM surface have been reported such as the attachment of hydrophobic residues. In the present work, we studied the complexation of DNA duplexes with different low-generation PAMAM, ammonia-cored G0(N) and G1(N) PAMAM, native or chemically modified with aromatic residues, i.e., phenyl-modified-PAMAM G0(N) and phenylalanine-modified-PAMAM G1(N). To investigate the interactions involved in the PAMAM/DNA complexes, also called dendriplexes, we used electrospray ionization (ESI) coupled to ion mobility spectrometry-mass-spectrometry (IM-MS). ESI is known to allow the study of non-covalent complexes in native conditions while IM-MS is a bidimensional separation technique particularly useful for the characterization of complex mixtures. IM-MS allows the separation of the expected complexes, possible additional non-specific complexes and the free ligands. Tandem mass spectrometry (MS/MS) was also used for the structural characterization. This work highlights the contribution of IM-MS and MS/MS for the study of small dendriplexes. The stoichiometries of the complexes and the equilibrium dissociation constants were determined. The [DNA/native PAMAM] and [DNA/modified-PAMAM] dendriplexes were compared.

International audience; Rational modulations of molecular interactions are of significant importance in compound properties optimization. We have previously shown that fluorination of conformationally rigid cyclohexanols leads to attenuation of their hydrogen-bond (H-bond) donating capacity (designated by pK(AHY)) when OH center dot center dot center dot F intramolecular hydrogen-bond (IMHB) interactions occur, as opposed to an increase in pK(AHY) due to the fluorine electronegativity. This work has now been extended to a wider range of aliphatic beta-fluorohydrins with increasing degrees of conformational flexibility. We show that the observed differences in pK(AHY) between closely related diastereomers can be fully rationalized by subtle variations in populations of conformers able to engage in OH center dot center dot center dot F IMHB, as well as by the strength of these IMHBs. We also show that the Kenny theoretical V-alpha(r) descriptor of H-bond acidity accurately reflects the observed variations and a calibration equation extended to fluorohydrins is proposed. This work clearly underlines the importance of the weak OH center dot center dot center dot F IMHB in the modulation of alcohol H-bond donating capacity.

International audience; The synthesis of nanostructured anionic-surfactant-templated mesoporous silica (AMS) recently appeared as a new strategy for the formation of nanostructured silica based materials. This method is based on the use of anionic surfactants together with a co-structure-directing agent (CSDA), mostly a silylated ammonium precursor. The presence of this CSDA is necessary in order to create ionic interactions between template and silica forming phases and to ensure sufficient affinity between the two phases. This synthetic strategy was for the first time applied in view of the synthesis of surface functionalized silica bearing ammonium groups and was then extended on the formation of materials functionalized with anionic carboxylate and bifunctional amine-carboxylate groups. In the field of silica hybrid materials, the “anionic templating” strategy has recently been applied for the synthesis of silica hybrid materials from cationic precursors. Starting from di- or oligosilylated imidazolium and ammonium precursors, only template directed hydrolysis-polycondensation reactions involving complementary anionic surfactants allowed accessing structured ionosilica hybrid materials. The mechanistic particularity of this approach resides in the formation of precursor-surfactant ion pairs in the hydrolysis-polycondensation mixture. This review gives a systematic overview over the various types of materials accessed from this cooperative ionic templating approach and highlights the high potential of this original strategy for the formation of nanostructured silica based materials which appears as a complementary strategy to conventional soft templating approaches.

International audience; Convenient access to homochiral fluoroalkenes is described via a Julia-Kocienski olefination reaction. The required homochiral fluorosulfone is synthesized by a Mitsunobu reaction from readily available enantiopure secondary alcohols.

International audience; The conformational preferences of o-cresols driven by fluorination were thoroughly investigated from a theoretical point of view with quantum-chemical methods, and the results were compared to those recently reported for benzyl alcohols. The key conformers of both families exhibit a six-membered intramolecular hydrogen-bond (IMHB) interaction. A significant enhancement in the strength of the IMHB is observed in -fluoro-o-cresols, owing to a simultaneous increase in the hydrogen bond (HB) basicity of the aliphatic fluorine and the HB acidity of the aromatic hydroxyl relative to that observed for o-fluorobenzyl alcohols, which are characterized by aromatic fluorine atoms and aliphatic hydroxyl groups. In the cases of the di- and trifluorinated derivatives, the occurrence of a three-centered HB is emphasized, and its features are discussed. The impact of these structural predilections on the HB properties of o-cresol was characterized from the estimation of the HB acidity parameter, pK(AHY), weighted according to their conformational populations. We found that -fluorination led to a decrease in the HB acidity of the hydroxyl group (in contrast with the o-fluorination of benzyl alcohols), whereas ,-difluorination resulted in no significant variation in pK(AHY). Finally, an increase in the HB acidity was predicted upon methyl perfluorination, which was confirmed experimentally. Theoretical descriptors based on atoms in molecules, noncovalent interactions, and natural bond orbital analyses allowed rationalization of the predicted trends and revealed a relationship with the strength of the established OH center dot center dot center dot F IMHB.

The success of fluorination in improving molecular properties over a wide range of applications (including pharmaceuticals,1 agrochemicals,2 materials,3 and crystal engineering4) has been remarkable. Up to 20 % of the pharmaceuticals prescribed or administered in the clinic, and a third of the leading 30 blockbuster drugs, contain at least one fluorine atom1a and 30–40 % of currently marketed agrochemicals contain fluorine.5

International audience; The first single-crystal X-ray diffraction study of tetrafluorinated monosaccharide derivatives is presented. Both α- and β-methyl 2,3-dideoxy-2,2,3,3-tetrafluoro-d-galactopyranoside anomers adopt the (4)C(1) conformation. The values for the C1-O1 and C1-O5 bond lengths and the O5-C1-O1-CH(3) dihedral angles are in line with what can be expected from the anomeric and exo-anomeric effects. The chair conformations are slightly distorted, presumably due to repulsion between 1,3-diaxial C-O and C-F bonds. The asymmetric unit of both compounds contains up to three independent molecules, which differ in the conformation of the hydroxymethyl group (including in one case a 'forbidden'gg rotamer). The molecular packing of the β-anomer shows a clear segregation between fluorinated and hydrophilic domains, while for the α-anomer the regions of fluorine segregation are broken by interleafing of OMe groups. There is one close OH⋯F contact, which is likely to arise from the crystal packing. NMR studies show that the two anomers also adopt a (4)C(1) conformation in solution (D(2)O, CDCl(3)).

International audience; A variety of amide-subsituted anthracene derivates have been synthesised and their anion complexation properties studied using 1H-NMR titration techniques. Additionally, bis-urea functionalised anthracene derivatives have been shown to serve as excellent receptors for oxo-anions and to function as sensors via fluorescence quenching in DMSO-d6/0.5% water and MeCN/DMSO (96.5:3.5 v/v).

International audience; 1. Introduction Spontaneously distorted nematic states have been theoretically predicted long ago for bent-shaped mesogens [1-3]. Recent experiments [4] confirmed the existence of the twist-bend nematic phase, NTB, with short-pitch heliconical precession of the director n. Another predicted state [3], the splay-bend nematic, NSB, with n oscillating in a plane, is still elusive. However, a recent birefringence study [5] suggested NSB structure of the defect wall separating two NTB domains with opposite chiralities.2. Twist-bend to splay-bend transition under strong electric fieldHere we investigate the NTB state of the bent-shaped dimer CB7CB under strong a.c. electric field, (E ~10 V/µm) parallel to the helix axis. This in-plane field is applied in a 2 µm cell using two ITO electrodes (Fig.1). Crossing the N- NTB transition under field, we observe in the interelectrode region slightly lower transition temperature and much stronger birefringence than that reported in the NTB phase [5], suggesting an electric-field induced NTB – NSB transition.3. ConclusionA strong electric field applied to the NTB phase induces a transition to the splay-bend nematic phase, instead to the usual uniform nematic N. We explain this in the framework of the elastic-instability model [3] of the NTB and NSB phases by taking into account the strong biaxiality of the bent-shape nematic.References[1]R. B. Meyer, in Molecular Fluids, edited by R. Balian and G. Weill (Gordon and Breach, New York 1976), pp. 273 [2]V. L. Lorman and B. Mettout, Phys. Rev. Lett. 82, 940 (1999).[3]I. Dozov, EPL (Europhysics Letters) 56, 247 (2001).[4]M. Cestari, S. Diez-Berart, D. A. Dunmur, A. Ferrarini, M. R. de la Fuente, D. J. B. Jackson, D. O. Lopez, G. R. Luckhurst, M. A. Perez-Jubindo, R. M. Richardson, J. Salud, B. A. Timimi and H. Zimmermann, Physical Review E 84, 031704 (2011).[5]C. Meyer, G. R. Luckhurst and I. Dozov, Journal of Materials Chemistry C 3, 318 (2015).

International audience; The preparation route has been shown to have a significant influence upon the catalytic behaviour of Ni2Mo3N samples for ambient pressure ammonia synthesis. Materials prepared from a NiMoO4 precursor necessarily contain a significant fraction of Ni impurity phase. Materials prepared from this precursor are relatively inactive for ammonia synthesis, whereas Ni2Mo3N of much greater phase purity and catalytic activity can be prepared from precursors employing a modified Pechini method with the use of citrate gels. Ni2Mo3N can be prepared by N-2/H-2 pre-treatment which represents a significant advantage over routes employing ammonolysis. Bulk lattice nitrogen appears to be relatively unreactive in Ni2Mo3N, although heterolytic nitrogen isotopic exchange studies indicate that a significant degree is exchangeable subject to pre-treatment conditions. The modified Pechini method based route has also been shown to be applicable to the preparation of CoNiMo3N of relatively high phase purity, thereby allowing access to the preparation of quaternary nitrides for catalytic screening.

International audience; The deuterium NMR spectrum of benzene-d(6) in a high field spectrometer (1 GHz protons) exhibits a magnetic field-induced deuterium quadrupolar splitting Delta v. The magnitude of Delta v observed for the central resonance is smaller than that observed for the C-13 satellite doublets Delta v'. This difference, Delta(Delta v) Delta v' - Delta v, is due to unresolved fine structure contributions to the respective resonances. We determine the origins of and simulate this difference, and report pulse sequences that exploit the connectivity of the peaks in the C-13 and H-2 spectra to determine the relative signs of the indirect coupling, J(CD), and Delta v. The positive sign found for Delta v is consonant with the magnetic field biasing of an isolated benzene molecule-the magnetic energy of the aromatic ring is lowest for configurations where the C-6 axis is normal to the field. In the neat liquid the magnitude of Delta v is decreased by the pair correlations in this prototypical molecular liquid.

International audience

International audience; Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH center dot center dot center dot F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time-and in contrast to earlier reports-the occurrence of OH center dot center dot center dot F IMHBs in acyclic saturated g-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding (h1)J(OH center dot center dot center dot F) values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9 Hz). The magnitude of OH center dot center dot center dot F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the ``rule of shielding'' applies to OH center dot center dot center dot F IMHB energies. Surprisingly, the predicted OH center dot center dot center dot F IMHB energies are only moderately weaker than these of the corresponding OH center dot center dot center dot OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design.

International audience; Organofluorine is a weak hydrogen-bond (HB) acceptor. Bernet et al. have demonstrated its capability to perturb OH center dot center dot center dot O intramolecular hydrogen bonds (IMHBs), using conformationally rigid carbohydrate scaffolds including levoglucosan derivatives. These investigations are supplemented here by experimental and theoretical studies involving six new levoglucosan derivatives, and complement the findings of Bernet et al. However, it is shown that conformational analysis is instrumental in interpreting the experimental data, due to the occurrence of non-intramolecular hydrogen-bonded populations which, although minor, cannot be neglected and appears surprisingly significant. The DFT conformational analysis, together with the computation of NMR parameters (coupling constants and chemical shifts) and wavefunction analyses (AIM, NBO), provides a full picture. Thus, for all compounds, the most stabilized structures show the OH groups in a conformation allowing IMHB with O5 and O6, when possible. Furthermore, the combined approach points out the occurrence of various IMHBs and the effect of the chemical modulations on their features. Thus, two-center or three-center IMHB interactions are observed in these compounds, depending on the presence or absence of additional HB acceptors, such as methoxy or fluorine.

International audience; The selective synthesis of fluoroalkenoates is reported from a pyrimidinyl fluorosulfone. This sulfone allowed the preparation of Z-fluoroalkenoates with very high stereoselectivity from both aromatic and aliphatic aldehydes. The nature of the heterocycle on the course of the JuliaeKocienski reaction is discussed.

International audience

248th National Meeting of the American-Chemical-Society (ACS), San Francisco, CA, AUG 10-14, 2014; International audience

The Reformatsky reaction of ethyl bromodifluoroacetate to ?-oxygenated sulfinylimines is described. Using Honda–Reformatsky conditions, the reaction proceeds with double diastereodifferentiation, with the configuration of the sulfinyl group determining the stereochemical course of the reaction. Excellent diastereoselectivities (>94:6) are obtained for the matched cases. In contrast, reaction with sulfinylimines derived from unsubstituted alkanals proceeded with virtually no diastereoselectivity

248th National Meeting of the American-Chemical-Society (ACS), San Francisco, CA, AUG 10-14, 2014; International audience

International audience; The sets of residual dipolar couplings between carbon and hydrogen nuclei obtained from the proton-encoded 13C 2D NMR experiment are used to investigate the conformational changes which occur when the achiral symmetric liquid crystal dimer CB7CB changes from the achiral nematic to the chiral twist-bend nematic phase. It is found that these changes are a consequence of the chirality of the twist-bend nematic phase, rather than being the driving force for the stability of this phase.

To the Editor: Human enteroviruses (EVs) are small, nonenveloped RNA viruses belonging to the family Picornaviridae. Approximately 100 EV genotypes have been identified. Recently, EV68 epidemics in respiratory tract infections (RTIs) have been reported worldwide (1,2). Moreover, rarely detected EVs (e.g., EV-C104 and EV-C109) have been increasingly identified in patients with RTIs (3–7), indicating a possible association of EVs with respiratory syndromes. Little is known about the role of EV-C104 in RTIs. EV-C104 has been reported in 3 countries: Switzerland (7 children with pneumonia or otitis media) (3), Italy (3 adults and 4 children with RTIs) (4,7), and Japan (1 adult with an upper RTI [URTI](5). We report additional EV-C104 strains in 4 children with lower RTIs and in 1 adult with a URTI in China. To identify EV infections, we collected nasopharyngeal aspirates from 3,108 children (1,963 boys) ≤14 years of age (median age 12 months; age range 0.3–168 months) who had lower RTIs at admission to Beijing Children’s Hospital during March 2007–February 2012. Throat and nasal swab specimens were also collected from 9,232 adults (4,140 men) ≥ 15 years of age (median age 35.3 years; age range 15–97 years) with acute RTIs who received treatment at Peking Union Medical College Hospital during August 2006–February 2012. All samples were screened for influenza virus, parainfluenza virus type 1–4, respiratory syncytial virus (RSV), coronaviruses (229E, NL63, HKU1, and OC43), metapneumovirus, adenovirus, rhinovirus, bocavirus, and EVs (8). Overall, 37 (1.2%) children and 158 (1.7%) adults were positive for EV. Because we could not amplify EV-C104 by using primers specific for the viral protein (VP) 1 region (9), we used a reverse transcription PCR to amplify the 5′-untranslated region/VP4/VP2 gene (10). Amplicons of ≈600 bp were obtained for samples from 5 patients: 4 boys 2–11 months of age (BCH2859A, BCH2892A, BCH2894A, and BCH3034A) and a 30-year-old man (PUMCH12286). BLAST analysis (www.ncbi.nlm.nih.gov) of sequences of these amplicons showed that the 590-nt sequences had 94.0% identity with that of the EV-C104 prototype strain CL-12310945 ({"type":"entrez-nucleotide","attrs":{"text":"EU840733","term_id":"255682691"}}EU840733). The amplicon contained 155 nt in the 5′-untranslated region, 207 nt in VP4, and 228 nt in VP2. Phylogenetic analysis of VP4/VP2 sequences showed that the 5 sequences obtained in this study (GenBank accession nos. {"type":"entrez-nucleotide-range","attrs":{"text":"JX560522-JX560526","start_term":"JX560522","end_term":"JX560526","start_term_id":"472825516","end_term_id":"472825524"}}JX560522-JX560526) belonged to genotype EV-C104 within the EV-C species (Figure). Figure Phylogenetic tree of human enteroviruses (EVs) for nucleotide sequences of the viral protein (VP) 4/VP2 gene region (435 nt, corresponding to nt positions 654–1,088 of EV-C104 prototype strain CL-12310945 [{"type":"entrez-nucleotide","attrs":{"text":"EU840733","term_id":"255682691"}} ... Virus isolation for EV-C104 with Vero and H1-HeLa cells was unsuccessful. Although we screened 591, 797, 459, 664 and 597 samples from children for 5 consecutive years and 1,765, 1,978, 1,350, 1,562, 1,573, and 1,004 samples from adults for 6 consecutive years, we did not detect EV-C104 strains until November 2011–February 2012. Nucleotide identity of the EV-C104 sequences from this study was 99.5%–100% among BCH strains and 97.7%–98.0% between the PUMCH strain and the BCH strains. Deduced amino acid sequences in VP4/VP2 among the BCH strains were identical, albeit for 1 aa difference for the PUMCH strain (BCH strains had Pro110, but the PUMCH strain had Leu110, which was consistent with strains detected in children and adults in Italy). Deduced amino acid sequences for all 5 strains isolated in this study had 97.9%–100.0% identity with those from Switzerland, Italy, and Japan. BCH strains were community acquired because these 4 patients came from different cities and were admitted to different wards on different dates. The 4 EV-C104–positive boys all had fever and cough for >10 days before their hospitalization. Chest radiographs showed increased lung markings or patchy shadows diagnosed as pneumonia or bronchopneumonia. RSV or adenovirus was also detected in 3 of the boys. The fourth boy was positive for parainfluenza virus type 1, adenovirus, and bocavirus. Clinical outcomes for all 4 children were favorable. The EV-C104–positive man had fever, chills, pantalgia, and expectoration for 1 day before a URTI was diagnosed. EV-C104 was the only virus detected in this patient. We compared relative viral loads for all viruses in the 5 patients and quantified viral load of EV-C104 and other viruses by using real-time PCR (methods available upon request). Median viral load in the 5 patients was 2.4 × 106 RNA copies/mL (range 5.6 × 104–7.0 × 106 copies RNA/mL (Table, Appendix). Table Viral load of EV C104 and other viruses in 5 patient samples, People’s Republic of China, March 2007–February 2012* Overall, we found few (5/12,340) EV-C104–positive specimens. All EV-C104–positive children were co-infected with RSV or adenoviruses (high viral loads) in our study. The role of EV-C104 in RTIs needs to be further studied. Nevertheless, the finding of EV-C104–positive adults with high viral loads in China (3.9 × 106 RNA copies/mL) and Italy (2.0 × 106 RNA copies/mL) (7) indicates a possible association between EV-C104 with RTIs. Our data also confirm a wide distribution of EV-C104.

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract illnesses worldwide. Although the prevalence and clinical manifestations of the two subtypes, RSV‐A and RSV‐B, have been studied in some detail in infants and young children, they have not been determined in adults. To evaluate the prevalence of the RSV subtypes and disease severity between RSV‐A and RSV‐B infections in adults, nasal and throat swabs that were collected from patients ≥15 years old who sought medical care for acute respiratory infections at the Fever Clinic of the Peking Union Medical College Hospital in Beijing, China between May 2005 and April 2010. The samples were tested for RSV infection using PCR and sequencing analysis. RSV was detected in 95 (1%) of the adult patients, of whom 53 (55.8%) were positive for RSV‐A and 42 (44.2%) for RSV‐B. The incidence of RSV infections increased with age (χ2 = 37.17, P = 1.66E−07). Demographic data and clinical manifestations of RSV‐A were similar to those of RSV‐B. Although RSV‐A and RSV‐B co‐circulated during the 2005–2006 and 2008–2009 seasons, RSV‐A was predominant in the 2006–2008 seasons, whereas RSV‐B was predominant in the 2009–2010 season. Upper respiratory tract infections were diagnosed in most RSV‐infected patients (n = 80, 84.2%), and three patients suffered from pulmonary infection. This is the first study to provide data on the prevalence and clinical manifestations of RSV subgroups among Chinese adults with fever and acute illness, over five successive epidemic seasons. J. Med. Virol. 85:348–353, 2013. © 2012 Wiley Periodicals, Inc.

Analogues of potent 5-HT(4)R antagonists possessing a fluorinated N-alkyl chain have been synthesized in order to investigate the effect of the resulting change in basicity and lipophilicity on the affinity and selectivity profile. We demonstrate that for this series, the affinity is decreased with decreased basicity of the piperidine's nitrogen atom. In contrast, the resulting increase in lipophilicity has minimal impact on binding affinity and selectivity. 3,3,3-Trifluoropropyl and 4,4,4-trifluorobutyl derivatives 6d and 6e have shown to bind to the 5-HT(4)R while maintaining their pharmacological profile and selectivity toward other 5-HT receptors.

National audience

International audience; To determine the role of the pandemic influenza A/H1N1 2009 (A/H1N1 2009pdm) in acute respiratory tract infections (ARTIs) and its impact on the epidemic of seasonal influenza viruses and other common respiratory viruses, nasal and throat swabs taken from 7,776 patients with suspected viral ARTIs from 2006 through 2010 in Beijing, China were screened by real-time PCR for influenza virus typing and subtyping and by multiplex or single PCR tests for other common respiratory viruses. We observed a distinctive dual peak pattern of influenza epidemic during the A/H1N1 2009pdm in Beijing, China, which was formed by the A/H1N1 2009pdm, and a subsequent influenza B epidemic in year 2009/2010. Our analysis also shows a small peak formed by a seasonal H3N2 epidemic prior to the A/H1N1 2009pdm peak. Parallel detection of multiple respiratory viruses shows that the epidemic of common respiratory viruses, except human rhinovirus, was delayed during the pandemic of the A/H1N1 2009pdm. The H1N1 2009pdm mainly caused upper respiratory tract infections in the sampled patients; patients infected with H1N1 2009pdm had a higher percentage of cough than those infected with seasonal influenza or other respiratory viruses. Our findings indicate that A/H1N1 2009pdm and other respiratory viruses except human rhinovirus could interfere with each other during their transmission between human beings. Understanding the mechanisms and effects of such interference is needed for effective control of future influenza epidemics.

International audience; The synthesis of fluorosulfones by alkylation of fluoroacetate derivatives is reported. Their decarboxylation reaction under Krapcho conditions is a convenient process to prepare fluorosulfones as reagents for fluoroalkene synthesis.

International audience; Estrogen receptor-α (ER) is expressed in the great majority of breast cancers, and the inhibition of ER action is a key part of breast cancer treatment. The inhibition of ER action is achieved using anti-estrogens, primarily tamoxifen, and with aromatase inhibitors that inhibit estrogen biosynthesis, thereby preventing ER activation. However, resistance to these therapies is common. With the aim of identifying new molecular targets for breast cancer therapy, we have identified the liver receptor homolog-1 (LRH-1) as an estrogen-regulated gene. RNA interference and over-expression studies were used to investigate the role of the LRH-1 in regulating breast cancer growth and to identify the targets of an LRH-1 action. Promoter recruitment was determined using reporter gene and chromatin immunoprecipitation (ChIP) assays. We show that LRH-1 regulates breast cancer cell growth by regulating the ER expression. Reporter gene and in vitro DNA-binding assays identified an LRH-1-binding site in the ER gene promoter, and ChIP assays have demonstrated in vivo binding at this site. We also provide evidence for new LRH-1 variants in breast cancer cells arising from the use of alternative promoters. Previous studies have shown that LRH-1 functions in estrogen biosynthesis by regulating aromatase expression. Our findings extend this by highlighting LRH-1 as a key regulator of the estrogen response in breast cancer cells through the regulation of ER expression. Hence, inhibition of LRH-1 could provide a powerful new approach for the treatment of endocrine-resistant breast cancer.

International audience; A series of carbazolylurea and carbazolylthiourea-based receptors have been synthesized and their anion complexation and fluorescence properties studied. The urea compounds show selectivity for oxoanion complexation over chloride and the fluorescence of compound 1 is selectively quenched by benzoate anions in DMSO/0.5% water. However the thiourea compounds show reduced anion affinities compared to the urea analogues.

International audience; Four receptors containing either 2-amidoindole or 7-nitro-2-amidoindole groups have been synthesized and shown to complex oxo-anions in DMSO-d6/0.5% water solution. X-ray crystal structure elucidation reveals that receptor 1 complexes dihydrogen phosphate ion pairs in the solid state that are part of a continuous chain. Whilst this receptor binds dihydrogen phosphate in a 1:1 stoichiometry in solution, compound 4, which contains 7-nitroindole groups, does form 1:2 receptor:dihydrogen phosphate complexes in DMSO-d6/0.5% water.

International audience; Proton NMR titrations have been performed with meso-octacalix[4]pyrrole and a variety of organic chloride and bromide salts in dichloromethane-d2. The results show apparently increasing chloride stability constants within each set of anion salts (tetrabutylammonium < imidazolium < pyridinium). Addition of 1-ethyl-3-methylimidaolium (EMIM) nitrate to dichloromethane-d2 solutions of calix[4]pyrrole caused significantly larger downfield shifts of the pyrrole NH protons of calix[4]pyrrole than addition of equimolar quantities of tetrabutylammonium nitrate. The first crystal structure of a nitrate complex of a calix[4]pyrrole is also presented.

International audience; We report the controlled release of immobilized cholesteryl-tetraethyleneglycol-DNA (chol-DNA) from micropatterned SU-8 surfaces by a spreading lipid film. The release of chol-DNA is rapid and on the order of the spreading rate of the lipid film β = 1−3 μm2/s (∼105 molecules of DNA per second). The lipid film serves as a poor solvent for the DNA adduct, which upon contact redistributes into the aqueous phase. Thus, the release of DNA is accompanied by a change in surface hydrophobicity. The method can be used for creating arbitrary concentration profiles of DNA in solution over time or to dynamically change surface properties on demand in, for example, micro- and nanofluidic devices. Examples of DNA release from spiral, comb, meander, and triangular as well as from nanoscale SU-8 lanes are shown.

International audience; Two new ortho-phenylenediamine based bis-urea compounds have been synthesised with pendant amide groups. The stability constants of the new compounds with a variety of anionic guests have been measured by 1H NMR titration techniques and compared to the parent bis-urea. The X-ray crystal structure of the acetate and benzoate complexes of a bis-amide functionalised system have been solved and reveal the receptor forming a dimer with two anions bound at the termini of the hydrogen bonded assembly.

A new double-quantum solid-state NMR pulse sequence is presented and used to measure one-bond 13C-13C J-couplings in a set of 13C2-labeled rhodopsin isotopomers. The measured J-couplings reveal a perturbation of the electronic structure at the terminus of the conjugated chain but show no evidence for protein-induced electronic perturbation near the C11-C12 isomerization site. This work establishes NMR methodology for measuring accurate 1JCC values in noncrystalline macromolecules and shows that the measured J-couplings may reveal local electronic perturbations of mechanistic significance.

In magic-angle-spinning solid-state NMR, the homonuclear J-couplings between pairs of spin-1/2 nuclei may be determined by studying the modulation of the spin echo induced by a pi-pulse, as a function of the echo duration. We present the theory of J-induced spin-echo modulation in magic-angle-spinning solids, and derive a set of modulation regimes which apply under different experimental conditions. In most cases, the dominant spin-echo modulation frequency is exactly equal to the J-coupling. Somewhat surprisingly, the chemical shift anisotropies and dipole-dipole couplings tend to stabilise--rather than abscure--the J-modulation. The theoretical conclusions are supported by numerical simulations and experimental results obtained for three representative samples containing 13C spin pairs.

Using a molecular field theory with atomistic modelling, we provide a complete description of the elastic and flexoelectric properties of the nematic phase formed by liquid crystal dimers which, depending on the parity of the number of atoms in the spacer, have either a bent (odd) or a straight (even) average shape. We can then estimate the flexoelastic ratio and make a direct comparison with the outcome of flexoelectro-optic measurements. Our results demonstrate the extreme sensitivity of the bend elasticity and flexoelectricity to the molecular structure, with dramatic differences between even and odd dimers. An unusually low bend elastic constant is predicted for the latter; we discuss the implications of this result for the high flexoelastic response and the existence of Blue Phases stable over a wide temperature range, which were both recently claimed for odd liquid crystal dimers.