CD1 and iNKT cells mediate immune responses against the GBS hemolytic lipid toxin induced by a non-toxic analog.

Although hemolytic lipids have been discovered from many human pathogens including Group B Streptococcus (GBS), strategies that neutralize their function are lacking. GBS is a leading cause of pregnancy-associated neonatal infections, and adult GBS infections are on the rise. The GBS hemolytic lipid toxin or granadaene, is cytotoxic to many immune cells including T and B cells. We previously showed that mice immunized with a synthetic nontoxic analog of granadaene known as R-P4 had reduced bacterial dissemination during systemic infection. However, mechanisms important for R-P4 mediated immune protection was not understood. Here, we show that immune serum from R-P4-immunized mice facilitate GBS opsonophagocytic killing and protect naïve mice from GBS infection. Further, CD4+ T cells isolated from R-P4-immunized mice proliferated in response to R-P4 stimulation in a CD1d- and iNKT cell-dependent manner. Consistent with these observations, R-P4 immunized mice lacking CD1d or CD1d-restricted iNKT cells exhibit elevated bacterial burden. Additionally, adoptive transfer of iNKT cells from R-P4 vaccinated mice significantly reduced GBS dissemination compared to adjuvant controls. Finally, maternal R-P4 vaccination provided protection against ascending GBS infection during pregnancy. These findings are relevant in the development of therapeutic strategies targeting lipid cytotoxins.

Single-Molecule Conductance of Neutral Closed-Shell and Open-Shell Diradical Indenofluorenes.

Organic diradicals are highly promising candidates as future components in molecular electronic and spintronic devices because of their low spin-orbit coupling. To advance toward final circuit realizations, a thorough knowledge of the behavior of diradicals within a single-molecule junction framework is imperative. In this work, we have measured for the first time the single-molecule conductance of a neutral open-shell diradical compound, a [2,1-b] isomer of indenofluorene (IF). Our results reveal that the conductance of the [2,1-b] isomer is about 1 order of magnitude higher than that of the corresponding closed-shell regioisomer [1,2-b] IF. This is significant, as it fundamentally demonstrates the possibility of forming stable single-molecule junctions using neutral diradical compounds which are also highly conducting. This opens up a new approach to the development of externally addressable spintronic devices operable at room temperature.

Chiral Single-Molecule Potentiometers Based on Stapled ortho- Oligo(phenylene)ethynylenes.

We report on the chemical design of chiral molecular junctions with stress-dependent conductance, whose helicity is maintained during the stretching of a single molecule junction due to the stapling of both ends of the inner helix. In the reported compounds, different conductive pathways are observed, with clearly different conductance values and plateau-length distributions, attributed to different conformations of the helical structures. The large chiro-optical responses and the potential use of these molecules as unimolecular spin filters have been theoretically proved using state-of-the-art Density Functional Theory (DFT) calculations, including a fully ab-initio estimation of the CISS-originating spin polarization which is done, for the first time, for a realistic molecular system.

Single-Molecule Conductance of 1,4-Azaborine Derivatives as Models of BN-doped PAHs.

The single-molecule conductance of a series of BN-acene-like derivatives has been measured by using scanning tunneling break-junction techniques. A strategic design of the target molecules has allowed us to include azaborine units in positions that unambiguously ensure electron transport through both heteroatoms, which is relevant for the development of customized BN-doped nanographenes. We show that the conductance of the anthracene azaborine derivative is comparable to that of the pristine all-carbon anthracene compound. Notably, this heteroatom substitution has also allowed us to perform similar measurements on the corresponding pentacene-like compound, which is found to have a similar conductance, thus evidencing that B-N doping could also be used to stabilize and characterize larger acenes for molecular electronics applications. Our conclusions are supported by state-of-the-art transport calculations.

Stereocontrolled Synthesis of Polypropionate Fragments based on a Building Block Assembly Strategy using Lithiation-Borylation Methodologies.

Polypropionates are important structural motifs in nature and are commonly made by iterative aldol or crotylation methodologies. Herein, an alternative strategy is presented in which stereochemically predefined building blocks, bearing appropriate functionality, are coupled together using a lithiation-borylation methodology with complete stereocontrol. The building blocks comprise lithiated carbamates acting as donors, and boronic esters acting as acceptors. The acceptor building blocks contain ß-hydroxyl groups masked as silyl groups to avoid elimination of the boronate intermediates. Subsequent oxidation of both the boron and silyl moieties can then deliver an array of polypropionate fragments with full stereochemical control, including the synthetically challenging anti-anti isomers.

Iodine(III)-Mediated Selective Intermolecular C-H Amination for the Chemical Diversification of Tryptamines.

Defined hypervalent iodine reagents of the general structure PhI[N(SO2R)(SO2R')]2 promote the selective direct C-H-amination of the indole core of various tryptamines. Starting from a general C2-amination strategy, subsequent transformations enable a variety of site-selective functionalizations, which proceed with noteworthy high chemoselectivity and provide an overall access to structurally diversified products.

Tandem Allylboration-Prins Reaction for the Rapid Construction of Substituted Tetrahydropyrans: Application to the Total Synthesis of (-)-Clavosolide†A.

Tetrahydropyrans are common motifs in natural products and have now been constructed with high stereocontrol through a three-component allylboration-Prins reaction sequence. This methodology has been applied to a concise (13 steps) and efficient (14 % overall yield) synthesis of the macrolide (-)-clavosolide A. The synthesis also features an early stage glycosidation reaction to introduce the xylose moiety and a lithiation-borylation reaction to attach the cyclopropyl-containing side chain.

Ti(III)-catalyzed cyclizations of ketoepoxypolyprenes: control over the number of rings and unexpected stereoselectivities.

We describe a new strategy to control the number of cyclization steps in bioinspired radical (poly)cyclizations involving epoxypolyenes containing keto units positioned along the polyene chain. This approach provides an unprecedentedly straightforward access to natural terpenoids with pendant unsaturated side chains. Additionally, in the case of bi- and tricyclizations, decalins with cis stereochemistry have been obtained as a consequence of the presence of the ketone. The preferential formation of cis-fused adducts was rationalized using DFT calculations. This result is completely unprecedented in biomimetic cyclizations and permits the access to natural terpenoids with this stereochemistry, as well as to non-natural analogues.

Ti/Ni-mediated inter- and intramolecular conjugate addition of aryl and alkenyl halides and triflates.

In this work, we show that the unique combination of a nickel catalyst and Cp2TiCl allows the direct conjugate addition of aryl and alkenyl iodides, bromides, and to a lesser extent, chlorides and triflates to α,ß-unsaturated carbonyls at room temperature, without requiring the previous formation of an organometallic nucleophile. The reaction proceeds inter- and intramolecularly with good functional group compatibility, which is key for the development of free protecting group methodologies. Carbo- and heterocycles of five- and six-membered rings are obtained in good yields. Moreover, some insights about the mechanism involved have been obtained from cyclic voltammetry, UV-vis, and HRTEM measurements.

Indole synthesis based on a modified Koser reagent.

A new metal-free method for the rapid and productive preparation of indoles has been developed. This process is based on sterically congested hypervalent iodine compounds of the family of Koser reagents, and iodosobenzene in combination with 2,4,5-tris-isopropylbenzene sulfonic acid provides the highest yields and fastest reaction times. This reagent alone promotes the chemoselective oxidative cyclization of 2-amino styrenes to indoles in high yields under mild conditions.

Mild and Selective Hydrogenation of Unsaturated Compounds Using Mn/Water as a Hydrogen Gas Source.

A mild and highly selective reduction of alkenes and alkynes using Mn/water is described. The highly controlled generation of H2 allows the selective reduction of these compounds in the presence of labile functional groups under mild and environmentally acceptable conditions.

A Configurationally Stable Helical Indenofluorene.

We report the synthesis and study of the optoelectronic, magnetic, and chiroptical properties of a helically chiral diradicaloid based on dibenzoindeno[2,1-c]fluorene. The molecule shows a small HOMO-LUMO gap and a moderate singlet-triplet gap, which agrees with the results of DFT calculations. The helical structure of the compound, confirmed by X-ray diffraction, is configurationally stable, which allows the isolation of both enantiomers and the evaluation of the chiroptical properties (ECD).

Single-Molecule Identification of the Isomers of a Lipidic Antibody Activator.

Molecular structural elucidation can be accomplished by different techniques, such as nuclear magnetic resonance or X-ray diffraction. However, the former does not give information about the three-dimensional atomic arrangement, and the latter needs crystallizable solid samples. An alternative is direct, real-space visualization of the molecules by cryogenic scanning tunneling microscopy (STM). This technique is usually limited to thermally robust molecules because an annealing step is required for sample deposition. A landmark development has been the coupling of STM with electrospray deposition (ESD), which smooths the process and widens the scope of the visualization technique. In this work, we present the on-surface characterization of air-, light-, and temperature-sensitive rhamnopolyene with relevance in molecular biology. Supported by theoretical calculations, we characterize two isomers of this flexible molecule, confirming the potential of the technique to inspect labile, non-crystallizable compounds.

Ti/Pd bimetallic systems for the efficient allylation of carbonyl compounds and homocoupling reactions.

The allylation, crotylation and prenylation of aldehydes and ketones with stable and easily handled allylic carbonates is promoted by a Ti/Pd catalytic system. This Ti/Pd bimetallic system is especially convenient for the allylation of ketones, which are infrequent substrates in other related protocols, and can be carried out intramolecularly to yield five- and six-membered cyclic products with good stereoselectivities. In addition, Ti/Pd-mediated reductions and Würtz-type dimerisation reactions can be readily carried out from allyl carbonates and carboxylates.

Titanocene(III)-promoted Barbier-type crotylation of carbonyl compounds.

A mild, highly regio- and stereoselective method for the crotylation of aldehydes and ketones mediated/catalyzed by titanocene(III) is described. Optimized conditions permit the selective generation of γ-adducts in high yields together with high stereoselectivity, with a predominance of anti stereoisomers.

Lipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection.

Although certain microbial lipids are toxins, the structural features important for cytotoxicity remain unknown. Increased functional understanding is essential for developing therapeutics against toxic microbial lipids. Group B Streptococci (GBS) are bacteria associated with preterm births, stillbirths, and severe infections in neonates and adults. GBS produce a pigmented, cytotoxic lipid, known as granadaene. Despite its importance to all manifestations of GBS disease, studies towards understanding granadaene's toxic activity are hindered by its instability and insolubility in purified form. Here, we report the synthesis and screening of lipid derivatives inspired by granadaene, which reveal features central to toxin function, namely the polyene chain length. Furthermore, we show that vaccination with a non-toxic synthetic analog confers the production of antibodies that inhibit granadaene-mediated hemolysis ex vivo and diminish GBS infection in vivo. This work provides unique structural and functional insight into granadaene and a strategy to mitigate GBS infection, which will be relevant to other toxic lipids encoded by human pathogens.

O-H and (CO)N-H bond weakening by coordination to Fe(ii).

New N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)-ethane-1,2-diamine derivatives bearing covalently linked OH and (CO)NH groups have been synthesized. The coordination of those pendant hydroxyl/amide groups to a Fe(ii) metal center is demonstrated both in solution, even in the presence of chloride as the counterion, and in solid state, by means of X-ray diffraction crystal structures. As a result of this coordination, the experimental bond dissociation free energies (BDFE) of O-H and (CO)N-H bonds are remarkably diminished down to 76.0 and 80.5 kcal mol-1 respectively, which is also in agreement with DFT-based theoretical calculations. These BDFE values are in the range of commonly used hydrogen-atom donor reagents. The strategy presented here allows an unequivocal evaluation of the influence of metal coordination in X-H bond weakening in organic solvents which could be easily extended to other metal centers.

[How to improve hydration and fluid intake in institutionalized older people? A scientific literature review]. / ¿Cómo mejorar la hidratación y la ingesta hídrica en las personas mayores institucionalizadas? Una revisión de la literatura científica.

BACKGROUND: residents are vulnerable to suffer of dehydration due to physiological changes and the physical and cognitive limitations. AIM: to handle this situation, it has been decided to evaluate the interventions which are carried out for the management of dehydration and low fluid intake in older people living in nursing homes. METHODS: the revised scientific literature review methodology of PRISMA was applied. An electronic database search was performed in PubMed, Scopus, CINAHL and other sources databases. The literature search was carried out between October 2016 and January 2017. Out of a total of 3,379 articles extracted, eleven studies were selected for analysis. In addition, their quality was assessed through Cochrane and the Newcastle-Ottawa Scale. RESULTS: the risk of bias in the studies was mostly medium. Regarding the results, the interventions were classified according to whether they were invasive or non-invasive. Invasive interventions were intravenous and/or subcutaneous fluid therapy. Their effectiveness was related to the clinical improvement of dehydration. However, local reactions appeared. Non-invasive interventions focused on the individualized assistance, the stimulation to drink more and the consideration of the preferences of each resident, producing an increase in fluid intake and an improvement in analytical parameters. CONCLUSIONS: given the peculiarities of the institutionalized elderly population, both types of intervention have been shown to have a positive effect on improving hydration. Nonetheless, non-invasive interventions have confirmed to be more efficient given their simplicity of application and cause fewer adverse effects.

INTRODUCCIÓN: los residentes son vulnerables a sufrir deshidratación por los cambios fisiológicos y las limitaciones físicas y cognitivas que padecen. OBJETIVO: para manejar esta situación, se ha decidido evaluar las intervenciones que se llevan a cabo para el manejo de la deshidratación y la baja ingesta hídrica en las personas mayores institucionalizadas en residencias geriátricas. MÉTODOS: se realizó una revisión de la literatura científica siguiendo la metodología PRISMA mediante búsquedas sistemáticas en las bases de datos PubMed, Scopus, CINAHL y otras fuentes. De un total de 3.379 artículos extraídos, se seleccionaron once estudios para su análisis. Además, se avaluó su calidad a través de Cochrane y la Newcastle-Ottawa Scale. RESULTADOS: el riesgo de sesgo de los estudios fue medio en su mayoría. En cuanto a los resultados, las intervenciones se clasificaron según fuesen invasivas o no invasivas. Las intervenciones invasivas fueron la sueroterapia intravenosa y/o subcutánea y su efectividad estuvo relacionada con la mejora clínica de la deshidratación. No obstante, aparecieron reacciones locales. Las no invasivas se centraron en la asistencia individualizada, la estimulación para beber más y tener en cuenta las preferencias de cada residente, produciendo un aumento de la ingesta y una mejora en los parámetros analíticos. CONCLUSIONES: dadas las peculiaridades de la población mayor institucionalizada, ambos tipos de intervención han demostrado tener un efecto positivo en la mejora de la hidratación. No obstante, las intervenciones no invasivas han confirmado ser más eficientes dada su sencillez de aplicación y provocar menos efectos Adversos.

Synthesis of distorted nanographenes containing seven- and eight-membered carbocycles.

This feature article focuses on the bottom-up approaches (solution-phase) based on organic synthesis for the preparation of saddle-shaped distorted polycyclic aromatic hydrocarbons (PAHs). We summarise the recent progress on the synthetic strategies followed to obtain well-defined nanographenes containing heptagonal and octagonal carbocycles, highlighting the novel strategy developed by our group together with our recent contributions in the area of distorted aromatics. The presence of seven- or eight-membered rings induces a saddle-shape curvature in the planar network pushing the structure out of the plane, which influences the physical properties exhibited. Some brief details on the optical and electronic properties of these curved nanostructures are also discussed.

Water control over the chemoselectivity of a Ti/Ni multimetallic system: Heck- or reductive-type cyclization reactions of alkyl iodides.

A versatile Ti/Ni multimetallic protocol is described for the efficient catalysis of two different reactions, namely a Heck- and reductive-type cyclization of alkyl iodides, in the absence or presence of water, respectively. Noteworthy, the versatility of Ti(III) chemistry allows an oxidative ending step under reductive conditions to give Heck-type products, and the good H-atom transfer capabilities of Ti(III)-aqua complexes ensure reductive-type cyclizations.