High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis [version 2]

Background: The only available tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG), has variable efficacy. New vaccines are therefore urgently needed. Why BCG fails is incompletely understood, and the tools used for early assessment of new vaccine candidates do not account for BCG variability. Taking correlates of risk of TB disease observed in human studies and back-translating them into mice to create models of BCG variability should allow novel vaccine candidates to be tested early in animal models that are more representative of the human populations most at risk. Furthermore, this could help to elucidate the immunological mechanisms leading to BCG failure. We have chosen the monocyte to lymphocyte (ML) ratio as a correlate of risk of TB disease and have back-translated this into a mouse model. // Methods: Four commercially available, inbred mouse strains were chosen. We investigated their baseline ML ratio by flow cytometry; extent of BCG-mediated protection from Mycobacterium tuberculosis infection by experimental challenge; vaccine-induced interferon gamma (IFNγ) response by ELISPOT assay; and tissue distribution of BCG by plating tissue homogenates. // Results: The ML ratio varied significantly between A/J, DBA/2, C57Bl/6 and 129S2 mice. A/J mice showed the highest BCG-mediated protection and lowest ML ratio, while 129S2 mice showed the lowest protection and higher ML ratio. We also found that A/J mice had a lower antigen specific IFNγ response than 129S2 mice. BCG tissue distribution appeared higher in A/J mice, although this was not statistically significant. // Conclusions: These results suggest that the ML ratio has an impact on BCG-mediated protection in mice, in alignment with observations from clinical studies. A/J and 129S2 mice may therefore be useful models of BCG vaccine variability for early TB vaccine testing. We speculate that failure of BCG to protect from TB disease is linked to poor tissue distribution in a ML high immune environment

Modular and predictable assembly of porous organic molecular crystals

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules

Three-dimensional lanthanide-organic frameworks based on di-, tetra-, and hexameric clusters

Three-dimensional lanthanide-organic frameworks formulated as (CH3)2NH2[Ln(pydc)2] · 1/2H2O [Ln3+ ) Eu3+ (1a) or Er3+ (1b); pydc2- corresponds to the diprotonated residue of 2,5-pyridinedicarboxylic acid (H2pydc)], [Er4(OH)4(pydc)4(H2O)3] ·H2O (2), and [PrIII 2PrIV 1.25O(OH)3(pydc)3] (3) have been isolated from typical solvothermal (1a and 1b in N,N-dimethylformamide - DMF) and hydrothermal (2 and 3) syntheses. Materials were characterized in the solid state using single-crystal X-ray diffraction, thermogravimetric analysis, vibrational spectroscopy (FT-IR and FT-Raman), electron microscopy, and CHN elemental analysis. While synthesis in DMF promotes the formation of centrosymmetric dimeric units, which act as building blocks in the construction of anionic ∞ 3{[Ln(pydc)2]-} frameworks having the channels filled by the charge-balancing (CH3)2NH2 + cations generated in situ by the solvolysis of DMF, the use of water as the solvent medium promotes clustering of the lanthanide centers: structures of 2 and 3 contain instead tetrameric [Er4(μ3-OH)4]8+ and hexameric |Pr6(μ3-O)2(μ3-OH)6| clusters which act as the building blocks of the networks, and are bridged by the H2-xpydcx- residues. It is demonstrated that this modular approach is reflected in the topological nature of the materials inducing 4-, 8-, and 14-connected uninodal networks (the nodes being the centers of gravity of the clusters) with topologies identical to those of diamond (family 1), and framework types bct (for 2) and bcu-x (for 3), respectively. The thermogravimetric studies of compound 3 further reveal a significant weight increase between ambient temperature and 450 °C with this being correlated with the uptake of oxygen from the surrounding environment by the praseodymium oxide inorganic core

Host-guest and guest-guest interactions between xylene isomers confined in the MIL-47(V) pore system

The porous MIL-47 material shows a selective adsorption behavior for para-, ortho-, and meta-isomers of xylenes, making the material a serious candidate for separation applications. The origin of the selectivity lies in the differences in interactions (energetic) and confining (entropic). This paper investigates the xylene-framework interactions and the xylene-xylene interactions with quantum mechanical calculations, using a dispersion-corrected density functional and periodic boundary conditions to describe the crystal. First, the strength and geometrical characteristics of the optimal xylene-xylene interactions are quantified by studying the pure and mixed pairs in gas phase. An extended set of initial structures is created and optimized to sample as many relative orientations and distances as possible. Next, the pairs are brought in the pores of MIL-47. The interaction with the terephthalic linkers and other xylenes increases the stacking energy in gas phase (-31.7 kJ/mol per pair) by roughly a factor four in the fully loaded state (-58.3 kJ/mol per xylene). Our decomposition of the adsorption energy shows various trends in the contributing xylene-xylene interactions. The absence of a significant difference in energetics between the isomers indicates that entropic effects must be mainly responsible for the separation behavior

Magnetic and Photoluminescent Sensors Based on Metal-Organic Frameworks Built up from 2-aminoisonicotinate

Red Guipuzcoana de Ciencia, Tecnologia e Innovacion OF218/2018 University of Basque Country GIU 17/13 Basque Government IT1005-16 IT1291-19 IT1310-19 Junta de Andalucia FQM-394 Spanish Ministry of Science, Innovation and Universities (MCIU/AEI/FEDER, UE) PGC2018-102052-A-C22 PGC2018-102052-B-C21 MAT2016-75883-C2-1-P European Union (EU) ESFIn this work, three isostructural metal-organic frameworks based on frst row transition metal ions and 2-aminoisonicotinate (2ain) ligands, namely, {[M(μ-2ain)2]·DMF}n [MII=Co (1), Ni (2), Zn (3)], are evaluated for their sensing capacity of various solvents and metal ions by monitoring the modulation of their magnetic and photoluminescence properties. The crystal structure consists of an open diamond-like topological 3D framework that leaves huge voids, which allows crystallizing two-fold interpenetrated architecture that still retains large porosity. Magnetic measurements performed on 1 reveal the occurrence of feld-induced spin-glass behaviour characterized by a frequency-independent relaxation. Solvent-exchange experiments lead successfully to the replacement of lattice molecules by DMSO and MeOH, which, on its part, show dominating SIM behaviour with low blocking temperatures but substantially high energy barriers for the reversal of the magnetization. Photoluminescence studied at variable temperature on compound 3 show its capacity to provide bright blue emission under UV excitation, which proceeds through a ligand-centred charge transfer mechanism as confrmed by timedependent DFT calculations. Turn-of and/or shift of the emission is observed for suspensions of 3 in diferent solvents and aqueous solutions containing metal ions

Geometry analysis and systematic synthesis of highly porous isoreticular frameworks with a unique topology

Porous coordination polymers are well known for their easily tailored framework structures and corresponding properties. Although systematic modulations of pore sizes of binary prototypes have gained great success, simultaneous adjustment of both pore size and shape of ternary prototypes remains unexplored, owing to the difficulty in controlling the self-assembly of multiple molecular building blocks. Here we show that simple geometry analysis can be used to estimate the influence of the linker lengths and length ratios on the synthesis/construction difficulties and framework stabilities of a highly symmetric, ternary prototype composed of a typical trinuclear metal cluster and two types of bridging carboxylate ligands. As predicted, systematic syntheses with 5×5 ligand combinations produced 13 highly porous isoreticular frameworks, which show not only systematic adjustment of pore volumes (0.49–2.04 cm3 g−1) and sizes (7.8–13.0 Å; 5.2–12.0 Å; 7.4–17.4 Å), but also anisotropic modulation of the pore shapes