Metformin can be repurposed as host-directed therapy for tuberculosis.

Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize conserved bacterial antigens derived from riboflavin precursors, presented by the nonpolymorphic MHC class I-like molecule MR1. Here we show that human MAIT cells are remarkably oligoclonal in both the blood and liver, display high inter-individual homology and exhibit a restricted length CDR3b domain of the TCRVb chain. We extend this analysis to a second sub-population of MAIT cells expressing a semi-invariant TCR conserved between individuals. Similar to 'conventional' MAIT cells, these lymphocytes react to riboflavin-synthesizing microbes in an MR1-restricted manner and infiltrate solid tissues. Both MAIT cell types release Th0, Th1 and Th2 cytokines, and sCD40L in response to bacterial infection, show cytotoxic capacity against infected cells and promote killing of intracellular bacteria, thus suggesting important protective and immunoregulatory functions of these lymphocytes.

The side effects associated with tuberculosis therapy bring with them the risk of noncompliance and subsequent drug resistance. Increasing the therapeutic index of antituberculosis drugs should thus improve treatment effectiveness. Several antituberculosis compounds require in situ metabolic activation to become inhibitory. Various thiocarbamide-containing drugs, including ethionamide, are activated by the mycobacterial monooxygenase EthA, the production of which is controlled by the transcriptional repressor EthR. Here we identify drug-like inhibitors of EthR that boost the bioactivation of ethionamide. Compounds designed and screened for their capacity to inhibit EthR-DNA interaction were co-crystallized with EthR. We exploited the three-dimensional structures of the complexes for the synthesis of improved analogs that boosted the ethionamide potency in culture more than tenfold. In Mycobacterium tuberculosis-infected mice, one of these analogs, BDM31343, enabled a substantially reduced dose of ethionamide to lessen the mycobacterial load as efficiently as the conventional higher-dose treatment. This provides proof of concept that inhibiting EthR improves the therapeutic index of thiocarbamide derivatives, which should prompt reconsideration of their use as first-line drugs.

The electrochemical reactivity of cations such as Ca 2ϩ , Mg 2ϩ , and Y 3ϩ into crystalline V 2 O 5 materials was investigated. The ionic diffusion constant of Li ϩ and Y 3ϩ into microcrystalline and nanocrystalline V 2 O 5 was measured by the galvanostatic intermittent titration technique. The Y 3ϩ ion diffusion constant into a 500 nm crystalline V 2 O 5 was found to be approximately two orders of magnitude lower than for the Li ϩ ion. In order to enable practical intercalation of Y 3ϩ , a nanocrystalline V 2 O 5 was fabricated through a combustion flame synthesis technique. For the first time, reversible electrochemical intercalation of Y 3ϩ into a host structure was shown to be feasible. An asymmetric hybrid cell configuration was utilized in order to provide a reversible counter electrode during intercalation. Preliminary data indicates Y 3ϩ can be reversibly intercalated into V 2 O 5 with apparent gravimetric capacities exceeding that of Ca 2ϩ , Mg 2ϩ , or Li ϩ over the limited voltage range of 2.5 to 4.2 V (Li/Li ϩ ). The concept of polyvalent intercalation is discussed relative to intercalation, pseudocapacitance, apparent specific capacity, and practical energy storage systems.High energy density electrochemically rechargeable energy storage systems are the key to the future realization of a myriad of next generation applications ranging from biomedical to electric vehicles. Currently, there exist two commercialized single-ion room temperature secondary battery technologies utilizing at least one intercalation electrode, NiMeH ͑proton͒ and Li ion ͑lithium͒. NiMeH batteries utilize the reversible intercalation of a H ϩ guest cation into NiOOH and alloying reactions with rare earth or misch metal counter electrodes. The basic Li-ion battery utilizes intercalation reactions of Li ϩ into transition metal positive electrodes or carbonbased negative electrodes. Presently, the Li-ion battery is the highest energy density commercialized rechargeable battery technology. This technology has the future potential to far exceed the theoretical energy densities of the aqueous NiMeH technology. Although much research has focused on the improvement of the host electrodes for Li-ion guest cation intercalation, little work has focused on alternative guest cation species to replace the Li ϩ cation.The use of Na ϩ as a low cost, potentially less reactive cation for rocking chair intercalation batteries is the most prevalent of the reported research on alternative guest cation intercalation. 1-7 Na ϩ cells have seen little commercial success because of the lack of suitable electroactive negative electrode materials. Fewer papers have focused on polyvalent cation intercalation reactions in order to develop alternative rocking chair cells using guest cations with valences greater than one. 8 Of these, the development of Mg 2ϩ -based batteries and related electrolytes 9-12 are the most widely discussed. Electrochemical intercalation of Mg 2ϩ into a number of metal oxides and sulfides were investigated, 13 however, electrochemica...

Small-angle X-ray scattering measurements were performed on zirconium acidic aqueous solutions to investigate the structure and the size of polynuclear species larger than the previously identified tetrameric species. Solutions with [H+]added and [OH-]added ranging from 0.0 to 1.0 M and 0.0 to 0.02 M, respectively, were analyzed. This study demonstrates that an octameric species, Zr8(OH)20(H2O)24Cl12, exists in equilibrium with the tetrameric species, Zr4(OH)8(H2O)16Cl6 2+, such that, for 0.05 M Zr(IV) in highly acidic solutions ([H+]added ≥ 0.6 M), the tetramer is the dominant species; and at conditions with [H+]added ≤ 0.05 M, the octameric species becomes predominant. The estimated value of the equilibrium quotient obtained for the tetramer/octamer equilibrium is 0.20 ± 0.05 M3. The tetramer and octamer have radii of gyration of 3.8 and 5.1 ± 0.2 Å and a hydrolysis ratio of 2.0 and 2.5, respectively. The octamer forms by stacking two tetramers on top of each other. At conditions where small amounts of NaOH are added, unidentified polymeric Zr(IV) species larger in size than the octameric species appear.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

The development and maturation of semi-invariant natural killer T cells (iNKT cells) rely on the recognition of self antigens presented by CD1d restriction molecules in thymus. The nature of the stimulatory thymic self lipids remains elusive. We isolated lipids from thymocytes and found that ether-bonded mono-alkyl glycerophosphates and the precursors and degradation products of plasmalogens stimulated iNKT cells. Synthetic analogs showed high potency in activating thymic and peripheral iNKT cells. Mice deficient in the peroxisomal enzyme glyceronephosphate O-acyltransferase (GNPAT), essential for the synthesis of ether lipids, had significant alteration of the thymic maturation of iNKT cells and fewer iNKT cells in both thymus and peripheral organs, which confirmed the role of ether-bonded lipids as iNKT cell antigens. Thus, peroxisome-derived lipids are nonredundant self antigens required for the generation of a full iNKT cell repertoire.

In this paper, we report on the development of a new and broadly applicable strategy to produce thermally mendable polymeric materials, demonstrated with an epoxy/poly(-caprolactone) (PCL) phase-separated blend. The initially miscible blend composed of 15.5 wt % PCL undergoes polymerization-induced phase separation during cross-linking of the epoxy, yielding a "bricks and mortar" morphology wherein the epoxy phase exists as interconnected spheres (bricks) interpenetrated with a percolating PCL matrix (mortar). The fully cured material is stiff, strong, and durable. A heating-induced "bleeding" behavior was witnessed in the form of spontaneous wetting of all free surfaces by the molten PCL phase, and this bleeding is capable of repairing damage by crack-wicking and subsequent recrystallization with only minor concomitant softening during that process. The observed bleeding is attributed to volumetric thermal expansion of PCL above its melting point in excess of epoxy brick expansion, which we term differential expansive bleeding (DEB). In controlled thermal-mending experiments, heating of a cracked specimen led to PCL extrusion from the bulk to yield a liquid layer bridging the crack gap. Upon cooling, a "scar" composed of PCL crystals formed at the site of the crack, restoring a significant portion of the mechanical strength. When a moderate force was applied to assist crack closure, thermal-mending efficiencies exceeded 100%. We further observed that the DEB phenomenon enables strong and facile adhesion of the same material to itself and to a variety of materials, without any requirement for macroscopic softening or flow.