Computationally-guided development of a chelated NHC-P iridium(I) complex for the directed hydrogen isotope exchange of aryl sulfones

Herein we report the rational, computationally-guided design of an iridium(I) catalyst system capable of enabling directed hy-drogen isotope exchange (HIE) with the challenging sulfone directing group. Substrate binding energy was used as a parame-ter to guide rational ligand design via an in-silico catalyst screen, resulting in a lead series of chelated iridium(I) NHC-phosphine complexes. Subsequent preparative studies show that the optimal catalyst system displays high levels of activity in HIE, and we demonstrate the labeling of a broad scope of substituted aryl sulfones. We also show that the activity of the cata-lyst is maintained at low pressures of deuterium gas, and apply these conditions to tritium radiolabeling, including the expedi-ent synthesis of a tritium-labeled drug molecule

Effect of Salt Concentration in Water‐In‐Salt Electrolyte on Supercapacitor Applications

Electrical double‐layer supercapacitors offer numerous advantages in the context of energy storage; however, their widespread use is hindered by the high unit energy cost and low specific energy. Recently, water‐in‐salt (WIS) electrolytes have garnered interest for use in energy storage devices. Nevertheless, their direct application in high‐power devices is limited due to their high viscosity. In this study, we investigate the WIS Lithium bis(trifluoromethanesulfonyl)Imide (LiTFSI) electrolyte, revealing a high specific capacitance despite its elevated viscosity and restricted ionic conductivity. Our approach involves nuclear magnetic resonance (NMR) analysis alongside electrochemical analyses, highlighting the pronounced advantage of the WIS LiTFSI electrolyte over the WIS LiCl electrolyte at the molecular level. The NMR analysis shows that the LiTFSI electrolyte ions preferentially reside within the activated carbon pore network in the absence of an applied potential, in contrast to LiCl where the ions are more evenly distributed between the in‐pore and ex‐pore environments. This difference may contribute to the difference in capacitance between the two electrolytes observed during electrochemical cycling

Landscape genomic prediction for restoration of a Eucalyptus foundation species under climate change

As species face rapid environmental change, we can build resilient populations through restoration projects that incorporate predicted future climates into seed sourcing decisions. Eucalyptus melliodora is a foundation species of a critically endangered community in Australia that is a target for restoration. We examined genomic and phenotypic variation to make empirical based recommendations for seed sourcing. We examined isolation by distance and isolation by environment, determining high levels of gene flow extending for 500 km and correlations with climate and soil variables. Growth experiments revealed extensive phenotypic variation both within and among sampling sites, but no site-specific differentiation in phenotypic plasticity. Model predictions suggest that seed can be sourced broadly across the landscape, providing ample diversity for adaptation to environmental change. Application of our landscape genomic model to E. melliodora restoration projects can identify genomic variation suitable for predicted future climates, thereby increasing the long term probability of successful restoration.Australian Research Council Linkage Grant LP130100455; Jason G Bragg, Linda M Broadhurst, Adrienne B Nicotra, Margaret Byrne, Justin O Borevit

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen–free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function

Polymer hydrogel-based microneedles for metformin release

Drug delivery devices ensure the effective delivery of a broad range of therapeutics to millions of patients worldwide on a daily basis.1 Microneedles are a class of drug delivery device that provide pain free transdermal delivery with improved patient compliance.2-4 The release of metformin, a drug used in the treatment of cancer and diabetes, from polymer hydrogel-based microneedle patches was demonstrated in vitro. Tuning the composition of the polymer hydrogels enabled preparation of robust microneedle patches with mechanical properties such that they would penetrate skin (insertion force of a single microneedle to be ca. 40 N). Swelling experiments conducted at 20°C, 35°C and 60°C show temperature dependent degrees of swelling and kinetics (Fickian diffusion). Drug release from the hydrogel-based microneedles was fitted to various models (e.g., zero order, first order, second order, Korsmeyer-Peppas, Peppas-Sahlins), observing the best fit for the zero-order model. Such microneedles have potential application for transdermal delivery of metformin for the treatment of cancer and diabetes

Poly(2-Hydroxyethyl Methacrylate) Hydrogel-Based Microneedles for Metformin Release

The release of metformin, a drug used in the treatment of cancer and diabetes, from poly(2-hydroxyethyl methacrylate), pHEMA, hydrogel-based microneedle patches is demonstrated in vitro. Tuning the composition of the pHEMA hydrogels enables preparation of robust microneedle patches with mechanical properties such that they would penetrate skin (insertion force of a single microneedle to be ≈40 N). Swelling experiments conducted at 20, 35, and 60 °C show temperature-dependent degrees of swelling and diffusion kinetics. Drug release from the pHEMA hydrogel-based microneedles is fitted to various models (e.g., zero order, first order, second order). Such pHEMA microneedles have potential application for transdermal delivery of metformin for the treatment of aging, cancer, diabetes, etc

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen-free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function.Additional co-authors: Emily K. Osterweil, Andrew S. MacDonald, Chris J. Schofield, Saverio Tardito, Josephine Bunch, Gillian Douce, Julia M. Edgar, RuAngelie Edrada-Ebel, Richard J. A. Goodwin, Richard Burchmore, Daniel M. Wal