Insulin resistance in brain alters dopamine turnover and causes behavioral disorders.

Diabetes and insulin resistance are associated with altered brain imaging, depression, and increased rates of age-related cognitive impairment. Here we demonstrate that mice with a brain-specific knockout of the insulin receptor (NIRKO mice) exhibit brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens. NIRKO mice also exhibit increased levels of monoamine oxidase A and B (MAO A and B) leading to increased dopamine turnover in these areas. Studies in cultured neurons and glia cells indicate that these changes in MAO A and B are a direct consequence of loss of insulin signaling. As a result, NIRKO mice develop age-related anxiety and depressive-like behaviors that can be reversed by treatment with MAO inhibitors, as well as the tricyclic antidepressant imipramine, which inhibits MAO activity and reduces oxidative stress. Thus, insulin resistance in brain induces mitochondrial and dopaminergic dysfunction leading to anxiety and depressive-like behaviors, demonstrating a potential molecular link between central insulin resistance and behavioral disorders.

Preparative and mechanistic studies toward the rational development of catalytic, enantioselective selenoetherification reactions.

A systematic investigation into the Lewis base catalyzed, asymmetric, intramolecular selenoetherification of olefins is described. A critical challenge for the development of this process was the identification and suppression of racemization pathways available to arylseleniranium ion intermediates. This report details a thorough study of the influences of the steric and electronic modulation of the arylselenenyl group on the configurational stability of enantioenriched seleniranium ions. These studies show that the 2-nitrophenyl group attached to the selenium atom significantly attenuates the racemization of seleniranium ions. A variety of achiral Lewis bases catalyze the intramolecular selenoetherification of alkenes using N-(2-nitrophenylselenenyl)succinimide as the electrophile along with a Brønsted acid. Preliminary mechanistic studies suggest the intermediacy of ionic Lewis base-selenium(II) adducts. Most importantly, a broad survey of chiral Lewis bases revealed that 1,1'-binaphthalene-2,2'-diamine (BINAM)-derived thiophosphoramides catalyze the cyclization of unsaturated alcohols in the presence of N-(2-nitrophenylselenenyl)succinimide and methanesulfonic acid. A variety of cyclic seleno ethers were produced in good chemical yields and in moderate to good enantioselectivities, which constitutes the first catalytic, enantioselective selenofunctionalization of unactivated olefins.

Observation of direct sulfenium and selenenium group transfer from thiiranium and seleniranium ions to alkenes.

Sulfenium and selenenium ions undergo a stereospecific transfer from the corresponding three-membered ring species ("-iranium ions") to unactivated alkenes with varying facility. The thiiranium and seleniranium hexafluoroantimonates could be generated by treatment of the corresponding chloro sulfides or selenides with silver hexafluoroantimonate, followed by removal of the silver chloride by filtration. Clean (1)H, (13)C, and (77)Se NMR spectra could be recorded for these species. Treatment of the S-phenylthiiranium ion with an alkene leads to a slow transfer of the sulfenium group at 0 degrees C. However, the S-methylthiiranium ion did not transfer the sulfenium group, even at room temperature. On the other hand, both the Se-phenyl- and Se-butylseleniranium ions transferred the selenenium moiety instantaneously at -70 degrees C. By measuring the equilibrium position for these transfers from both directions, the relative stability of the 1-phenylseleniranium ions could be established: cis-tetramethylene < trans-2,3-dipropyl approximately trans-2,3-diisopropyl < cis-hexamethylene.

Natural Product Medicines for Honey Bees: Perspective and Protocols.

The western honey bee remains the most important pollinator for agricultural crops. Disease and stressors threaten honey bee populations and productivity during winter- and summertime, creating costs for beekeepers and negative impacts on agriculture. To combat diseases and improve overall bee health, researchers are constantly developing honey bee medicines using the tools of microbiology, molecular biology and chemistry. Below, we present a manifesto alongside standardized protocols that outline the development and a systematic approach to test natural products as 'bee medicines.' These will be accomplished in both artificial rearing conditions and in colonies situated in the field. Output will be scored by gene expression data of host immunity, bee survivorship, reduction in pathogen titers, and more subjective merits of the compound in question. Natural products, some of which are already encountered by bees in the form of plant resins and nectar compounds, provide promising low-cost candidates for safe prophylaxis or treatment of bee diseases.

Lewis base activation of Lewis acids: development of a Lewis base catalyzed selenolactonization.

The concept of Lewis base activation of Lewis acids has been applied to the selenolactonization reaction. Through the use of substoichiometric amounts of Lewis bases with "soft" donor atoms (S, Se, P) significant rate enhancements over the background reaction are seen. Preliminary mechanistic investigations have revealed the resting state of the catalyst as well as the significance of a weak Brønsted acid promoter.

Graphene oxide as an electrophile for carbon nucleophiles.

The covalent, surface functionalization of graphene oxide with the malononitrile anion has been demonstrated. Once installed, these surface-bound "molecular lynchpins" can be chemically modified to increase the solubility of the graphene derivative in either organic or aqueous environments.