High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.

Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear.

Ligand-directed delivery of fluorophores to track native calcium-permeable AMPA receptors in neuronal cultures.

Subcellular trafficking of neuronal receptors is known to play a key role in synaptic development, homeostasis, and plasticity. We have developed a ligand-targeted and photo-cleavable probe for delivering a synthetic fluorophore to AMPA receptors natively expressed in neurons. After a receptor is bound to the ligand portion of the probe molecule, a proteinaceous nucleophile reacts with an electrophile on the probe, covalently bonding the two species.

Methods to locate and track ion channels and receptors expressed in live neurons.

Brain cells use electrical and chemical signaling to communicate with each other and to send and receive information from the body. These neurons also encode information such as memories and are constantly adapting to changes as a result of positive alterations, such as learning, or negative events, such as neurological insults or neurodegeneration. In the last two decades, it has become clear that the placement of minute branches of neurons and, more importantly for the topic of this review, the placement of individual protein molecules, are the key events that enable neuronal network building and pruning.

Prodrug approaches to reduce hyperexcitation in the CNS.

Hyperexcitation in the central nervous system is the root cause of a number of disorders of the brain ranging from acute injury to chronic and progressive diseases. The major limitation to treatment of these ailments is the miniscule, yet formidable blood-brain barrier. To deliver therapeutic agents to the site of desired action, a number of biomedical engineering strategies have been developed including prodrug formulations that allow for either passive diffusion or active transport across this barrier.

Silent, fluorescent labeling of native neuronal receptors.

We have developed a minimally-perturbing strategy that enables labeling and subcellular visualization of endogenous dendritic receptors on live, wild-type neurons. Specifically, calcium-permeable non-NMDA glutamate receptors expressed in hippocampal neurons can be targeted with this novel synthetic tri-functional molecule. This ligand-directed probe was targeted towards AMPA receptors and bears an electrophilic group for covalent bond formation with an amino acid side chain on the extracellular side of the ion channel.