Information-Theoretic Analysis of Neural Coding

We describe an approach to analyzing single- and multiunit (ensemble) discharge patterns based on information-theoretic distance measures and on empirical theories derived from work in universal signal processing. In this approach, we quantify the difference between response patterns, whether time-varying or not, using information-theoretic distance measures. We apply these techniques to single- and multiple-unit processing of sound amplitude and sound location. These examples illustrate that neurons can simultaneously represent at least two kinds of information with different levels of fidelity. The fidelity can persist through a transient and a subsequent steady-state response, indicating that it is possible for an evolving neural code to represent information with constant fidelity.     

Characterization of an antigenically related family of cell-type specific proteins implicated in slug migration in Dictyostelium discoideum

The monoclonal antibody MUD50 recognizes a group of developmentally regulated proteins, which are almost exclusively expressed by prespore cells in developing aggregates of Dictyostelium discoideum. Some of these antigens are integrally associated with the cell membrane, as assessed by physical and detergent-fractionation procedures. The MUD50-reactive proteins are glycosylated and some are phosphorylated. Post-translational modification is the common antigenic feature that is recognized by the MUD50 antibody in these cell-type-specific proteins. A glycosylation-defective mutant, DL118, (modB) does not express the MUD50 epitope, but does express the MUD52 epitope, which is found on a different group of glycoproteins. Therefore, we conclude that MUD50 recognizes a particular carbohydrate epitope on a restricted group of proteins. These proteins are structurally diverse, but are apparently involved in the maintenance of structure and movement of the multicellular D. discoideum slug.     

Discovery of 1-amino-4-phenylcyclohexane-1-carboxylic acid and its influence on agonist selectivity between human melanocortin-4 and -1 receptors in linear pentapeptides

Linear pentapeptides (Penta-cis-Apc-DPhe-Arg-Trp-Gly-NH2) containing 1-amino-4-phenylcyclohexane-1-carboxylic acid (cis-Apc) and substituted Apc are potent hMC4R agonists and they are inactive or weakly active in hMC1R, hMC3R, and hMC5R agonist assays. This study, together with our earlier report on 5-BrAtc, demonstrated the importance of replacing His6 with phenyl-containing rigid templates in achieving good hMC4R agonist potency and selectivity against hMC1R in linear pentapeptides.     

Human Alzheimer’s disease synaptic <Emphasis Type=Italic>O</Emphasis>-GlcNAc site mapping and iTRAQ expression proteomics with ion trap mass spectrometry

Neuronal synaptic functional deficits are linked to impaired learning and memory in Alzheimer’s disease (AD). We recently demonstrated that O-GlcNAc, a novel cytosolic and nuclear carbohydrate post-translational modification, is enriched at neuronal synapses and positively regulates synaptic plasticity linked to learning and memory in mice. Reduced levels of O-GlcNAc have been observed in AD, suggesting a possible link to deficits in synaptic plasticity. Using lectin enrichment and mass spectrometry, we mapped several human cortical synaptic O-GlcNAc modification sites. Overlap in patterns of O-GlcNAcation between mouse and human appears to be high, as previously mapped mouse synaptic O-GlcNAc sites in Bassoon, Piccolo, and tubulin polymerization promoting protein p25 were identified in human. Novel O-GlcNAc modification sites were identified on Mek2 and RPN13/ADRM1. Mek2 is a signaling component of the Erk 1/2 pathway involved in synaptic plasticity. RPN13 is a component of the proteasomal degradation pathway. The potential interplay of phosphorylation with mapped O-GlcNAc sites, and possible implication of those sites in synaptic plasticity in normal versus AD states is discussed. iTRAQ is a powerful differential isotopic quantitative approach in proteomics. Pulsed Q dissociation (PQD) is a recently introduced fragmentation strategy that enables detection of low mass iTRAQ reporter ions in ion trap mass spectrometry. We optimized LTQ ion trap settings for PQD-based iTRAQ quantitation and demonstrated its utility in O-GlcNAc site mapping. Using iTRAQ, abnormal synaptic expression levels of several proteins previously implicated in AD pathology were observed in addition to novel changes in synaptic specific protein expression including Synapsin II.     

Learning to walk with a robotic ankle exoskeleton

We used a lower limb robotic exoskeleton controlled by the wearer's muscle activity to study human locomotor adaptation to disrupted muscular coordination. Ten healthy subjects walked while wearing a pneumatically powered ankle exoskeleton on one limb that effectively increased plantar flexor strength of the soleus muscle. Soleus electromyography amplitude controlled plantar flexion assistance from the exoskeleton in real time. We hypothesized that subjects' gait kinematics would be initially distorted by the added exoskeleton power, but that subjects would reduce soleus muscle recruitment with practice to return to gait kinematics more similar to normal. We also examined the ability of subjects to recall their adapted motor pattern for exoskeleton walking by testing subjects on two separate sessions, 3 days apart. The mechanical power added by the exoskeleton greatly perturbed ankle joint movements at first, causing subjects to walk with significantly increased plantar flexion during stance. With practice, subjects reduced soleus recruitment by approximately 35% and learned to use the exoskeleton to perform almost exclusively positive work about the ankle. Subjects demonstrated the ability to retain the adapted locomotor pattern between testing sessions as evidenced by similar muscle activity, kinematic and kinetic patterns between the end of the first test day and the beginning of the second. These results demonstrate that robotic exoskeletons controlled by muscle activity could be useful tools for testing neural mechanisms of human locomotor adaptation.     

The design and discovery of novel amide CCR5 antagonists

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR’s which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.