Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.

A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model.

Aminonaphthalene 2-cyanoacrylate (ANCA) probes fluorescently discriminate between amyloid-ß and prion plaques in brain.

A major challenge for diagnosing and monitoring the progression of amyloid-based diseases is the capability to distinguish between amyloid deposits that are associated with related, but distinctly different, diseases. Here, we demonstrate that aminonaphthalenyl 2-cyanoacrylate-based probes can fluorescently discriminate between different types of amyloid deposits in brain. The discriminating capability of these molecular rotors is due to the stabilization of the ground versus excited states of these probes as a function of the polarity of their microenvironment (i.e., within the binding pocket on the amyloid). This property makes it possible, for the first time, to estimate the inherent static relative permittivity (ε(0)) of the binding pocket of each amyloid within tissue. The capability to selectively follow the deposition of specific amyloids in tissue may provide important information for therapeutic development that is not readily accessible from currently available technology.

ANCA: A Family of Fluorescent Probes that Bind and Stain Amyloid Plaques in Human Tissue.

A new family of fluorescent markers containing an Amino Naphthalenyl-2-Cyano-Acrylate (ANCA) motif has been synthesized and evaluated for its capability to associate with aggregated ß-amyloid (Aß) peptides. These fluorescent probes contain a nitrogen donor group that is connected via a naphthalene unit to an electron acceptor motif containing Water Solubilizing Groups (WSG). Chemical modifications were introduced to explore their effect on the capability of the ANCA-based probes to fluorescently label aggregated Aß peptides. All synthesized probes bind to aggregated Aß fibrils with low micromolar affinity and fluorescently stain amyloid deposits in human brain tissue from patients with Alzheimer's disease. We found that structural modifications of the WSG site do not affect considerably the binding affinity. However, changes of the nitrogen donor group alter significantly the binding affinity of these probes. Also, increasing the hydrophilicity of the donor group leads to improved contrast between the Aß deposits and the surrounding tissue in histological staining experiments.

Synthesis and evaluation of self-calibrating ratiometric viscosity sensors.

We describe the design, synthesis and fluorescent profile of a family of self-calibrating dyes that provide ratiometric measurements of fluid viscosity. The design is based on covalently linking a primary fluorophore (reference) that displays a viscosity-independent fluorescence emission with a secondary fluorophore (sensor) that exhibits a viscosity-sensitive fluorescence emission. Characterization of fluorescent properties was made with separate excitation of the units and through Resonance Energy Transfer from the reference to the sensor dye. The chemical structures of both fluorophores and the linker length have been evaluated in order to optimize the overall brightness and sensitivity of the viscosity measurements. We also present an application of such ratiometric dyes for the detection of membrane viscosity changes in a liposome model.

Thermoelectric and magnetothermoelectric transport measurements of graphene.

The conductance and thermoelectric power (TEP) of graphene is simultaneously measured using a microfabricated heater and thermometer electrodes. The sign of the TEP changes across the charge neutrality point as the majority carrier density switches from electron to hole. The gate dependent conductance and TEP exhibit a quantitative agreement with the semiclassical Mott relation. In the quantum Hall regime at a high magnetic field, quantized thermopower and Nernst signals are observed and are also in agreement with the generalized Mott relation, except for strong deviations near the charge neutrality point.

An in vitro evaluation of the reliability and validity of an electronic pantograph by testing with five different articulators.

STATEMENT OF PROBLEM: The degree of reliability and validity of a new electronic pantographic instrument, the Cadiax Compact, has not been established. PURPOSE: The purpose of this study was to test the reliability and validity of the electronic pantograph in calculating condylar settings for 5 different articulators (Denar D5A, Denar Mark II, Whip Mix 8500, Hanau Modular, and Panadent PCH). MATERIAL AND METHODS: Pantograph sensors were mounted to each articulator with custom-made mounting devices. Border movements were made on each articulator with known condylar settings to produce readings at 3-, 5-, and 10-mm condylotrack distances. The condylar settings investigated included horizontal condylar inclination (HCI), immediate mandibular lateral translation (IMLT), progressive mandibular lateral translation (PMLT), top wall, and rear wall. Reliability was assessed by the relative size of standard deviations. Validity was tested with 1-way analysis of variance and the Tukey HSD Test (alpha=.05). RESULTS: The reliability readings for the condylar settings at the 10-mm condylotrack distance, for the most part, were more consistent than those at the 5-mm distance, which, in turn, were more consistent than those at the 3-mm distance. When there were exceptions to this trend, the differences in standard deviations were very small (0.006 mm for IMLT, 0.03 and 0.12 degrees for HCI). When comparing validity between the condylotrack distances, the smallest deviations, in general, were found at the 10-mm distance, the next smallest at the 5-mm distance, and the largest, at the 3-mm distance for HCI. For PMLT, in general, the 10-mm and 5-mm deviations were smaller than the 3-mm deviation. For IMLT, there was no significant difference between the 3-, 5-, and 10-mm deviations. In analyzing validity between the articulators, the smallest deviations from the preset values, in general, were found with the Denar Mark II. CONCLUSION: The standard deviations for assessing reliability and the mean deviations for assessing validity were both relatively small in comparison to the average values of the condylar determinants. Therefore, the electronic pantograph was determined to be both reliable and valid.