Development of proneurogenic, neuroprotective small molecules

Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apoptotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.     

Formation and relaxation dynamics of iso-CH2Cl-I in cryogenic matrices

Photolysis of chloroiodomethane (CH(2)ClI) in cryogenic matrices followed by recombination of the nascent radical pair produces an isomer (CH(2)Cl-I) that features a halogen-halogen (Cl-I) bond. Using ultrafast laser pulses, it is possible to follow the formation of this isomer by transient electronic absorption in low-temperature matrices of N(2), CH(4), and Ar. Frequency-domain measurements provide vibrational and electronic spectra, and electronic structure calculations give the structures of the isomers and the minimum energy path that connects them. The ultrafast experiments cleave the C-I bond with a 267-nm photolysis pulse and probe the formation of the isomer at wavelengths between 435 nm and 510 nm. The longest wavelengths preferentially interrogate vibrationally excited molecules, and their transient absorption shows that the highly vibrationally excited isomer appears within 1 to 2 ps, depending on the matrix, likely reflecting the loss of 2000 cm(-1) or more of energy in a strong, inelastic collision of the fragments with the matrix. The subsequent relaxation of the vibrationally excited isomer occurs in 20 to 40 ps, a time that is comparable to those observed for halomethane molecules and their isomers in liquids and in supercritical CO(2). These observations suggest that the formation and initial relaxation of the isomer in dense media do not depend strongly on the identity of the surroundings.     

Diversity-oriented synthesis of 13- to 18-membered macrolactams via ring-closing metathesis

An efficient build/couple/pair approach to diversity-oriented synthesis was employed to access several structurally complex macrolactams. In this paper, we describe the successful evaluation of ring-closing metathesis toward the systematic generation of skeletal diversity. By appropriately varying the nature and chain length of the alkenol fragment, a diverse collection of 13- to 18-membered macrolactams were obtained.     

Synthesis and structure of a dinuclear gold(II) complex with terminal fluoride ligands

The potential for reductive elimination of fluorine from dinuclear gold(II) for catalysis has prompted our efforts to synthesize a dinuclear gold(II) fluoride complex. This has been achieved with bis(2,6-dimethylphenyl)formamidinate bridging ligands. In order to obtain this product, it was necessary first to synthesize the corresponding dinuclear gold(II) nitrate, which reacts readily with KF in a metathesis reaction. The nitrate complex and fluoride complexes have been structurally characterized. The Au-Au distance in the dinuclear fluoride, 2.595 ?, is longer than the distance found in the analogous chloride complex, 2.567 ?. This result is consistent with the presence of a fluoride "π electron effect" on the filled Au 5d orbitals. The Raman spectrum shows an Au-Au stretch at 206 cm(-1), which agrees with Woodruff's rules and the density functional theory computational model used for modeling the complex.     

Extraction of small boat harmonic signatures from passive sonar

This paper investigates the extraction of acoustic signatures from small boats using a passive sonar system. Noise radiated from a small boats consists of broadband noise and harmonically related tones that correspond to engine and propeller specifications. A signal processing method to automatically extract the harmonic structure of noise radiated from small boats is developed. The Harmonic Extraction and Analysis Tool (HEAT) estimates the instantaneous fundamental frequency of the harmonic tones, refines the fundamental frequency estimate using a Kalman filter, and automatically extracts the amplitudes of the harmonic tonals to generate a harmonic signature for the boat. Results are presented that show the HEAT algorithms ability to extract these signatures.     

North Pacific right whale up-call source levels and propagation distance on the southeastern Bering Sea shelf

Call source levels, transmission loss, and ambient noise levels were estimated for North Pacific right whale (Eubalaena japonica) up-calls recorded in the southeastern Bering Sea in autumn of 2000 and 2001. Distances to calling animals, needed to estimate source levels, were based on two independent techniques: (1) arrival-time differences on three or more hydrophones and (2) shallow-water dispersion of normal modes on a single receiver. Average root-mean-square (rms) call source levels estimated by the two techniques were 178 and 176 dB re 1 μPa at 1 m, respectively, over the up-call frequency band, which was determined per call and averaged 90 to 170 Hz. Peak-to-peak source levels were 14 to 22 dB greater than rms levels. Transmission loss was approximately 15?log(10)(range), intermediate between cylindrical and spherical spreading. Ambient ocean noise within the up-call band varied from 72 to 91 dB re 1 μPa(2)/Hz. Under average noise conditions, call spectrograms were detectable for whales at distances up to 100 km, but propagation and detection distance may vary depending on environmental parameters and anthropogenic noise. Obtaining distances to animals and acoustic detection range is a step toward using long-term passive acoustic recordings to estimate abundance for this critically endangered whale population.     

Axial thermal rotation of slender rods

Axial rotational diffusion of rodlike polymers is important in processes such as microtubule filament sliding and flagella beating. By imaging the motion of small kinks along the backbone of chains of DNA-linked colloids, we produce a direct and systematic measurement of axial rotational diffusivity of rods both in bulk solution and near a wall. The measured diffusivities decrease linearly with the chain length, irrespective of the distance from a wall, in agreement with slender-body hydrodynamics theory. Moreover, the presence of small kinks does not affect the chain's axial diffusivity. Our system and measurements provide insights into fundamental axial diffusion processes of slender objects, which encompass a wide range of entities including biological filaments and linear polymer chains.     

Nonlinear phase dispersion spectroscopy

Nonlinear phase dispersion spectroscopy is introduced as a means to retrieve wideband, high spectral resolution profiles of the wavelength-dependent real part of the refractive index. The method is based on detecting dispersion effects imparted to a light field with low coherence transmitted through a thin sample and detected interferometrically in the spectral domain. The same sampled signal is also processed to yield quantitative phase maps and spectral information regarding the total attenuation coefficient using spectral-domain phase microscopy and spectroscopic optical coherence tomography (SOCT), respectively. Proof-of-concept experiments using fluorescent and nonfluorescent polystyrene beads and another using a red blood cell demonstrate the ability of the method to quantify various absorptive/dispersive features. The increased sensitivity of this method, novel to our knowledge, is compared to intensity-based spectroscopy (e.g., SOCT), and potential applications are discussed.     

Neonatal EEG signal characteristics using time frequency analysis

Time-frequency analysis is a way to represent the energy contents of a signal in the joint time-frequency domain. It provides a good visual way to separate the frequency contents of a multi-component signal, and display the changes of these components with respect to time. This paper outlines investigative work on neonatal EEG signals using time-frequency analysis. The Cohen’s class distributions are discussed, and kernel optimisation for the Cohen’s class distributions is outlined. Segments of EEG with different background continuity states are analysed using a Cohen’s class distribution, and their characteristics are discussed. Through this paper, interesting information that offers insight towards the EEG signal can be visualized from the time frequency analysis.