Molecular dynamics, flexible docking, virtual screening, ADMET predictions, and molecular interaction field studies to design novel potential MAO-B inhibitors

Monoamine oxidase is a flavoenzyme bound to the mitochondrial outer membranes of the cells, which is responsible for the oxidative deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for antidepressant, Parkinson`s disease, and neuroprotective drugs. Elucidation of the x-ray crystallographic structure of MAO-B has opened the way for the molecular modeling studies. In this work we have used molecular modeling, density functional theory with correlation, virtual screening, flexible docking, molecular dynamics, ADMET predictions, and molecular interaction field studies in order to design new molecules with potential higher selectivity and enzymatic inhibitory activity over MAO-B.

Analysis of Liquid Crystalline Nanoparticles by Small Angle X-Ray Diffraction: Evaluation of Drug and Pharmaceutical Additives Influence on the Internal Structure

The goal of this work was to study the liquid crystalline structure of a nanodispersion delivery system intended to be used in photodynamic therapy after loading with photosensitizers (PSs) and additives such as preservatives and thickening polymers. Polarized light microscopy and light scattering were performed on a standard nanodispersion in order to determine the anisotropy of the liquid crystalline structure and the mean diameter of the nanoparticles, respectively. Small angle X-ray diffraction (SAXRD) was used to verify the influence of drug loading and additives on the liquid crystalline structure of the nanodispersions. The samples, before and after the addition of PSs and additives, were stable over 90 days, as verified by dynamic light scattering. SAXRD revealed that despite the alteration observed in some of the samples analyzed in the presence of photosensitizing drugs and additives, the hexagonal phase still remained in the crystalline phase. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100: 2849-2857, 2011

Distortion product otoacoustic emissions in schoolchildren: Effects of ear asymmetry, handedness and gender

The present study examined effects of ear asymmetry, handedness, and gender on distortion-product otoacoustic emissions (DPOAEs) obtained from schoolchildren. A total of 1003 children (528 boys and 475 girls), with a mean age of 6.2 years (SD = 0.4, range = 5.2-7.9 years), were tested in a quiet room at their schools using the GSI-60 DPOAE system. A distortion-product (DP)-gram was obtained for each ear, with f2 varying from 1.1 to 6.0 kHz and the ratio of f2/f1 at 1.21. The signal-to-noise ratios (SNRs) (DPOAE amplitude minus the mean noise floor) at the tested frequencies 1.1, 1.5, 1.9, 2.4, 3.0, 3.8, 4.8, and 6.0 kHz were measured. The results revealed a small but significant difference in SNR between ears, with right ears showing a higher mean SNR than left ears at 1.9, 3.0, 3.8, and 6.0 kHz. At these frequencies, the difference in mean SNR between ears was less than 1 dB. A significant gender effect was also found. Girls exhibited a higher SNR than boys at 3.8, 4.8, and 6.0 kHz. The difference in mean SNR, as a result of the gender effect, was about 1 to 2 dB at these frequencies. There was no significant difference in mean SNR between left-handed and right-handed children for all tested frequencies.

Distortion product otoacoustic emissions in children at school entry: A comparison with pure tone screening and tympanometry results

This study examined the test performance of distortion product otoacoustic emissions (DPOAEs) when used as a screening tool in the school setting. A total of 1003 children (mean age 6.2 years, SD = 0.4) were tested with pure-tone screening, tympanometry, and DPOAE assessment. Optimal DPOAE test performance was determined in comparison with pure-tone screening results using clinical decision analysis. The results showed hit rates of 0.86, 0.89, and 0.90, and false alarm rates of 0.52, 0.19, and 0.22 for criterion signal-to-noise ratio (SNR) values of 4, 5, and 11 dB at 1.1, 1.9, and 3.8 kHz respectively. DPOAE test performance was compromised at 1.1 kHz. In view of the different test performance characteristics across the frequencies, the use of a fixed SNR as a pass criterion for all frequencies in DPOAE assessments is not recommended. When compared to pure tone plus tympanometry results, the DPOAEs showed deterioration in test performance, suggesting that the use of DPOAEs alone might miss children with subtle middle ear dysfunction. However, when the results of a test protocol, which incorporates both DPOAEs and tympanometry, were used in comparison with the gold standard of pure-tone screening plus tympanometry, test performance was enhanced. In view of its high performance, the use of a protocol that includes both DPOAEs and tympanometry holds promise as a useful tool in the hearing screening of schoolchildren, including difficult-to-test children.

Bubbly Flow Structure in Hydraulic Jump

In an open channel, a hydraulic jump is the rapid transition from super- to sub-critical flow associated with strong turbulence and air bubble entrainment in the mixing layer. New experiments were performed at relatively large Reynolds numbers using phase-detection probes. Some new signal analysis provided characteristic air-water time and length scales of the vortical structures advecting the air bubbles in the developing shear flow. An analysis of the longitudinal air-water flow structure suggested little bubble clustering in the mixing layer, although an interparticle arrival time analysis showed some preferential bubble clustering for small bubbles with chord times below 3 ms. Correlation analyses yielded longitudinal air-water time scales Txx*V1/d1 of about 0.8 in average. The transverse integral length scale Z/d1 of the eddies advecting entrained bubbles was typically between 0.25 and 0.4, irrespective of the inflow conditions within the range of the investigations. Overall the findings highlighted the complicated nature of the air-water flow

Roof structure internal, Raun Raun Theatre, Goroka

View of carved king post.

Roof structure, internal, PNG Coffee Industry Board Office and Warehouse, Goroka

View to underside of roof with steel beam and insulation.

A first-principles density-functional calculation of the electronic and vibrational structure of the key melanin monomers

We report first-principles density-functional calculations for hydroquinone (HQ), indolequinone (IQ), and semiquinone (SQ). These molecules are believed to be the basic building blocks of the eumelanins, a class of biomacromolecules with important biological functions (including photoprotection) and with the potential for certain bioengineering applications. We have used the difference of self-consistent fields method to study the energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, HL. We show that HL is similar in IQ and SQ, but approximately twice as large in HQ. This may have important implications for our understanding of the observed broadband optical absorption of the eumelanins. The possibility of using this difference in HL to molecularly engineer the electronic properties of eumelanins is discussed. We calculate the infrared and Raman spectra of the three redox forms from first principles. Each of the molecules have significantly different infrared and Raman signatures, and so these spectra could be used in situ to nondestructively identify the monomeric content of macromolecules. It is hoped that this may be a helpful analytical tool in determining the structure of eumelanin macromolecules and hence in helping to determine the structure-property-function relationships that control the behavior of the eumelanins.

Modifying insect population age structure to control vector-borne disease

Age is a critical determinant of the ability of most arthropod vectors to transmit a range of human pathogens. This is due to the fact that most pathogens require a period of extrinsic incubation in the arthropod host before pathogen transmission can occur. This developmental period for the pathogen often comprises a significant proportion of the expected lifespan of the vector. As such, only a small proportion of the population that is oldest contributes to pathogen transmission. Given this, strategies that target vector age would be expected to obtain the most significant reductions in the capacity of a vector population to transmit disease. The recent identification of biological agents that shorten vector lifespan, such as Wolbachia, entomopathogenic fungi and densoviruses, offer new tools for the control of vector-borne diseases. Evaluation of the efficacy of these strategies under field conditions will be possible due to recent advances in insect age-grading techniques. Implementation of all of these strategies will require extensive field evaluation and consideration of the selective pressures that reductions in vector longevity may induce on both vector and pathogen.

Quantum symmetries and the Weyl–Wigner product of group representations

In the usual formulation of quantum mechanics, groups of automorphisms of quantum states have ray representations by unitary and antiunitary operators on complex Hilbert space, in accordance with Wigner's theorem. In the phase-space formulation, they have real, true unitary representations in the space of square-integrable functions on phase space. Each such phase-space representation is a Weyl–Wigner product of the corresponding Hilbert space representation with its contragredient, and these can be recovered by 'factorizing' the Weyl–Wigner product. However, not every real, unitary representation on phase space corresponds to a group of automorphisms, so not every such representation is in the form of a Weyl–Wigner product and can be factorized. The conditions under which this is possible are examined. Examples are presented.