Structure optimization combining soft-core interaction functions, the diffusion equation method, and molecular dynamics

Smoothing the potential energy surface for structure optimization is a general and commonly applied strategy. We propose a combination of soft-core potential energy functions and a variation of the diffusion equation method to smooth potential energy surfaces, which is applicable to complex systems such as protein structures; The performance of the method was demonstrated by comparison with simulated annealing using the refinement of the undecapeptide Cyclosporin A as a test case. Simulations were repeated many times using different initial conditions and structures since the methods are heuristic and results are only meaningful in a statistical sense.

Structure of galactosylononitol

A cyclitol galactoside was isolated from the seeds of Vigna angularis and shown to be identical with galactosylononitol. However, detailed 2D NMR data and methylation analysis resulted in the revision of the structure of galactosylononitol to O-alpha-D-galactopyranosyl-(1-->3)-4-O-methyl-D-myo-inositol (1). Thus, compound 1 represents the only naturally occuring methylated derivative of galactinol.

A two-dimensional fuzzy random model of soil pore structure

A new conceptual model for soil pore-solid structure is formalized. Soil pore-solid structure is proposed to comprise spatially abutting elements each with a value which is its membership to the fuzzy set ''pore,'' termed porosity. These values have a range between zero (all solid) and unity (all pore). Images are used to represent structures in which the elements are pixels and the value of each is a porosity. Two-dimensional random fields are generated by allocating each pixel a porosity by independently sampling a statistical distribution. These random fields are reorganized into other pore-solid structural types by selecting parent points which have a specified local region of influence. Pixels of larger or smaller porosity are aggregated about the parent points and within the region of interest by controlled swapping of pixels in the image. This creates local regions of homogeneity within the random field. This is similar to the process known as simulated annealing. The resulting structures are characterized using one-and two-dimensional variograms and functions describing their connectivity. A variety of examples of structures created by the model is presented and compared. Extension to three dimensions presents no theoretical difficulties and is currently under development.

Crystal structure at 1.1 angstrom resolution of alpha-conotoxin PnIB: Comparison with alpha-conotoxins PnIA and GI

Conotoxins are small, cysteine-rich peptides isolated from the venom of Conus spp. of predatory marine snails, which selectively target specific receptors and ion channels critical to the functioning of the neuromuscular system. alpha-Conotoxins PnIA and PnIB are both 16-residue peptides (differing in sequence at only two positions) isolated from the molluscivorous snail Conus pennaceus. In contrast to the muscle-selective alpha-conotoxin GI from Conus geographus, PnIA and PnIB block the neuronal nicotinic acetylcholine receptor (nAChR). Here, we describe the crystal structure of PnIB, solved at a resolution of 1.1 Angstrom and phased using the Shake-and-Bake direct methods program. PnIB crystals are orthorhombic and belong to the space group P2(1)2(1)2(1) with the following unit cell dimensions: a = 14.6 Angstrom, b = 26.1 Angstrom, and c = 29.2 Angstrom. The final refined structure of alpha-conotoxin PnIB includes all 16 residues plus 23 solvent molecules and has an overall R-factor of 14.7% (R-free of 15.9%). The crystal structures of the alpha-conotoxins PnIB and PnIA are solved from different crystal forms, with different solvent contents. Comparison of the structures reveals them to be very similar, showing that the unique backbone and disulfide architecture is not strongly influenced by crystal lattice constraints or solvent interactions. This finding supports the notion that this structural scaffold is a rigid support for the presentation of important functional groups. The structures of PnIB and PnIA differ in their shape and surface charge distribution from that of GI.

Targeted drug delivery to the skin and deeper tissues: Role of physiology, solute structure and disease

1. Drug delivery through the skin has been used to target the epidermis, dermis and deeper tissues and for systemic delivery, The major barrier for the transport of drugs through the skin is the stratum corneum, with most transport occurring through the intercellular region, The polarity of the intercellular region appears to be similar to butanol, with the diffusion of solutes being hindered by saturable hydrogen bonding to the polar head groups of the ceramides, fatty acids and other intercellular lipids, Accordingly, the permeability of the more lipophilic solutes is greatest from aqueous solutions, whereas polar solute permeability is favoured by hydrocarbon-based vehicles. 2. The skin is capable of metabolizing many substances and, through its microvasculature, limits the transport of most substances into regions below the dermis. 3. Although the flux of solutes through the skin should be identical for different vehicles when the solute exists as a saturated solution, the fluxes vary in accordance with the skin penetration enhancement properties of the vehicle. It is therefore desirable that the regulatory standards required for the bioequivalence of topical products include skin studies. 4. Deep tissue penetration can be related to solute protein binding, solute molecular size and dermal blood flow. 5. Iontophoresis is a promising area of skin drug delivery, especially for ionized solutes and when a rapid effect is required. 6. In general, psoriasis and other skin diseases facilitate drug delivery through the skin. 7. It is concluded that the variability in skin permeability remains an obstacle in optimizing drug delivery by this route.

Tubular eyes of deep-sea fishes: A comparative study of retinal topography

The world's deep oceans are home to a number of teleosts with asymmetrical or tubular eyes. These immobile eyes possess large spherical lenses and subtend a large binocular visual field directed either dorsally or rostrally. Derived from a lateral non-tubular eye, the tubular eye is comprised of a thick main retina, subserving the rostrally or dorsally directed binocular visual field, and a thin accessory retina subserving, the lateral, monocular visual field. The main retina is thought to receive a focussed image, while the accessory retina is too close to the lens for a focussed image to be received. Several species also possess retinal diverticula, which are small evaginations of differentiated retina located in the rostrolateral wall of the eye and thought to increase the visual field. In order to investigate the spatial resolving power of these retinae (main, accessory and diverticulum), the distribution of cells within the ganglion cell layer was analysed from retinal wholemounts and sectioned material in ten species representing four genera. In all species, the main retina possesses a marked increase in cell density towards a specialised retinal region (area centralis), with a centro-peripheral gradient range between 7.1 and 60:1 and a peak density range of between 30 and 55 x 10(3) cells per mm(2). The accessory retinae and the transitional zone between the main and accessory retinae possess relatively low cell densities (between 1 and 10 x 10(3) cells per mm(2)) and lack an area centralis. Retinal diverticula examined in four species possess mean ganglion cell densities of between 7.2 and 109.4 x 10(3) cells per mm(2). Analyses of soma areas show that the ganglion cell layer of most species possesses cells with areas in a range of 8.0 to 15.4 mu m(2) in the main retina and between 15.1 and 17.4 mu m(2) in the accessory retina. The peak spatial resolving power of the main retina of the ten species varies from 4.1 to 9.1 cycles per degree. The positions of the retinal areae centrales relative to each species' binocular visual field are discussed in relation to what is known of feeding behaviour of these fishes in the deep-sea.

The structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel

Background: Versutoxin (delta-ACTX-Hv1) is the major component of the venom of the Australian Blue Mountains funnel web spider, Hadronyche versuta. delta-ACTX-Hv1 produces potentially fatal neurotoxic symptoms in primates by slowing the inactivation of voltage-gated sodium channels; delta-ACTX-Hv1 is therefore a useful tool for studying sodium channel function. We have determined the three-dimensional structure of delta ACTX-Hv1 as the first step towards understanding the molecular basis of its interaction with these channels. Results: The solution structure of delta-ACTX-Hv1, determined using NMR spectroscopy, comprises a core beta region containing a triple-stranded antiparallel beta sheet, a thumb-like extension protruding from the beta region and a C-terminal 3(10) helix that is appended to the beta domain by virtue of a disulphide bond. The beta region contains a cystine knot motif similar to that seen in other neurotoxic polypeptides. The structure shows homology with mu-agatoxin-l, a spider toxin that also modifies the inactivation kinetics of vertebrate voltage-gated sodium channels. More surprisingly, delta-ACTX-Hv1 shows both sequence and structural homology with gurmarin, a plant polypeptide. This similarity leads us to suggest that the sweet-taste suppression elicited by gurmarin may result from an interaction with one of the downstream ion channels involved in sweet-taste transduction. Conclusions: delta-ACTX-Hv1 shows no structural homology with either sea anemone or alpha-scorpion toxins, both of which also modify the inactivation kinetics of voltage-gated sodium channels by interacting with channel recognition site 3. However, we have shown that delta-ACTX-Hv1 contains charged residues that are topologically related to those implicated in the binding of sea anemone and alpha-scorpion toxins to mammalian voltage-gated sodium channels, suggesting similarities in their mode of interaction with these channels.

Comments on the Drinfeld realization of the quantum affine superalgebra U-q[gl(m backslash n)(1)] and its Hopf algebra structure

By generalizing the Reshetikhin and Semenov-Tian-Shansky construction to supersymmetric cases, we obtain the Drinfeld current realization for the quantum affine superalgebra U-q[gl(m\n)((1))]. We find a simple coproduct for the quantum current generators and establish the Hopf algebra structure of this super current algebra.

Evaluation of retinal nerve fiber layer thickness measurements using optical coherence tomography in patients with tobacco-alcohol-induced toxic optic neuropathy

Three patients with progressive visual loss, chronic alcoholism and tabagism were submitted to a complete neuro-ophthalmic examination and to retinal nerve fiber layer (RNFL) measurements using optical coherence tomography (OCT) scanning. Two patients showed marked RNFL loss in the temporal sector of the optic disc. However, a third patient presented RNFL measurements within or above normal limits, based on the Stratus-OCT normative database. Such findings may be due to possible RNFL edema similar to the one that may occur in the acute phase of toxic optic neuropathies. Stratus-OCT was able to detect RNFL loss in the papillomacular bundle of patients with tobacco-alcohol-induced toxic optic neuropathy. However, interpretation must be careful when OCT does not show abnormality in order to prevent diagnostic confusion, since overestimation of RNFL thickness measurements is possible in such cases.

Comparison of Fourier-Domain and Time-Domain Optical Coherence Tomography in the Detection of Band Atrophy of the Optic Nerve

PURPOSE: To compare the ability of Fourier-domain (FD) optical coherence tomography (3D OCT-1000; Top, con, Tokyo, Japan) and time domain (TD) OCT (Stratus; Carl Zeiss Meditec Inc, Dublin, California, USA) to detect axonal loss in eyes with band atrophy (BA) of the optic nerve. DESIGN: Cross-sectional study. METHODS: Thirty-six eyes from 36 patients with BA and temporal visual field (VF) defect from chiasmal compression and 36 normal eyes were studied. Subjects were submitted to standard automated perimetry and macular and retinal nerve fiber layer (RNFL) measurements were taken using 3D OCT-1000 and Stratus OCT. Receiver operating characteristic (ROC) curves were calculated for each parameter. Spearman correlation coefficients were obtained to evaluate the relationship between RNFL and macular thickness parameters and severity of VF loss. Measurements from the two devices were compared. RESULTS: Regardless of OCT device, all RNFL and macular thickness parameters were significantly lower in eyes with BA compared with normal eyes, but no statistically significant difference was found with regard to the area under the ROC curve. Structure-function relationships were also similar for the two devices. In both groups, RNFL and macular thickness measurements were generally and in some cases significantly smaller with 3D OCT-1000 than with Stratus OCT. CONCLUSIONS: The introduction of FD technology did not lead to better discrimination ability for detecting BA of the optic nerve compared with TD technology when using the software currently provided by the manufacturer. 3D OCT-1000 FD OCT RNFL and macular measurements were generally smaller than TD Stratus OCT measurements. Investigators should be aware of this fact when comparing measurements obtained with these two devices. (Am J Oplathalmol 2009;147: 56-63. (c) 2009 by Elsevier Inc. All rights reserved.)

Effect of temporal lobe structure volume on memory in elderly depressed patients

Objective: To compare the volume of the hippocampus and parahippocampal gyrus in elderly individuals with and without depressive disorders, and to determine whether the volumes of these regions correlate with scores on memory tests. Method: Clinical and demographic differences, as well as differences in regional gray matter volumes, were assessed in 48 elderly patients with depressive disorders and 31 control subjects. Brain (structural MRI) scans were processed using statistical parametric mapping and voxel-based morphometry. Cognitive tests were administered to subjects in both groups. Results: There were no between-group gray matter volume differences in the hippocampus or parahippocampal gyrus. In the elderly depressed group only, the volume of the left parahippocampal gyrus correlated with scores on the delayed naming portion of the visual verbal learning test. There were also significant direct correlations in depressed subjects between the volumes of the left hippocampus, right and left parahippocampal gyrus and immediate recall scores on verbal episodic memory tests and visual learning tests. In the control group, there were direct correlations only between overall cognitive performance (as assessed with the MMSE) and the volume of right hippocampus, and between the total score on the visual verbal learning test and the volume of the right and left parahippocampal gyrus. Conclusions: These findings highlight different patterns of relationship between cognitive performance and volumes of medial temporal structures in depressed individuals and healthy elderly subjects. The direct correlation between delayed visual verbal memory recall scores with left parahippocampal volumes specifically in elderly depressed individuals provides support to the view that depression in elderly populations may be a risk factor for dementia. (C) 2009 Elsevier Inc. All rights reserved.

A Comparison of Rates of Change in Neuroretinal Rim Area and Retinal Nerve Fiber Layer Thickness in Progressive Glaucoma

PURPOSE. To evaluate and compare rates of change in neuro-retinal rim area (RA) and retinal nerve fiber layer thickness (RNFLT) measurements in glaucoma patients, those with suspected glaucoma, and normal subjects observed over time. METHODS. In this observational cohort study, patients recruited from two longitudinal studies (Diagnostic Innovations in Glaucoma Study-DIGS and African Descent and Evaluation Study-ADAGES) were observed with standard achromatic perimetry (SAP), optic disc stereophotographs, confocal scanning laser ophthalmoscopy (HRT-3; Heidelberg Engineering, Heidelberg, Germany), and scanning laser polarimetry (GDx-VCC; Carl Zeiss Meditec, Inc., Dublin, CA). Glaucoma progression was determined by the Guided Progression Analysis software for standard automated perimetry [SAP] and by masked assessment of serial optic disc stereophotographs by expert graders. Random-coefficients models were used to evaluate rates of change in average RNFLT and global RA measurements and their relationship with glaucoma progression. RESULTS. At baseline, 194 (31%) eyes were glaucomatous, 347 (55%) had suspected glaucoma, and 88 (14%) were normal. Forty-six (9%) eyes showed progression by SAP and/or stereophotographs, during an average follow-up of 3.3 (+/-0.7) years. The average rate of decline for RNFLT measurements was significantly higher in the progressing group than in the non-progressing group (-0.65 vs. -0.11 mu m/y, respectively; P < 0.001), whereas RA decline was not significantly different between these groups (-0.0058 vs. -0.0073 mm(2)/y, respectively; P = 0.727). The areas under the receiver operating characteristic (ROC) curves used to discriminate progressing versus nonprogressing eyes were 0.811 and 0.507 for the rates of change in the RNFLT and RA, respectively (P < 0.001). CONCLUSIONS. The ability to discriminate eyes with progressing glaucoma by SAP and/or stereophotographs from stable eyes was significantly greater for RNFLT than for RA measurements. (Invest Ophthalmol Vis Sci. 2010;51:3531-3539) DOI: 10.1167/iovs.09-4350