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Postoperative retinal demarcation lines on infrared imaging serve as crucial indicators gradually fading with time. These lines may unveil the progression of subretinal fluid, particularly in cases of macula-split retinal detachment. Additional studies are needed to elucidate the mechanism and factors influencing the appearance and evolution of these lines.

To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1532-5415.2008.01666.x Byline: Shelagh M. Szabo (*[dagger][double dagger]), Patricia A. Janssen (*[double dagger]), Karim Khan ([double dagger]), Michael J. Potter ([dagger]), Stephen R. Lord (s.) Keywords: age-related macular degeneration (AMD); falls; elderly; prevention Abstract: OBJECTIVES: To determine whether older women with exudative age-related macular degeneration (AMD) are at greater risk of falls. DESIGN: Cross-sectional study. SETTING: A hospital-based ophthalmology clinic in Vancouver, Canada. PARTICIPANTS: One hundred fifteen older (aged [greater than or equal to]70) community-dwelling women with exudative AMD (AMD cohort) and two control groups: 54 community-dwelling women without exudative AMD drawn from the same community (non-AMD cohort) and 341 community-dwelling Australian women (Australian normative cohort). MEASUREMENTS: Participants were assessed for falls risk using the short-form Physiological Profile Assessment (PPA), which provides a fall risk index score and subcomponent measures of vision, proprioception, strength, reaction time, and postural sway. RESULTS: The mean fall risk index score in the AMD cohort (3.20) was significantly greater than that of the non-AMD cohort (1.21; P CONCLUSION: Older women with AMD have impaired balance, slow visual reaction times, and poor vision, which in combination result in a significantly greater risk of falls than population norms. These deficits are clearly indicated in the physiological falls profile for the group. Strategies to enhance balance may be particularly beneficial to prevent falls in this group. Author Affiliation: (*)Health Care and Epidemiology and ([dagger])Ophthalmology and Visual Sciences, University of British Columbia, Vancouver Canada ([double dagger])Vancouver Coastal Health Research Institute Bone Health Research Group, Vancouver, Canada (s.)Prince of Wales Medical Research Institute, University of New South Wales, Sydney, New South Wales, Australia. Article note: Address correspondence to Shelagh M. Szabo, MSc, 450-688 W. Hastings St, Vancouver, BC, Canada, V6B 1P1. E-mail: shelaghs@telus.net

Purpose To compare enhanced depth imaging in swept-source optical coherence tomography and non–enhanced depth imaging optical coherence tomography in their ability to capture choroidal and scleral details.Methods Averaged foveal B-Scans were obtained from 40 eyes of 20 healthy volunteers by swept-source optical coherence tomography with and without enhanced depth imaging. Visibility and contrast of vascular details within the choroid, choroidoscleral junction, and sclera were evaluated by masked readers using an ordinal scoring scale. Outcomes were analyzed using the Wilcoxon signed rank-sum test.Results Visibility of the choroidal vascular details (Z= 5.94, p< .001), the choroidoscleral junction (Z= 5.85, p< .001), and the sclera (Z= 6.80, p< .001) was significantly higher with enhanced depth imaging than with non–enhanced depth imaging swept-source optical coherence tomography. Similarly, image contrast was significantly higher with enhanced depth imaging than with non–enhanced depth imaging swept-source optical coherence tomography for the choroidal vascular details (Z= 9.47, p< .001), for the choroidoscleral junction (Z= 9.28, p< .001), and for the sclera (Z= 9.42, p< .001).Conclusion Enhanced depth imaging applied to swept-source optical coherence tomography–averaged foveal B-scans enhances visualization of the choroidal details, of the choroidoscleral junction, and of the sclera. This novel modality can easily be implemented in clinics and could improve our understanding of conditions involving the choroid or the sclera.

The structure-based technologies most widely used to rank the affinities of candidate small molecule drugs for proteins range from faster but less reliable docking methods to slower but more accurate explicit solvent free energy methods. In recent years, we have advanced another technology, which is called mining minima because it “mines” out the main contributions to the chemical potentials of the free and bound molecular species by identifying and characterizing their main local energy minima. The present study provides systematic benchmarks of the accuracy and computational speed of mining minima, as implemented in the VeraChem Mining Minima Generation 2 (VM2) code, across two well-regarded protein–ligand benchmark data sets, for which there are already benchmark data for docking, free energy, and other computational methods. A core result is that VM2’s accuracy approaches that of explicit solvent free energy methods at a far lower computational cost. In finer-grained analyses, we also examine the influence of various run settings, such as the treatment of crystallographic water molecules, on the accuracy, and define the costs in time and dollars of representative runs on Amazon Web Services (AWS) compute instances with various CPU and GPU combinations. We also use the benchmark data to determine the importance of VM2’s correction from generalized Born to finite-difference Poisson–Boltzmann results for each energy well and find that this correction affords a remarkably consistent improvement in accuracy at a modest computational cost. The present results establish VM2 as a distinctive technology for early-stage drug discovery, which provides a strong combination of efficiency and predictivity.

Accurate free-energy calculations provide mechanistic insights into molecular recognition and conformational equilibrium. In this work, we performed free-energy calculations to study the thermodynamic properties of different states of molecular systems in their equilibrium basin, and obtained accurate absolute binding free-energy calculations for protein-ligand binding using a newly developed M2 algorithm. We used a range of Asp-Phe-Gly (DFG)-in/out p38αmitogen-activated protein kinase inhibitors as our test cases. We also focused on the flexible DFG motif, which is closely connected to kinase activation and inhibitor binding. Our calculations explain the coexistence of DFG-in and DFG-out states of the loop and reveal different components (e.g., configurational entropy and enthalpy) that stabilize the apo p38αconformations. To study novel ligand-binding modes and the key driving forces behind them, we computed the absolute binding free energies of 30 p38αinhibitors, including analogs with unavailable experimental structures. The calculations revealed multiple stable, complex conformations and changes in p38αand inhibitor conformations, as well as balance in several energetic terms and configurational entropy loss. The results provide relevant physics that can aid in designing inhibitors and understanding protein conformational equilibrium. Our approach is fast for use with proteins that contain flexible regions for structure-based drug design.

We present the first application of the mining minima algorithm to protein−small molecule binding. This end-point approach uses an empirical force field and implicit solvent models, treats the protein binding site as fully flexible, and estimates free energies as sums over local energy wells. The calculations are found to yield encouraging agreement with experimental results for three sets of HIV-1 protease inhibitors and a set of phosphodiesterase 10a inhibitors. The contributions of various aspects of the model to its accuracy are examined, and the Poisson−Boltzmann correction is found to be the most critical. Interestingly, the computed changes in configurational entropy upon binding fall roughly along the same entropy−energy correlation previously observed for smaller host−guest systems. Strengths and weaknesses of the method are discussed, as are the prospects for enhancing accuracy and speed.

Background:Neovascularization is a serious consequence of several eye diseases, including age-related macular degeneration. Neovascularization is under the control of proangiogenic factors, such as vascular endothelial growth factor and fibroblast growth factor. Recent work in our laboratory has focused on other, novel angiogenic factors, such as neuropilin-I, and their potential role in neovascularization. The purpose of this study was to investigate the role of neuropilin-1 in choroidal neovascularization (CNV).

Background:The most widely used models of proliferative vitreoretinopathy (PVR) rely on injection of cells into the vitreous of animals. Using retinal pigment epithelial (RPE) cells from human PVR membranes may produce a more accurate model of human PVR. We performed a study to determine whether human RPE cells derived from a single epiretinal membrane (ERM) are capable of inducing the same disease in the rabbit eye, and whether the induced ERMs had cellular components similar to those of human PVR membranes.

It has been argued that the stacking of adenyl groups in water must be driven primarily by electrostatic interactions, based upon NMR data showing stacking for two adenyl groups joined by a 3-atom linker but not for two naphthyl groups joined by the same linker. In contrast, theoretical work has suggested that adenine stacking is driven primarily by nonelectrostatic forces, and that electrostatic interactions actually produce a net repulsion between adenines stacking in water. The present study provides evidence that the experimental data for the 3-atom-linked bis-adenyl and bis-naphthyl compounds are consistent with the theory indicating that nonelectrostatic interactions drive adenine stacking. First, a theoretical conformational analysis is found to reproduce the observed ranking of the stacking tendencies of the compounds studied experimentally. A geometric analysis identifies two possible reasons, other than stronger electrostatic interactions, why the 3-atom-linked bis-adenyl compounds should stack more than the bis-naphthyl compounds. First, stacked naphthyl groups tend to lie further apart than stacked adenyl groups, based upon both quantum calculations and crystal structures. This may prevent the bis-naphthyl compound from stacking as extensively as the bis-adenyl compound. Second, geometric analysis shows that more stacked conformations are sterically accessible to the bis-adenyl compound than to the bis-naphthyl compound because the linker is attached to the sides of the adenyl groups, but to the ends of the naphthyl groups. Finally, ab initio quantum mechanics calculations and energy decompositions for relevant conformations of adenine and naphthalene dimers support the view that stacking in these compounds is driven primarily by nonelectrostatic interactions. The present analysis illustrates the importance of considering all aspects of a molecular system when interpreting experimental data, and the value of computer models as an adjunct to chemical intuition.

Time scales currently obtainable in explicit–solvent molecular dynamics simulations are inadequate for the study of many biologically important processes. This has led to increased interest in the use of continuum solvent models. For such models to be used effectively, it is important that their behavior relative to explicit simulation be clearly understood. Accordingly, 5 ns stochastic dynamics simulations of a derivative of cryptophane‐E alone, and complexed with tetramethylammonium and neopentane were carried out. Solvation electrostatics were accounted for via solutions to the Poisson equation. Nonelectrostatic aspects of solvation were incorporated using a surface area‐dependent energy term. Comparison of the trajectories to those from previously reported 25 ns explicit–solvent simulations shows that use of a continuum solvent model results in enhanced sampling. Use of the continuum solvent model also results in a considerable increase in computational efficiency. The continuum solvent model is found to predict qualitative structural characteristics that are similar to those observed in explicit solvent. However, some differences are significant, and optimization of the continuum parameterization will be required for this method to become an efficient alternative to explicit–solvent simulation. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 956–970, 1999

The bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) carries out two distinct reactions, with the dihydrofolate produced by the TS-catalyzed reaction acting as the substrate for the DHFR-catalyzed reaction. Brownian dynamics simulation techniques were used to investigate the possible role of electrostatics in determining efficient channeling of the substrate, by explicitly simulating substrate diffusion between the two active sites. With a substrate charge of −2, almost all (>95%) substrate molecules leaving the TS active site reached the DHFR active site at zero ionic strength. Under the same conditions, but in the absence of electrostatic effects, successful channeling was reduced to only around 6%: electrostatic effects therefore appear essential to explain the efficient channeling observed experimentally. The importance of substrate charge, the relative contributions of specific basic residues in the protein, the role played by the second monomer of the dimer in channeling and the effects of changing ionic strength were all investigated. Simulations performed for substrate transfer in the opposite direction suggest that channeling in DHFR-TS is not strongly directional and that the role of electrostatics is perhaps more one of restricting diffusion of the substrate than one of actively guiding it from the TS to the DHFR active site. The results demonstrate that electrostatic channeling can be a highly efficient means of transferring charged substrates between active sites in solvent-exposed environments.

The article offers information on a hydrated magnesium-aluminum-iron silicate mineral called vermiculite. It states that the mineral is fire resistant and has good insulating properties, a high liquid absorption capacity and low density. It says that South Africa generated approximately 200,000 metric tons of vermiculite in 2006.

In order to understand the mechanism of chromosomal breakage at the DNA level, we recently studied a patient with a de novo ring 21 chromosome. His karyotype was described as 45, XY, -21/46, XY, r(21) (p13q22). Thus, he is monosomic for the sub band 21q22.3 in every cell and trisomic for the remainder of chromosome 21 in at least 70% of his cells.Using five single copy DNA fragments randomly isolated from chromosome 21 as probes, we have found the following: (i) Four of DNA fragments mapped to the trisomic portion of chromosome 21. (ii) Using DNA polymorphisms associated with these fragments, we determined that the ring chromosome had originated from the mother. (iii) One DNA fragment (pPW231C) mapped at the break-points of the r(21). This latter conclusion was based on the fact that abnormal fragments were present in Southern blots of DNA derived from the proband's leukocytes and fibroblasts and absent from parental DNA. Using several restriction digests we were able to localize the breakpoints to within a 2.1 Kb EcoRI DNA genomic fragment. Nucleotide sequencing of both the normal and the rearranged DNA will provide important information concerning the DNA sequences involved in the rearrangement leading to formation of the ring 21 chromosome.