Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10,337 cases and 11,174 controls (OR=1.10; p-value=3.79×10(-5)). Thus, it appears that rare and common variants in a single gene - FBN2 - can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

Electron scattering by atoms and ions using the Breit-Pauli Hamiltonian:An R-matrix approach

The R-matrix method describing the scattering of low-energy electrons by complex atoms and ions is extended to include terms of the Breit-Pauli Hamiltonian. An application is made to the astrophysically important 1s 2s S-1s 2s2p P transition in Fe XXIII, where in the most accurate calculations carried out all terms of the 1s 2s, 1s2s2p and 1s2p configurations are included in the expansion describing the collision. This gives up to 28 coupled channels for each total angular momentum and parity which are solved on a CRAY-1. The collision strengths are increased by more than a factor of two from their non-relativistic values at all energies considered.

2-D R-matrix Propagator: Application and Future Developments

Ongoing developments of the 2-D R-matrix propagator are discussed. These include application to electron and photon collisions with H-like ions; computational innovations; and important theoretical developments to enable the accurate treatment of electron and photon collisions with multi-electron atoms at intermediate energies.

Living in The Matrix: Virtual Reality Systems and Hyperspatial Representation in Architecture

In the digital age, the hyperspace of virtual reality systems stands out as a new spatial concept creating a parallel realm to "real" space. Virtual reality influences one’s experience of and interaction with architectural space. This "otherworld" brings up the criticism of the existing conception of space, time and body. Hyperspaces are relatively new to designers but not to filmmakers. Their cinematic representations help the comprehension of the outcomes of these new spaces. Visualisation of futuristic ideas on the big screen turns film into a medium for spatial experimentation. Creating a possible future, The Matrix (Andy and Larry Wachowski, 1999) takes the concept of hyperspace to a level not-yet-realised but imagined. With a critical gaze at the existing norms of architecture, the film creates new horizons in terms of space. In this context, this study introduces science fiction cinema as a discussion medium to understand the potentials of virtual reality systems for the architecture of the twenty first century. As a "role model" cinema helps to better understand technological and spatial shifts. It acts as a vehicle for going beyond the spatial theories and designs of the twentieth century, and defining the conception of space in contemporary architecture.

Harmonic generation by noble-gas atoms in the near-IR regime using ab initio time-dependent R-matrix theory

We demonstrate the capability of ab initio time-dependent R-matrix theory to obtain accurate harmonic generation spectra of noble-gas atoms at near-IR wavelengths between 1200 and 1800 nm and peak intensities up to 1.8 × 10^(14) W/cm^(2). To accommodate the excursion length of the ejected electron, we use an angular-momentum expansion up to Lmax=279. The harmonic spectra show evidence of atomic structure through the presence of a Cooper minimum in harmonic generation for Kr, and of multielectron interaction through the giant resonance for Xe. The theoretical spectra agree well with those obtained experimentally.

Application of AAO Matrix in Aligned Gold Nanorod Array Substrates for Surface-Enhanced Fluorescence and Raman Scattering

In this paper, we probed surface-enhanced Raman scattering (SERS) and surface-enhanced fluorescence (SEF) from probe molecule Rhodamine 6G (R6G) on self-standing Au nanorod array substrates made using a combination of anodization and potentiostatic electrodeposition. The initial substrates were embedded within a porous alumina template (AAO). By controlling the thickness of the AAO matrix, SEF and SERS were observed exhibiting an inverse relationship. SERS and SEF showed a non-linear response to the removal of AAO matrix due to an inhomogeneous plasmon activity across the nanorod which was supported by FDTD calculations. We showed that by optimizing the level of AAO thickness, we could obtain either maximized SERS, SEF or simultaneously observe both SERS and SEF together.

Effects of particle/matrix interface and strengthening mechanisms on the mechanical properties of metal matrix composites

A randomly distributed multi-particle model considering the effects of particle/matrix interface and strengthening mechanisms introduced by the particles has been constructed. Particle shape, distribution, volume fraction and the particles/matrix interface due to the factors including element diffusion were considered in the model. The effects of strengthening mechanisms, caused by the introduction of particles on the mechanical properties of the composites, including grain refinement strengthening, dislocation strengthening and Orowan strengthening, are incorporated. In the model, the particles are assumed to have spheroidal shape, with uniform distribution of the centre, long axis length and inclination angle. The axis ratio follows a right half-normal distribution. Using Monte Carlo method, the location and shape parameters of the spheroids are randomly selected. The particle volume fraction is calculated using the area ratio of the spheroids. Then, the effects of particle/matrix interface and strengthening mechanism on the distribution of Mises stress and equivalent strain and the flow behaviour for the composites are discussed.

Lack of in vitro-in vivo correlation for a UC781-releasing vaginal ring in macaques

This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside re- verse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities consid- ered sufficient to maintain vaginal fluid concentrations at levels 82–860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal trans- mission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median con- centrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo–in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mecha- nism rather than the expected diffusion-controlled mechanism.

Attenuation of urokinase activity during experimental ischaemia protects the cerebral barrier from damage through regulation of matrix metalloproteinase-2 and NAD(P)H oxidase

Ischaemic injury impairs the integrity of the blood-brain barrier (BBB). In this study, we investigated the molecular causes of this defect with regard to the putative correlations among NAD(P)H oxidase, plasminogen-plasmin system components, and matrix metalloproteinases. Hence, the activities of NAD(P)H oxidase, matrix metalloproteinase-2, urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA), and superoxide anion levels, were assessed in human brain microvascular endothelial cells (HBMECs) exposed to oxygen-glucose deprivation (OGD) alone or OGD followed by reperfusion (OGD + R). The integrity of an in vitro model of BBB comprising HBMECs and astrocytes was studied by measuring transendothelial electrical resistance and the paracellular flux of albumin. OGD with or without reperfusion (OGD ± R) radically perturbed barrier function while concurrently enhancing uPA, tPA and NAD(P)H oxidase activities and superoxide anion release in HBMECs. Pharmacological inactivation of NAD(P)H oxidase attenuated OGD ± R-mediated BBB damage through modulation of matrix metalloproteinase-2 and tPA, but not uPA activity. Overactivation of NAD(P)H oxidase in HBMECs via cDNA electroporation of its p22-phox subunit confirmed the involvement of tPA in oxidase-mediated BBB disruption. Interestingly, blockade of uPA or uPA receptor preserved normal BBB function by neutralizing both NAD(P)H oxidase and matrix metalloproteinase-2 activities. Hence, selective targeting of uPA after ischaemic strokes may protect cerebral barrier integrity and function by concomitantly attenuating basement membrane degradation and oxidative stress.

Turbo-smt: Accelerating coupled sparse matrix-tensor factorizations by 200x

How can we correlate the neural activity in the human brain as it responds to typed words, with properties of these terms (like ‘edible’, ‘fits in hand’)? In short, we want to find latent variables, that jointly explain both the brain activity, as well as the behavioral responses. This is one of many settings of the Coupled Matrix-Tensor Factorization (CMTF) problem.

Can we accelerate any CMTF solver, so that it runs within a few minutes instead of tens of hours to a day, while maintaining good accuracy? We introduce Turbo-SMT, a meta-method capable of doing exactly that: it boosts the performance of any CMTF algorithm, by up to 200x, along with an up to 65 fold increase in sparsity, with comparable accuracy to the baseline.

We apply Turbo-SMT to BrainQ, a dataset consisting of a (nouns, brain voxels, human subjects) tensor and a (nouns, properties) matrix, with coupling along the nouns dimension. Turbo-SMT is able to find meaningful latent variables, as well as to predict brain activity with competitive accuracy.

Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post-myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IαI/IIIαI, connective tissue growth factor, fibronectin, TGF-β3) and inflammatory (IL-10, IL-1β, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3β and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP-1 signalling may be required to realise its clear therapeutic potential for post-MI heart failure.