Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that exist on a disease spectrum due to pathological, clinical and genetic overlap. In up to 97% of ALS cases and ~50% of FTLD cases, the primary pathological protein observed in affected tissues is TDP-43, which is hyperphosphorylated, ubiquitinated and cleaved. The TDP-43 is observed in aggregates that are abnormally located in the cytoplasm. The pathogenicity of TDP-43 cytoplasmic aggregates may be linked with both a loss of nuclear function and a gain of toxic functions. The cellular processes involved in ALS and FTLD disease pathogenesis include changes to RNA splicing, abnormal stress granules, mitochondrial dysfunction, impairments to axonal transport and autophagy, abnormal neuromuscular junctions, endoplasmic reticulum stress and the subsequent induction of the unfolded protein response. Here, we review and discuss the evidence for alterations to these processes that have been reported in cellular and animal models of TDP-43 proteinopathy.     

3D modeling and motion parallax for improved videoconferencing

Computational Visual Media - We consider a face-to-face videoconferencing system that uses a Kinect camera at each end of the link for 3D modeling and an ordinary 2D display for output. The Kinect...     

Adaptive quadtree simulation of shallow flows with wet-dry fronts over complex topography

Many natural terrains have complicated surface topography. The simulation of steep-fronted flows that occur after heavy rainfall flash floods or as inundation from dyke breaches is usually based on the non-linear shallow water equations in hyperbolic conservation form. Particular challenges to numerical modellers are posed by the need to balance correctly the flux gradient and source terms in Godunov-type finite volume shock-capturing schemes and by the moving wet-dry boundary as the flood rises or falls. This paper presents a Godunov-type shallow flow solver on adaptive quadtree grids aimed at simulating flood flows as they travel over natural terrain. By choosing the stage and discharge as dependent variables in the hyperbolic non-linear shallow water equations, a new deviatoric formulation is derived that mathematically balances the flux gradient and source terms in cases where there are wet-dry fronts. The new formulation is more general in application than previous a priori approaches. Three benchmark tests are used to validate the solver, and include steady flow over a submerged hump, flow disturbances propagating over an elliptical-shaped hump, and free surface sloshing motions in a vessel with a parabolic bed. The model is also used to simulate the propagation of a flood due to a dam break over an initially dry floodplain containing three humps.     

Benefit evaluation for off‐site production in construction

Evaluating to what extent a component or building system should be produced off‐site is inadequate within the industry. The potential benefits of off‐site production (OSP) are commonly cited when justifying an OSP approach, yet holistic and methodical assessments of the applicability and overall benefit of these solutions, to a particular project, have been found to be deficient. Common methods of evaluation simply take material, labour and transportation costs into account when comparing various options, often disregarding other cost‐related items such as site facilities, crane use and rectification of works. These cost factors are usually buried within the nebulous preliminaries figure, with little reference to the building approach taken. Further, softer issues such as health and safety, effects on management and process benefits are either implicit or disregarded within these comparison exercises. Yet it is demonstrated that these issues are some of the most significant benefits of OSP. A series of case studies demonstrated that evaluation focus is almost solely on direct material and labour costs of components, without explicit regard for the wider cost or soft issue implications of OSP on a project. The paper argues that until evaluation is more holistic and value‐based rather than cost‐based, OSP uptake in construction will be slow.     

Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice

The nitric oxide–guanylyl cyclase-1–cyclic guanylate monophosphate (NO–GC-1–cGMP) pathway is integral to the control of vascular tone and morphology. Mice lacking the alpha catalytic domain of guanylate cyclase (GC1^−/−) develop retinal ganglion cell (RGC) degeneration with age, with only modest fluctuations in intraocular pressure (IOP). Increasing the bioavailability of cGMP in GC1^−/− mice prevents neurodegeneration independently of IOP, suggesting alternative mechanisms of retinal neurodegeneration. In continuation to these studies, we explored the hypothesis that dysfunctional cGMP signaling leads to changes in the neurovascular unit that may contribute to RGC degeneration. We assessed retinal vasculature and astrocyte morphology in young and aged GC1^−/− and wild type mice. GC1^−/− mice exhibit increased peripheral retinal vessel dilation and shorter retinal vessel branching with increasing age compared to Wt mice. Astrocyte cell morphology is aberrant, and glial fibrillary acidic protein (GFAP) density is increased in young and aged GC1^−/− mice, with areas of dense astrocyte matting around blood vessels. Our results suggest that proper cGMP signaling is essential to retinal vessel morphology with increasing age. Vascular changed are preceded by alterations in astrocyte morphology which may together contribute to retinal neurodegeneration and loss of visual acuity observed in GC1^−/− mice.     

Absence of sterol biosynthesis in oyster tissue culture

An oyster heart tissue culture was used to investigate the ability of the American oyster (Crassostrea virginica) to synthesize sterols from [¹⁴C]acetate. Lipids were extracted from cultured oyster heart cells and no label was found in the purified fatty acid fraction, 90% of which was located in the saturated and monounsaturated fractions. Although these results cannot rule out the possibility of sterol synthesis in other oyster tissues, this and previous evidence are in support of the hypothesis that the American oyster is unable to synthesize sterols.