Loss of Cathepsin B and L Leads to Lysosomal Dysfunction, NPC-Like Cholesterol Sequestration and Accumulation of the Key Alzheimer's Proteins

Proper function of lysosomes is particularly important in neurons, as they cannot dilute accumulated toxic molecules and aggregates by cell division. Thus, impairment of lysosomal function plays an important role in neuronal degeneration and in the pathogenesis of numerous neurodegenerative diseases. In this work we analyzed how inhibition and/or loss of the major lysosomal proteases, the cysteine cathepsins B and L (CtsB/L), affects lysosomal function, cholesterol metabolism and degradation of the key Alzheimer's disease (AD) proteins. Here, we show that cysteine CtsB/L, and not the aspartyl cathepsin D (CtsD), represent a major lysosomal protease(s) that control lysosomal function, intracellular cholesterol trafficking and AD-like amyloidogenic features. Intriguingly, accumulation of free cholesterol in late endosomes/lysosomes upon CtsB/L inhibition resembled a phenotype characteristic for the rare neurodegenerative disorder Niemann-Pick type C (NPC). CtsB/L inhibition and not the inhibition of CtsD led to lysosomal impairment assessed by decreased degradation of EGF receptor, enhanced LysoTracker staining and accumulation of several lysosomal proteins LC3II, NPC1 and NPC2. By measuring the levels of NPC1 and ABCA1, the two major cholesterol efflux proteins, we showed that CtsB/L inhibition or genetic depletion caused accumulation of the NPC1 in lysosomes and downregulation of ABCA1 protein levels and its expression. Furthermore, we revealed that CtsB/L are involved in degradation of the key Alzheimer’s proteins: amyloid-β peptides (Aβ) and C-terminal fragments of the amyloid precursor protein (APP) and in degradation of β-secretase (BACE1). Our results imply CtsB/L as major regulators of lysosomal function and demonstrate that CtsB/L may play an important role in intracellular cholesterol trafficking and in degradation of the key AD proteins. Our findings implicate that enhancing the activity or levels of CtsB/L could provide a promising and a common strategy for maintaining lysosomal function and for preventing and/or treating neurodegenerative diseases

Exploring the effects of colouring graph diagrams on people of various backgrounds

Colour is one of the primary aesthetic elements of a visualization. It is often used successfully to encode information such as the importance of a particular part of the diagram or the relationship between two parts. Even so, there are few investigations into the human reading of colour coding on diagrams from the scientific community. In this paper we report on an experiment with graph diagrams comparing a black and white composition with two other colour treatments. We drew our subjects from engineering, art, visual design, physical education, tourism, psychology and social science disciplines. We found that colouring the nodes of interest reduced the time taken to find the shortest path between the two nodes for all subjects. Engineers, tourism and social scientists proved significantly faster with artist/designers just below the overall average speed. From this study, we contribute that adding particular colour treatments to diagrams increases legibility. In addition, preliminary work investigating colour treatments and schemes indicates potential for future gains. © 2014 Springer-Verlag

Empirical Evaluations with Domain Experts

Over the past thirty years, the visualization community has developed theories and models to explain visualization as a technology that augments human cognition by enabling the efficient, accurate, and timely discovery of meaningful information in data. Along the way, practitioners have also debated theories and practices for visualization evaluation: How do we generate durable, reliable evidence that a visualization is effective? Interestingly, there is still no consensus in the visualization research community how to evaluate visualization methods. The goal of this chapter is to rise awareness of still open issues in the visualization evaluation and to discuss appropriate evaluations suitable for different visualization approaches. This includes user studies and best practices to conduct them but also other approaches for suitable evaluation of visualization. The chapter is structured as a moderated dialog of two visualization experts