Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa.

PURPOSE: Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes. METHODS: We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing. RESULTS: We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5' untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family. CONCLUSIONS: The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin

Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis

Lysosome-related organelles are cell type–specific intracellular compartments with distinct morphologies and functions. The molecular mechanisms governing the formation of their unique structural features are not known. Melanosomes and their precursors are lysosome-related organelles that are characterized morphologically by intralumenal fibrous striations upon which melanins are polymerized. The integral membrane protein Pmel17 is a component of the fibrils and can nucleate their formation in the absence of other pigment cell–specific proteins. Here, we show that formation of intralumenal fibrils requires cleavage of Pmel17 by a furin-like proprotein convertase (PC). As in the generation of amyloid, proper cleavage of Pmel17 liberates a lumenal domain fragment that becomes incorporated into the fibrils; longer Pmel17 fragments generated in the absence of PC activity are unable to form organized fibrils. Our results demonstrate that PC-dependent cleavage regulates melanosome biogenesis by controlling the fibrillogenic activity of a resident protein. Like the pathologic process of amyloidogenesis, the formation of other tissue-specific organelle structures may be similarly dependent on proteolytic activation of physiological fibrillogenic substrates

Extended morphometric analysis of neuronal cells with Minkowski valuations

Minkowski valuations provide a systematic framework for quantifying different aspects of morphology. In this paper we apply vector- and tensor-valued Minkowski valuations to neuronal cells from the cat's retina in order to describe their morphological structure in a comprehensive way. We introduce the framework of Minkowski valuations, discuss their implementation for neuronal cells and show how they can discriminate between cells of different types.Comment: 14 pages, 18 postscript figure

Markbooks

A collection of carefully left traces — and their occasionally accompanying thoughts — Markbooks is the result of “an ongoing conversation about attention, its ecologies, its forms, and the markings of its passage.” “For many of the authors included here, the practice of making — and then reading — their little book located them in time… [T]here is paper, and there are pencils, and there are bodies to mark their own motion.

Collapse-and-revival dynamics of strongly laser-driven electrons

The relativistic quantum dynamics of an electron in an intense single-mode quantized electromagnetic field is investigated with special emphasis on the spin degree of freedom. In addition to fast spin oscillations at the laser frequency, a second time scale is identified due to the intensity dependent emissions and absorptions of field quanta. In analogy to the well-known phenomenon in atoms at moderate laser intensity, we put forward the conditions of collapses and revivals for the spin evolution in laser-driven electrons starting at feasible $10^{18}$ W/cm$^2$.Comment: 18 pages, 4 figure

Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology

Alzheimer's disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimer's disease amyloid pathology has remained incompletely understood. One known link involves synaptic acetylcholinesterase (AChE-S), shown to accelerate amyloid fibrils formation. Here, we report that the ‘Readthrough' AChE-R splice variant, which differs from AChE-S in its 26 C-terminal residues, inversely exerts neuroprotective effects from amyloid β (Aβ) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Aβ oligomers and fibrils and abolished Aβ toxicity to cultured cells, competing with the prevalent AChE-S protein which facilitates these processes. In vivo, double transgenic APPsw/AChE-R mice showed lower plaque burden, fewer reactive astrocytes and less dendritic damage than single APPsw mice, inverse to reported acceleration of these features in double APPsw/AChE-S mice. In hippocampi from Alzheimer's disease patients (n = 10), dentate gyrus neurons showed significantly elevated AChE-R mRNA and reduced AChE-S mRNA. However, immunoblot analyses revealed drastic reductions in the levels of intact AChE-R protein, suggesting that its selective loss in the Alzheimer's disease brain exacerbates the Aβ-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic event

Enhanced inverse bremsstrahlung heating rates in a strong laser field

Test particle studies of electron scattering on ions, in an oscillatory electromagnetic field have shown that standard theoretical assumptions of small angle collisions and phase independent orbits are incorrect for electron trajectories with drift velocities smaller than quiver velocity amplitude. This leads to significant enhancement of the electron energy gain and the inverse bremsstrahlung heating rate in strong laser fields. Nonlinear processes such as Coulomb focusing and correlated collisions of electrons being brought back to the same ion by the oscillatory field are responsible for large angle, head-on scattering processes. The statistical importance of these trajectories has been examined for mono-energetic beam-like, Maxwellian and highly anisotropic electron distribution functions. A new scaling of the inverse bremsstrahlung heating rate with drift velocity and laser intensity is discussed.Comment: 12 pages, 12 figure

Real-Time Cleaning and Refinement of Facial Animation Signals

With the increasing demand for real-time animated 3D content in the entertainment industry and beyond, performance-based animation has garnered interest among both academic and industrial communities. While recent solutions for motion-capture animation have achieved impressive results, handmade post-processing is often needed, as the generated animations often contain artifacts. Existing real-time motion capture solutions have opted for standard signal processing methods to strengthen temporal coherence of the resulting animations and remove inaccuracies. While these methods produce smooth results, they inherently filter-out part of the dynamics of facial motion, such as high frequency transient movements. In this work, we propose a real-time animation refining system that preserves -- or even restores -- the natural dynamics of facial motions. To do so, we leverage an off-the-shelf recurrent neural network architecture that learns proper facial dynamics patterns on clean animation data. We parametrize our system using the temporal derivatives of the signal, enabling our network to process animations at any framerate. Qualitative results show that our system is able to retrieve natural motion signals from noisy or degraded input animation.Comment: ICGSP 2020: Proceedings of the 2020 The 4th International Conference on Graphics and Signal Processin

Recognition of Facial Expressions by Cortical Multi-scale Line and Edge Coding

Face-to-face communications between humans involve emotions, which often are unconsciously conveyed by facial expressions and body gestures. Intelligent human-machine interfaces, for example in cognitive robotics, need to recognize emotions. This paper addresses facial expressions and their neural correlates on the basis of a model of the visual cortex: the multi-scale line and edge coding. The recognition model links the cortical representation with Paul Ekman's Action Units which are related to the different facial muscles. The model applies a top-down categorization with trends and magnitudes of displacements of the mouth and eyebrows based on expected displacements relative to a neutral expression. The happy vs. not-happy categorization yielded a. correct recognition rate of 91%, whereas final recognition of the six expressions happy, anger, disgust, fear, sadness and surprise resulted in a. rate of 78%