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Huntington’s disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. We successfully adapted a high-resolution correlative light and electron microscopy methodology, originally developed for mammalian and yeast cells, to allow us to correlate light microscopy and electron microscopy images on the same brain section within an accuracy of 100 nm. Using this approach, we identified these recruitment sites as single membrane bound, vesicle-rich endolysosomal organelles, specifically as (1) multivesicular bodies (MVBs), or amphisomes and (2) autolysosomes or residual bodies. The organelles were often found in close-proximity to phagophore-like structures. Immunogold labeling localized mutant HTT to non-fibrillar, electron lucent structures within the lumen of these organelles. In presymptomatic HD, the recruitment organelles were predominantly MVBs/amphisomes, whereas in late-stage HD, there were more autolysosomes or residual bodies. Electron tomograms indicated the fusion of small vesicles with the vacuole within the lumen, suggesting that MVBs develop into residual bodies. We found that markers of MVB-related exocytosis were depleted in presymptomatic mice and throughout the disease course. This suggests that endolysosomal homeostasis has moved away from exocytosis toward lysosome fusion and degradation, in response to the need to clear the chronically aggregating mutant HTT protein, and that this occurs at an early stage in HD pathogenesis.

Viewing the trajectory of a patient as a dynamical system, a recurrent neural network was developed to learn the course of patient encounters in the Pediatric Intensive Care Unit (PICU) of a major tertiary care center. Data extracted from Electronic Medical Records (EMR) of about 12000 patients who were admitted to the PICU over a period of more than 10 years were leveraged. The RNN model ingests a sequence of measurements which include physiologic observations, laboratory results, administered drugs and interventions, and generates temporally dynamic predictions for in-ICU mortality at user-specified times. The RNN's ICU mortality predictions offer significant improvements over those from two clinically-used scores and static machine learning algorithms., 18 pages (5 of which in appendix), 9 figures

Presence measurements are traditionally using a variety of subjective and objective measures. However, constraints often result in subjective measurements using questionnaires as a key method of data collection. In this paper we present a study of 44 participants of an augmented reality game known as TimeWarp which used both subjective and objective behavioural measures where both video recordings and self- reports about feelings of presence were compared. Our findings indicate that pointing behaviour and verbal responses to virtual content within an augmented reality scene are correlated negatively to sense of presence. As a result the paper indicates that there are behavioural measures that correlate and can predict subjective feelings of presence in the augmented reality game.

Session : Pathogenic mechanisms II; International audience; Huntington’s disease (HD) is a dominant neurodegenerative disorder associated with N-terminal expanded polyglutamines (polyGlns) in huntingtin (htt). The abnormal regulation of transcription may be central to HD neuronal pathology. We previously reported that the transcriptional regulator CA150 binds to htt and accumulates in a neuropathological grade dependent manner in the striatal and cortical neurons of HD patients, suggesting CA150 dysfunction in HD. Consistently, we report herein that CA150 overexpression rescued the toxicity of mutant htt in lentiviral overexpression (rat striatum) and knock-in (striatal cells from HdhQ111 mice) models of HD. In both systems, the rescue was dependent on the presence of the (Gln-Ala)38 repeat normally found in CA150. Our data indicate that the striatal pathology in HD may involve a loss of CA150 function. Additionally, our data provide a biological rationale for the previously reported influence of the enlarged and potentially hypomorphic repeat alleles on the age at onset in HD