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Robot-assisted minimally invasive surgery has shown to improve patient outcomes, as well as reduce complications and recovery time for several clinical applications. While increasingly configurable robotic arms can maximize reach and avoid collisions in cluttered environments, positioning them appropriately during surgery is complicated because safety regulations prevent automatic driving. We propose a head-mounted display (HMD) based augmented reality (AR) system designed to guide optimal surgical arm set up. The staff equipped with HMD aligns the robot with its planned virtual counterpart. In this user-centric setting, the main challenge is the perspective ambiguities hindering such collaborative robotic solution. To overcome this challenge, we introduce a novel registration concept for intuitive alignment of AR content to its physical counterpart by providing a multi-view AR experience via reflective-AR displays that simultaneously show the augmentations from multiple viewpoints. Using this system, users can visualize different perspectives while actively adjusting the pose to determine the registration transformation that most closely superimposes the virtual onto the real. The experimental results demonstrate improvement in the interactive alignment of a virtual and real robot when using a reflective-AR display. We also present measurements from configuring a robotic manipulator in a simulated trocar placement surgery using the AR guidance methodology.

Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC)n-containing RNAs into poly-dipeptides can initiate in vivo without a 5′-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2α), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2α-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease., Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here the authors show that (GGGGCC)n translation can initiate without a 5′-cap, and this cap-independent translation is upregulated by stress mediated through eIF2α phosphorylation.

Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most prevalent genetic cause ofamyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism isthe aberrant accumulation of dipeptide repeat (DPR) proteins produced by the unconventional translation of expanded RNA repeats. Here, we performed genome-wide CRISPR-Cas9 screens for modifiers of DPR protein production in human cells.We found that DDX3X, an RNA helicase, suppresses the repeat-associated non-AUG translation of GGGGCC repeats. DDX3X directly binds to (GGGGCC)n RNAs but not antisense (CCCCGG)n RNAs. Its helicase activity is essential for the translation repression. Reduction of DDX3X increases DPR levels in C9ORF72-ALS/FTD patient cells and enhances (GGGGCC)n-mediated toxicity in Drosophila. Elevating DDX3X expression is sufficient to decrease DPR levels, rescue nucleocytoplasmic transport abnormalities, and improve survival of patient iPSC-differentiated neurons. This work identifies genetic modifiers of DPR protein production and provides potential therapeutic targets for C9ORF72-ALS/FTD.