Summary Huntington’s disease (HD) is caused by an expanded CAG repeat in the Huntingtin (HTT) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic transport, the trafficking of macromolecules between the nucleus and cytoplasm is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt nucleocytoplasmic transport and a mutation of a NUP can cause HD-like pathology. Therefore, we evaluated the NPC and nucleocytoplasmic transport in multiple models of HD including mouse and fly models, neurons transfected with mHTT, HD iPSC-derived neurons and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective nucleocytoplasmic transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted nucleocytoplasmic transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this transport defect and neurotoxicity, providing future novel therapy targets.

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (Htt) protein. Current management strategies temporarily relieve disease symptoms, but fail to affect the underlying disease progression. We previously demonstrated that calorie restriction ameliorated HD pathogenesis and slowed disease progression in HD mice1. We now report that overexpression of SIRT1, a mediator of beneficial metabolic effects of calorie restriction, protects neurons against mutant Htt toxicity, whereas reduction of SIRT1 exacerbates mutant Htt toxicity. Overexpression of SIRT1 significantly improves motor function, reduces brain atrophy, and attenuates mutant Htt-mediated metabolic abnormalities in both fragment and full-length HD mouse models. Further mechanistic studies suggest that SIRT1 prevents mutant Htt-induced decline in BDNF levels and its receptor Trk-B signaling, and restores medium spiny neuronal DARPP32 levels in the striatum. SIRT1 deacetylase activity is required for SIRT1-mediated neuroprotection in HD models. Notably, we demonstrate that mutant Htt interacts with SIRT1 and inhibits SIRT1 deacetylase activity. Inhibition of SIRT1 deacetylase activity results in hyperacetylation of SIRT1 substrates such as FOXO3a thereby inhibiting its prosurvival function. Overexpression of SIRT1 counteracts mutant Htt-induced deacetylase deficit, enhances deacetylation of FOXO3a, and facilitates cell survival. These findings demonstrate a neuroprotective role of SIRT1 in mammalian HD models, indicate key mediators of this protection, and open new avenues for the development of neuroprotective strategies in HD.

Recent advances in both anthropomorphic robots and bimanual industrial manipulators had led to an increased interest in the specific problems pertaining to dual arm manipulation. For the future, we foresee robots performing humanlike tasks in both domestic and industrial settings. It is therefore natural to study specifics of dual arm manipulation in humans and methods for using the resulting knowledge in robot control. The related scientific problems range from low-level control to high level task planning and execution. This review aims to summarize the current state of the art from the heterogenous range of fields that study the different aspects of these problems specifically in dual arm manipulation.

Continuum robots provide inherent structural compliance with high dexterity to access the surgical target sites along tortuous anatomical paths under constrained environments and enable to perform complex and delicate operations through small incisions in minimally invasive surgery. These advantages enable their broad applications with minimal trauma and make challenging clinical procedures possible with miniaturized instrumentation and high curvilinear access capabilities. However, their inherent deformable designs make it difficult to realize 3-D intraoperative real-time shape sensing to accurately model their shape. Solutions to this limitation can lead themselves to further develop closely associated techniques of closed-loop control, path planning, human-robot interaction, and surgical manipulation safety concerns in minimally invasive surgery. Although extensive model-based research that relies on kinematics and mechanics has been performed, accurate shape sensing of continuum robots remains challenging, particularly in cases of unknown and dynamic payloads. This survey investigates the recent advances in alternative emerging techniques for 3-D shape sensing in this field and focuses on the following categories: fiber-optic-sensor-based, electromagnetic-tracking-based, and intraoperative imaging modality-based shape-reconstruction methods. The limitations of existing technologies and prospects of new technologies are also discussed.

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Background: Mitochondrial dysfunction is a key event mediating mutant Htt-induced neurotoxicity. Results: trans-(Ϫ)-⑀-Viniferin attenuates mutantHtt-induced SIRT3 depletion, activates AMPK, and preserves mitochondrial function. Conclusion: Increasing SIRT3 protects cells in HD.Significance: The result suggests a promising new target for development of HD therapeutics.

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White matter abnormalities have been reported in premanifest Huntington's disease (HD) subjects before overt striatal neuronal loss, but whether the white matter changes represent a necessary step towards further pathology and the underlying mechanism of these changes remains unknown. Here, we characterized a novel knock-in mouse model that expresses mouse HD gene homolog (Hdh) with extended CAG repeat- HdhQ250, which was derived from the selective breeding of HdhQ150 mice. HdhQ250 mice manifest an accelerated and robust phenotype compared with its parent line. HdhQ250 mice exhibit progressive motor deficits, reduction in striatal and cortical volume, accumulation of mutant huntingtin aggregation, decreased levels of DARPP32 and BDNF and altered striatal metabolites. The abnormalities detected in this mouse model are reminiscent of several aspects of human HD. In addition, disturbed myelination was evident in postnatal Day 14 HdhQ250 mouse brain, including reduced levels of myelin regulatory factor and myelin basic protein, and decreased numbers of myelinated axons in the corpus callosum. Thinner myelin sheaths, indicated by increased G-ratio of myelin, were also detected in the corpus callosum of adult HdhQ250 mice. Moreover, proliferation of oligodendrocyte precursor cells is altered by mutant huntingtin both in vitro and in vivo. Our data indicate that this model is suitable for understanding comprehensive pathogenesis of HD in white matter and gray matter as well as developing therapeutics for HD.