ARNOLD: A Benchmark for Language-Grounded Task Learning With Continuous States in Realistic 3D Scenes

Understanding the continuous states of objects is essential for task learning and planning in the real world. However, most existing task learning benchmarks assume discrete(e.g., binary) object goal states, which poses challenges for the learning of complex tasks and transferring learned policy from simulated environments to the real world. Furthermore, state discretization limits a robot's ability to follow human instructions based on the grounding of actions and states. To tackle these challenges, we present ARNOLD, a benchmark that evaluates language-grounded task learning with continuous states in realistic 3D scenes. ARNOLD is comprised of 8 language-conditioned tasks that involve understanding object states and learning policies for continuous goals. To promote language-instructed learning, we provide expert demonstrations with template-generated language descriptions. We assess task performance by utilizing the latest language-conditioned policy learning models. Our results indicate that current models for language-conditioned manipulations continue to experience significant challenges in novel goal-state generalizations, scene generalizations, and object generalizations. These findings highlight the need to develop new algorithms that address this gap and underscore the potential for further research in this area. See our project page at: https://arnold-benchmark.github.ioComment: The first two authors contributed equally; 20 pages; 17 figures; project availalbe: https://arnold-benchmark.github.io

TFEB regulates lysosomal proteostasis

Loss-of-function diseases are often caused by destabilizing mutations that lead to protein misfolding and degradation. Modulating the innate protein homeostasis (proteostasis) capacity may lead to rescue of native folding of the mutated variants, thereby ameliorating the disease phenotype. In lysosomal storage disorders (LSDs), a number of highly prevalent alleles have missense mutations that do not impair the enzyme's catalytic activity but destabilize its native structure, resulting in the degradation of the misfolded protein. Enhancing the cellular folding capacity enables rescuing the native, biologically functional structure of these unstable mutated enzymes. However, proteostasis modulators specific for the lysosomal system are currently unknown. Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show that TFEB activation results in enhanced folding, trafficking and lysosomal activity of a severely destabilized glucocerebrosidase (GC) variant associated with the development of Gaucher disease (GD), the most common LSD. TFEB specifically induces the expression of GC and of key genes involved in folding and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and its processing through the secretory pathway. TFEB activation also rescues the activity of a β-hexosaminidase mutant associated with the development of another LSD, Tay–Sachs disease, thus suggesting general applicability of TFEB-mediated proteostasis modulation to rescue destabilizing mutations in LSDs. In summary, our findings identify TFEB as a specific regulator of lysosomal proteostasis and suggest that TFEB may be used as a therapeutic target to rescue enzyme homeostasis in LSDs

Modulating the Lysosome-Autophagy System to Restore Homeostasis in in vitro Model Systems of Lysosomal Storage Disorders

The protein quality control system is a complex network that promotes the folding and trafficking of newly synthesized proteins and regulates the degradation of misfolded proteins and protein aggregates. Failure of the quality control system to maintain protein homeostasis (or proteostasis) characterizes the cellular pathogenesis of a number of human diseases. In particular, this study focuses on lysosomal storage disorders, a group of inherited metabolic diseases characterized by deficiencies in specific lysosomal hydrolytic activities that result from mutations in genes encoding for lysosomal proteins and consequent buildup of lysosomal storage material. The ultimate goal of this work is to develop cell engineering strategies to modulate cellular quality control machineries that control protein folding, processing, and degradation to restore cellular homeostasis under conditions of proteotoxic stress. Specifically, this study aims to manipulate the lysosome-autophagy system to enhance folding and processing of lysosomal enzymes as well as to enhance the cellular clearance capacity. To achieve this goal, I investigated the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in regulating lysosomal proteostasis and autophagic clearance. Specifically, chemical and genetic modulation of TFEB was found to enhance folding, trafficking and activity of unstable, degradation-prone lysosomal enzymes in in vitro models of lysosomal storage disorders. Moreover, pharmacologic activation of autophagy achieved by treating cells with 2-hydroxypropyl-β-cyclodextrin was found to enhance autophagic clearance of storage material specifically by activating TFEB. To further investigate the molecular mechanism of autophagy induction and activation of autophagic clearance, I tested the impact of polystyrene nanoparticles of different size and surface charge on the lysosome-autophagy system with the ultimate goal to link the physicochemical properties of nanomaterials with the specific nature of the autophagic response activated upon nanomaterial uptake into cells. Efficient autophagic clearance was found to depend highly on the surface charge. Specifically, cell exposure to polystyrene nanoparticles presenting neutral or negative surface charge results in activation of autophagic clearance, whereas cell exposure to polystyrene nanoparticles presenting cationic surface charge results in impairment of lysosomal function and blockage of autophagic flux. Ceria nanoparticles (or nanoceria) are widely used in a variety of applications including as UV blockers and catalysts in industrial processes. Recent studies also revealed that ceria nanoparticles present antioxidant properties, suggesting a potential role of nanoceria in a variety of biomedical applications. In this study, I investigated the impact of ceria nanoparticles stabilized by organic surface coatings on the lysosome-autophagy system, Ceria nanoparticles were found to activate the lysosome-autophagy system and enhance autophagic clearance. In summary, this work provides proof-of-principle demonstration of chemical and biological strategies to activate the lysosome-autophagy system for restoring lysosomal proteostasis and enhancing autophagic clearance in model systems of diseases characterized by deficiencies in lysosomal enzymes activities and aberrant accumulation of undegraded lysosomal substrates. These findings lay the foundation for the development of nanotherapeutics for the treatment of diseases associated with inefficient autophagic clearance

Transparent Thin-Film Transistors Based on Sputtered Electric Double Layer

Electric-double-layer (EDL) thin-film transistors (TFTs) have attracted much attention due to their low operation voltages. Recently, EDL TFTs gated with radio frequency (RF) magnetron sputtered SiO2 have been developed which is compatible to large-area electronics fabrication. In this work, fully transparent Indium-Gallium-Zinc-Oxide-based EDL TFTs on glass substrates have been fabricated at room temperature for the first time. A maximum transmittance of about 80% has been achieved in the visible light range. The transparent TFTs show a low operation voltage of 1.5 V due to the large EDL capacitance (0.3 µF/cm2 at 20 Hz). The devices exhibit a good performance with a low subthreshold swing of 130 mV/dec and a high on-off ratio &gt; 105. Several tests have also been done to investigate the influences of light irradiation and bias stress. Our results suggest that such transistors might have potential applications in battery-powered transparent electron devices.</jats:p