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Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as a pivotal membrane-less organelle responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, nanomolar pyrvinium pamoate alleviated retina degeneration and reduced tauopathy by promoting autophagy and ubiquitin-proteasome system in a SON-dependent manner without causing cellular stress. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were also observed in human tauopathies. Our study uncovers novel therapeutic targets for tackling protein misfolding disorders within an expanded proteostasis framework encompassing nuclear speckles and YAP1.

Proteostasis is vital for cellular health, with disruptions leading to pathologies including aging, neurodegeneration and metabolic disorders. Traditionally, proteotoxic stress responses were studied as acute reactions to various noxious factors; however, recent evidence reveals that many proteostasis stress-response genes exhibit ~12-hour ultradian rhythms under physiological conditions in mammals. These rhythms, driven by an XBP1s-dependent 12h oscillator, are crucial for managing proteostasis. By exploring the chromatin landscape of the murine 12h hepatic oscillator, we identified RBBP5, a key subunit of the COMPASS complex writing H3K4me3, as an essential epigenetic regulator of proteostasis. RBBP5 is indispensable for regulating both the hepatic 12h oscillator and transcriptional response to acute proteotoxic stress, acting as a co-activator for proteostasis transcription factor XBP1s. RBBP5 ablation leads to increased sensitivity to proteotoxic stress, chronic inflammation, and hepatic steatosis in mice, along with impaired autophagy and reduced cell survival in vitro . In humans, lower RBBP5 expression is associated with reduced adaptive stress-response gene expression and hepatic steatosis. Our findings establish RBBP5 as a central regulator of proteostasis, essential for maintaining mammalian organismal health., Competing Interests: Disclosure and competing interests: The authors have no competing interests to declare.

Purpose: In recent years, the FLASH effect, in which ultrahigh dose rate (UHDR) radiotherapy (RT) can significantly reduce toxicity to normal tissue while maintaining antitumor efficacy, has been verified in many studies and even applied in human clinical cases. This work evaluates whether a room-temperature radio-frequency (RF) linear accelerator (linac) system can produce UHDR high-energy X-rays exceeding a dose rate of 40 Gy/s at a clinical source-surface distance (SSD), exploring the possibility of a compact and economical clinical FLASH RT machine suitable for most hospital treatmentrooms., Methods: A 1.65 m long S-band backward-traveling-wave (BTW) electron linac was developed to generate high-current electron beams, supplied by a commercial klystron-based power source. A tungsten-copper electron-to-photon conversion target for UHDR X-rays was designed and optimized with Monte Carlo (MC) simulations using Geant4 and thermal finite element analysis (FEA) simulations using ANSYS. EBT3 and EBT-XD radiochromic films, which were calibrated with a clinical machine Varian VitalBeam, were used for absolute dose measurements. A PTW ionization chamber detector was used to measure the relative total dose and a plane-parallel ionization chamber detector was used to measure the relative normalized dose of each pulse., Results: The BTW linac generated 300-mA-pulse-current 11 MeV electron beams with 29 kW mean beam power, and the conversion target could sustain this high beam power within a maximum irradiation duration of 0.75 s. The mean energy of the produced X-rays was 1.66 MeV in the MC simulation. The measured flat-filter-free (FFF) maximum mean dose rate of the room-temperature linac exceeded 80 Gy/s at an SSD of 50 cm and 45 Gy/s at an SSD of 67.9 cm, both at a 2.1 cm depth of the water phantom. The FFF radiation fields at 50 cm and 67.9 cm SSD at a 2.1 cm depth of the water phantom showed Gaussian-like distributions with 14.3 and 20 cm full-width at half-maximum (FWHM) values, respectively., Conclusion: This work demonstrated the feasibility of UHDR X-rays produced by a room-temperature RF linac, and explored the further optimization of system stability. It shows that a simple and compact UHDR X-ray solution can be facilitated for both FLASH-RT scientific research and clinical applications., (© 2022 American Association of Physicists in Medicine.)

This paper investigates the effects of thermal referral and tactile masking illusions to achieve localized thermal feedback on the upper body. Two experiments are conducted. The first experiment uses a 2D array of sixteen vibrotactile actuators (4 × 4) with four thermal actuators to explore the thermal distribution on the user's back. A combination of thermal and tactile sensations is delivered to establish the distributions of thermal referral illusions with different numbers of vibrotactile cues. The result confirms that localized thermal feedback can be achieved through cross-modal thermo-tactile interaction on the user's back of the body. The second experiment is conducted to validate our approach by comparing it with thermal-only conditions with an equal and higher number of thermal actuators in VR. The results show that our thermal referral with a tactile masking approach with a lesser number of thermal actuators achieves higher response time and better location accuracy than thermal-only conditions. Our findings can contribute to thermal-based wearable design to achieve greater user performance and experiences.

Optimizing factor allocation is the premise of promoting high-quality development of agriculture. Based on the panel data of 31 provinces in China from 2004 to 2020, this paper examines the relationship between factor mismatch and high-quality agricultural development. We found that the high-quality development level of China's agriculture shows a state of fluctuation and improvement, but the overall level is relatively low and the inter-provincial difference is expanding. Factor mismatch significantly inhibited the improvement of agricultural high-quality development, and the inhibition effect showed obvious temporal and spatial heterogeneity. We also found that the allocation of factors in extreme cases will lead to a 0.01% inter-provincial difference in the high-quality agricultural development. However, with the optimization and upgrading of the agricultural industrial structure and the improvement of the agricultural science and technology, the inhibitory effect of factor mismatch on high-quality agricultural development is constantly weakening. The above conclusion still holds after a series of robustness tests. The conclusions of this paper enrich the theoretical literature on the influencing factors of high-quality agricultural development, and provide an empirical reference for the policy maker of reducing factor mismatch and promoting high-quality agricultural development.

D, D-carboxypeptidase DacA plays an important role in the synthesis and stabilization of Escherichia coli cell wall peptidoglycan. The production level of extracellular recombinant proteins in E. coli can be enhanced by high D, D-carboxypeptidase activity. Construction of expression systems under optimal promoters is one of the main strategies to realize high protein production in E. coli. In this study, the promoter PdacA-3 from DacA on the genome of E. coli BL21 (DE3) was verified to be efficient for recombinant green fluorescent protein using the plasmid mutant pET28a-PdacA with PdacA-3. Meanwhile, the promoter PdacA-3 was engineered to increase the production level of proteins via inserting one or two Shine-Dalgarno (SD) sequences between the promoter PdacA-3 and the target genes. The expression level of dacA on the genome was increased by the improved transcription of the engineered promoters (especially after inserting one additional SD sequence). The engineered promoters increased cell membrane permeabilities to significantly enhance the secretion production of extracellular recombinant proteins in E. coli. Among them, the extracellular recombinant amylase activities in E. coli BL21::1SD-pET28a-amyK and E. coli BL21::2SD-pET28a-amyK were increased by 2.0- and 1.6-fold that of the control (E. coli BL21-pET28a-amyK), respectively. Promoter engineering also affected the morphology and growth of the E. coli mutants. It was indicated that the engineered promoters enhanced the expression of dacA on the genome to disturb the synthesis and structural stability of cell wall peptidoglycans., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society of Industrial Microbiology and Biotechnology.)

As the most important driving force for ensuring the effective supply of grain in the country, the production stability of the major grain-producing areas directly concerns the national security of China. In this paper, considering the "water-soil-energy-carbon" correlation, water, soil and energy resource factors, and carbon emission constraints were included in an index system, and the global common frontier boundary three-stage super-efficient EBM-GML model was used to measure the grain production resource utilization efficiency of the major grain-producing areas in China from 2000 to 2019. This paper also analyzed the static and dynamic spatiotemporal characteristics and the restrictions of utilization efficiency. The results showed that, under the measurement of the traditional data envelopment analysis model, the grain production resource utilization efficiency in the major producing areas is relatively high, but there is still room to improve by more than 20%, and grain production still has enormous growth potential. After excluding external environmental and random factors, it was found that the utilization efficiency of grain production resources in the major producing areas decreased, and the efficiency and ranking of provinces changed significantly. External factors inhibit pure technical efficiency and expand the scale efficiency. The utilization efficiency of Northeast China was much higher than that of the Huang-Huai-Hai region and the middle and upper reaches of the Yangtze River region, and its grain production resource allocation management had obvious advantages. The total factor productivity index of food production resources showed an upward trend as a whole, and its change was affected by both technological efficiency and technological progress, of which technological progress had the greater impact. Therefore, reducing the differences in the external environment of different regions while making adjustments in accordance with their own potential is an effective way to further improve the utilization efficiency of food production resources.

Besides direct interaction, human hands are also skilled at using tools to manipulate objects for typical life and work tasks. This paper proposes DeepClaw 2.0 as a low-cost, open-sourced data collection platform for learning human manipulation. We use an RGB-D camera to visually track the motion and deformation of a pair of soft finger networks on a modified kitchen tong operated by human teachers. These fingers can be easily integrated with robotic grippers to bridge the structural mismatch between humans and robots during learning. The deformation of soft finger networks, which reveals tactile information in contact-rich manipulation, is captured passively. We collected a comprehensive sample dataset involving five human demonstrators in ten manipulation tasks with five trials per task. As a low-cost, open-sourced platform, we also developed an intuitive interface that converts the raw sensor data into state-action data for imitation learning problems. For learning-by-demonstration problems, we further demonstrated our dataset's potential by using real robotic hardware to collect joint actuation data or using a simulated environment when limited access to the hardware., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Liu, Qiu, Guo, Wan and Song.)

d-Alanyl-d-alanine carboxypeptidase DacC is important for synthesis and stabilization of the peptidoglycan layer of Escherichia coli . In this work, dacC of E . coli BL21 (DE3) was successfully deleted, and the effects of this deletion on extracellular protein production in E . coli were investigated. The extracellular activities and fluorescence value of recombinant amylase, green fluorescent protein, and α-galactosidase of the deletion mutants were increased by 82.3, 29.1, and 37.7%, respectively, compared with that of control cells. The outer membrane permeability and intracellular soluble peptidoglycan accumulation of deletion mutant were also enhanced compared with those of control cells, respectively. Based on fluorescence-assisted cell sorting analyses, we found that the morphology of the E. coli deletion mutant cells was altered compared with that of control cells. Local transparent bulges in the poles of the E . coli mutant with deletion of the dacC gene were found by transmission electron microscopy analysis. These bulges in the poles could explain the improvement in the production of extracellular protein by the E. coli mutant with deletion of the dacC gene. These findings provide important insights into the extracellular production of proteins using E . coli as microbial cell factories., Competing Interests: The authors have declared no conflict of interest., (© 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

The problem of joint input and state estimation for linear stochastic systems with a rank-deficient direct feedthrough matrix is discussed in this paper. Results from previous studies only solve the state estimation problem; globally optimal estimation of the unknown input is not provided. Based on linear minimum-variance unbiased estimation, a five-step recursive filter with global optimality is proposed to estimate both the unknown input and the state. The relationship between the proposed filter and the existing results is addressed. We show that the unbiased input estimation does not require any new information or additional constraints. Both the state and the unknown input can be estimated under the same unbiasedness condition. Global optimalities of both the state estimator and the unknown input estimator are proven in the minimum-variance unbiased sense., (Copyright © 2015 ISA. Published by Elsevier Ltd. All rights reserved.)