Summary Regulation of p53 by ubiquitination and deubiquitination is important for its functions. In this study, we demonstrate that USP24 deubiquitinates p53 in human cells. Functional USP24 is required for p53 stabilization and p53 destabilization in USP24 depleted cells can be corrected by the forced expression of USP24. We show that USP24 depletion renders cells resistant to apoptosis after UV irradiation, consistent with the requirement of USP24 for p53 stabilization and PUMA activation in vivo. Additionally, purified USP24 protein is able to cleave ubiquitinated p53 in vitro. Importantly, cells with USP24 depletion exhibited significantly elevated mutation rates at the endogenous HPRT locus, implying an important role for USP24 in maintaining genome stability. Our data reveal that the USP24 deubiquitinase regulates the DNA damage response by directly targeting the p53 tumor suppressor.

Background The ankle joint complex (AJC) is of fundamental importance for balance, support, and propulsion. However, it is particularly susceptible to musculoskeletal and neurological injuries, especially neurological injuries such as drop foot following stroke. An important factor in ankle dysfunction is damage to the central nervous system (CNS). Correspondingly, the fundamental goal of rehabilitation training is to stimulate the reorganization and compensation of the CNS, and to promote the recovery of the motor system’s motor perception function. Therefore, an increasing number of ankle rehabilitation robots have been developed to provide long-term accurate and uniform rehabilitation training of the AJC, among which the parallel ankle rehabilitation robot (PARR) is the most studied. The aim of this study is to provide a systematic review of the state of the art in PARR technology, with consideration of the mechanism configurations, actuator types with different trajectory tracking control techniques, and rehabilitation training methods, thus facilitating the development of new and improved PARRs as a next step towards obtaining clinical proof of their rehabilitation benefits. Methods A literature search was conducted on PubMed, Scopus, IEEE Xplore, and Web of Science for articles related to the design and improvement of PARRs for ankle rehabilitation from each site’s respective inception from January 1999 to September 2020 using the keywords “ parallel”, “ ankle”, and “ robot”. Appropriate syntax using Boolean operators and wildcard symbols was utilized for each database to include a wider range of articles that may have used alternate spellings or synonyms, and the references listed in relevant publications were further screened according to the inclusion criteria and exclusion criteria. Results and discussion Ultimately, 65 articles representing 16 unique PARRs were selected for review, all of which have developed the prototypes with experiments designed to verify their usability and feasibility. From the comparison among these PARRs, we found that there are three main considerations for the mechanical design and mechanism optimization of PARRs, the choice of two actuator types including pneumatic and electrically driven control, the covering of the AJC’s motion space, and the optimization of the kinematic design, actuation design and structural design. The trajectory tracking accuracy and interactive control performance also need to be guaranteed to improve the effect of rehabilitation training and stimulate a patient’s active participation. In addition, the parameters of the reviewed 16 PARRs are summarized in detail with their differences compared by using figures and tables in the order they appeared, showing their differences in the two main actuator types, four exercise modes, fifteen control strategies, etc., which revealed the future research trends related to the improvement of the PARRs. Conclusion The selected studies showed the rapid development of PARRs in terms of their mechanical designs, control strategies, and rehabilitation training methods over the last two decades. However, the existing PARRs all have their own pros and cons, and few of the developed devices have been subjected to clinical trials. Designing a PARR with three degrees of freedom (DOFs) and whereby the mechanism’s rotation center coincides with the AJC rotation center is of vital importance in the mechanism design and optimization of PARRs. In addition, the design of actuators combining the advantages of the pneumatic-driven and electrically driven ones, as well as some new other actuators, will be a research hotspot for the development of PARRs. For the control strategy, compliance control with variable parameters should be further studied, with sEMG signal included to improve the real-time performance. Multimode rehabilitation training methods with multimodal motion intention recognition, real-time online detection and evaluation system should also be further developed to meet the needs of different ankle disability and rehabilitation stages. In addition, the clinical trials are in urgent need to help the PARRs be implementable as an intervention in clinical practice.

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: Combination therapy involving different therapeutic strategies mostly provides more rapid and effective results as compared to monotherapy in diverse areas of clinical practice. The most worldwide famous acetylcholinesterase inhibitor (AChEIs) donepezil for its dominant role in Alzheimer’s disease (AD) has also attracted the eyes of many pharmaceuticals regarding its promising pharmacological potencies such as neuroprotective, muscle relaxant, and sleep. Recently a combination of donepezil with other agents has displayed better desirable results in the management of several disorders, including most common Alzheimer’s disease (AD). This study encircles all the data regarding the therapeutic effect of donepezil in its combination with other agents and explains its therapeutic targets, mode of action. Furthermore, this review also puts light on the current status of donepezil with other agents in clinical trials. The combo therapy of donepezil with symptomatic relief drugs and disease-modifying agents opens a new road for the treatment of multiple pathological disorders. To best known to our knowledge, this is the first report encircling all the pharmacologic effects of donepezil in its combination therapy with other agents and their current status in clinical trials.

Purpose The purpose of this paper is to implement a passive compliance training strategy for our newly designed 2-UPS/RRR parallel ankle rehabilitation robot (PARR) to enhance its rehabilitation training safety. Design/methodology/approach First, a kinematic analysis of the PARR is introduced, and the mechanism ensures that the rotation centre of the ankle joint complex (AJC) coincides with robot’s rotation centre. Then, a passive compliance training strategy based on admittance control is described in detail and is implemented on our PARR. Findings Experiments involving healthy subjects were conducted, and the performance of trajectory tracking was quantitatively evaluated, with the results showing excellent compliance and trajectory tracking accuracy, which can ensure that a secondary injury to the AJC during passive rehabilitation training is avoided. The influence of different admittance parameters was also simulated and analysed, which can contribute to the development of adaptive parameter adjustment research. Originality/value The paper can be used to improve the effectiveness of ankle rehabilitation, to alleviate manual therapy problems in terms of labour intensiveness, precision and subjectivity and to ensure safety and comfort during rehabilitation sessions.