Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α-synuclein aggregates in neurodegenerative diseases. However, due to the complex structure and ambiguous pathogenic species of the misfolded proteins, a universal approach to remove the misfolded proteins remains unavailable. Here, we found that a polyphenol, α-mangostin, reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation, which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins. Nanoformulation of α-mangostin efficiently delivered α-mangostin to microglia, relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia, which thus impressively relieved the neuropathological changes in both Alzheimer's disease and Parkinson's disease model mice. These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming, and demonstrate nanoformulated α-mangostin as a potential and universal therapy against neurodegenerative diseases.

Compared with conventional radiotherapy, FLASH radiotherapy has advantages in protecting normal tissues, while the dose rate is increased by more than 100 times. If the shielding design of the treatment room is carried out according to the existing standard, the thickness and cost of the shielding wall will be significantly increased, or even hardly to meet the requirement of the standards, resultsing in the failure of the application of FLASH radiotherapy. By investigating the domestic and foreign standards and literature, this paper analyzes the challenges brought by FLASH radiotherapy technology to the shielding design of radiotherapy treatment room in China. Dose rate control standards adopted by different countries in the shielding design are emphatically compared as well. In several countries, the average dose rate under the actual treatment conditions was considered in the shielding design. In China, the method of instantaneous dose rate taking acount of occupancy factor is adopted. However, if FLASH radiotherapy technology is applied, the requirement of instantaneous dose rate will be difficult to meet. In order to improve the high dose rate radiotherapy technology such as FLASH radiotherapy, the revision of the existing standards is advised if the authorized limits are not changed. To use the average dose rate limit within a certain period of time for control, or to raise the control standard in the case of flash radiotherapy, are also avaliable.

Objective: To determine the association between physical health fitness with Chinese reading ability of schoolaged children, so as to provide evidence for improving children s reading ability. Methods: A questionnaire survey was conducted among 1 923 school aged children in grades 2-6 in a primary school in Wuhan, Hubei Province, China. The questionnaire included basic demographic information and Dyslexia Checklist for Chinese Children and the Pupil Rating Scale Revised Screening. At the same time, participants underwent physical fitness tests which included an assessment of height, weight, and lung capacity, as well as a 50 meter run, sit forward bend, one minute skipping rope task, sit ups, and a 50 × 8 round trip. Results: A total of 59 children were identified with dyslexia. Normal children achieved higher scores than children with dyslexia in the total physical health score, as well as the one minute skipping rope score, one minute sit up score, and sitting forward score ( P <0.05). Multiple linear regression analyses showed that the reading ability of girls was higher than that of boys ( β =-3.04, P <0.01), and the children who regularly participated in more intense physical activity and who had higher fitness scores had a higher reading ability ( β =-1.68, -0.08, P <0.01). Children s reading ability increased significantly with parental educational level( P <0.05). Conclusion Gender, parents education level, physical exercise intensity, and children s physical fitness were identified as influencing factors of school age children s reading ability. A positive correlation was found between children s physical health level and reading ability.

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

Objective:To evaluate the application of visual feedback coaching method, which is embedded in an optical surface monitoring system, in deep inspiration breath holding during the radiotherapy in left breast cancer patients after breast-conserving surgery.Methods:Thirty patients with left breast cancer, who were scheduled to receive the whole breast radiotherapy after breast-conserving surgery, met the requirements of deep inspiration breath holding after respiratory coaching with the visual feedback coaching module in the optical surface monitoring system. Active breathing control equipment was used to control breath-holding state and CT simulation was performed. During treatment, optical surface monitoring system was used to guide radiotherapy. All patients were randomly divided into two groups. In group A ( n=15), visual feedback respiratory training method was utilized and not employed in group B ( n=15). In group A, the visual feedback coaching bar of the optical surface monitoring system was implemented, while audio interactive method was employed to guide patients to hold their breath. Real-time data of optical body surface monitoring were used to compare the interfraction reproducibility and intrafraction stability of breath holding fraction between two groups. Besides, the number of breath holding and treatment time per fraction were also compared. GraphPad prism 6.0 software was used for data processing and mapping, and SPSS 21.0 software was used for analyzing mean value and normality testing. Results:Compared with the control group, the reproducibility in the experiment group was reduced from 1.5 mm to 0.7 mm, the stability was reduced from 1.1 mm to 0.8 mm, the mean number of breath holding required per fraction was decreased from 4.6 to 2.4, the mean beam-on time per fraction from 336 s to 235 s, and the treatment time per fraction was shortened from 847 s to 602 s (all P<0.05), respectively. Conclusions:The application of visual feedback coaching method can improve the reproducibility and stability of breath holding during radiotherapy for left breast cancer, and it can also effectively reduce the number of breath holding and shorten the treatment time per fraction.

Objective:To explore the correlations of micro-calcification load in carotid plaques and plaque vulnerability scores detected by Micropure? ultrasonic technology with 18F-sodium fluoride ( 18F-NaF) uptake ratio (tissue-background ratio [TBR]) in positron emission tomography-computed tomography (PET-CT). Methods:Baseline data of patients with carotid atherosclerotic plaques admitted to our hospital from March 2017 to November 2020 were collected. Carotid arteries of these patients simultaneously positive on Micropure? ultrasound examination and 18F-NaF PET-CT were included. The number of spots in carotid plaques detected by Micropure? ultrasonic technology was defined as load of micro-calcification: they were divided into large number of micro-calcifications group (≥5 spots) and small number of micro-calcifications group (1-4 spots). The scores of carotid plaque vulnerability were evaluated according to carotid atherosclerosis scores in Diagnostic Value of Carotid Atherosclerosis Score for Ischemic Stroke. Correlations of TBR with micro-calcification load and plaque vulnerability scores in these 39 carotid arteries were analyzed. Results:Thirty-nine carotid arteries from 28 patients were enrolled: 24 carotid arteries were classified into the large number of micro-calcifications group and 15 carotid arteries were classified into the small number of micro-calcifications group. TBR of the large number of micro-calcifications group (2.61±0.73) was significantly increased as cpmpared with that of the small number of micro-calcifications group (1.93±0.43, t=-3.657, P=0.001). In the 39 carotid arteries, micro-calcification load was 5(3, 5), while the carotid plaque vulnerability scores were 2 (2, 3); micro-calcification load was positively correlated with TBR (2.35±0.71, r s=0.519, P=0.001), but no correlation was noted between TBR and carotid plaque vulnerability scores ( r s=0.086, P=0.602). Conclusion:Carotid plaque micro-calcification load detected by Micropure? ultrasound examination is associated with 18F-NaF uptake ratio; the larger the micro-calcification load, the more obvious the uptake of 18F-NaF.

Objective:To establish the basic procedures of the application of optical surface monitoring system (OSMS) in the deep inspiration breath hold (DIBH) radiotherapy for patients with left sided breast cancer and compare the performance of OSMS and cone-beam CT (CBCT) in the determination of the set-up errors of DIBH radiotherapy for patients with left sided breast cancer.Methods:Twenty patients with left sided breast cancer received DIBH radiotherapy. Through the registration of CBCT images with the planning CT images, and the registration of OSMS radiography images with the outer contour of the body surface, translational set-up errors and rotational errors were determined along the lateral-medial ( Rx), superior-inferior ( Ry) and anterior-posterior ( Rz) directions. Pearson correlation analysis was performed to evaluate the correlation of the set-up errors determined by two methods, and Bland- Altman plot analysis was used to assess the coincidence of these two methods. Results:Two methods were positively correlated. The Rz volume was 0.84, 0.74 and 0.84 in the x, y and z directions, and 0.65, 0.41 and 0.54 in the Rx, Ry and Rz directions, respectively (all P<0.01). The 95% CI of agreement were within preset 5 mm tolerance (-0.37-0.42cm, -0.39-0.41cm, -0.29-0.49cm ) in x, y and z directions for two methods. The 95% CI of agreement were within preset 3 ° tolerance -2.9°-1.4°, -2.6°-1.4°, -2.4°-2.5°in Rx, Ry and Rz directions for two methods. The system errors of 20 patients with left sided breast cancer receiving DIBH radiotherapy were <0.18cm and the random errors were <0.24cm. Conclusions:OSMS is equivalent to CBCT in the determination and stimulation of set-up errors for patients with left sided breast cancer receiving DIBH radiotherapy. The combination of CBCT and OSMS is a safe and reliable method.

Objective: To investigate the dosimetric characteristics of conventional two-dimensional radiotherapy of the chest wall, supra-and infra-clavicular regions, and the incidental irradiation dosage of the internal mammary region after modified mastectomy in breast cancer patients. Methods: Clinical data of 20 breast cancer patients including 10 left and 10 right cases who received radiotherapy after modified mastectomy between 2015 and 2016 were retrospectively analyzed. All patients received irradiation to the chest wall, supra-and infraclavicular regions at a prescription dose of 43.5 Gy in 15 fractions with conventional technique. One anterior-posterior (AP) photon field irradiation was delivered for the supra-and infra-clavicular regions, and one electron field for the chest wall. The supra-and infraclavicular regions were re-planned by using two AP/PA fields and the doses of organ at risk were evaluated. Results: With conventional radiotherapy, the D₉₀ of the supra-and infra-clavicular regions were more than 39.15 Gy (EQD₂≥45 Gy) in 17 patients (85%), and the median D₉₀ of the chest wall was 35.38 Gy. The median dose of incidental internal mammary region was 13.65 Gy. Patients with lower body mass index (BMI) received higher D₉₀ in both supra-and infra-clavicular and chest wall irradiation (P=0.039, 0.347). Conclusions Irradiation at D₉₀ of 39.15 Gy to the supra-and infra-clavicular regions with AP/PA fields can meet the prescription dose requirement of ≥90% in most cases and does not increase the irradiation dose to normal tissues. The dose distribution of one electron field of the chest wall is poor. Incidental internal mammary region can be irradiated at a limited dosage. BMI is an influencing factor for dose distribution.

Objective To observe the clinical efficacy of Shuxuening injection combined with compound coenzyme in the treatment of chronic allograft nephropathy (CAN). Methods A retrospective analysis of 108 patients with chronic allograft nephropathy (CAN) admitted to our hospital from June 2014 to May 2018 were divided into two groups according to different treatments. The 43 cases in the experimental group were given Shuxuening injection combined with compound coenzyme, and the 65 cases in control group were given non-Shu Xuening + compound coenzyme. The original immunization protocol was maintained in both groups. After 4 weeks of treatment, the changes of hemodynamic parameters, clinical efficacy, biochemical parameters, coagulation function and adverse reactions were observed before and after treatment. Results There was no significant difference in baseline data between the two groups before treatment (P> 0.05). After treatment, the peak systolic velocity of the intersegmental artery and cortical arteriole in the experimental group were significantly higher than that the control group (P < 0.05) , and the resistance index was lower than that in the control group (P < 0.05). After treatment, serum creatinine, 24 h urine protein quantitation, urinary microalbumin, total cholesterol and triglycerides were lower than that before treatment (P < 0.05) , and estimated glomerular filtration rate (eGFR) and serum. Albumin increased significantly (P < 0.05) , but the 24 h urine protein quantitation and urinary albumin decreased significantly in the experimental group compared with the control group (P < 0.05). After treatment, the total amount of cholesterol, triglycerides showed no significant difference (P> 0.05). After treatment, the platelet count, fibrinogen and D-dimer of the experimental group were significantly lower than those before treatment (P < 0.05) , and the activated partial thrombin time (APT) was significantly higher than that before treatment (P < 0.05). Significant difference in platelet count, fibrinogen, D-dimer and APTT was found after treatment (P < 0.05). After 4 weeks of treatment, the values of urea nitrogen and serum creatinine were significantly lower than those of the control group (P < 0.05). The recovery of transplanted kidney function in the experimental group was higher than that in the control group (P < 0.05). The experimental group reported 2 cases of fatigue complain and 1 case of dizziness, but no special treatment was given to them and their condition improved after symptomatic treatment; 1 case of mild phlebitis which was cured after given slowed drip rate and local hot compress therapy. The incidence of adverse events was 9.3％ (4/43). The control group reported 2 cases of fatigue complain, 1 case of nausea, 1 case of facial flushing, and all cured with no special treatment was given; 1 case of mild phlebitis, and cured after slowed the i.v. drip rate and ocal hot compress; The adverse events rate was 7.7％ (5/65). No serious adverse reactions occurred during the entire clinical trial. There was no significant difference in the incidence of adverse events between the experimental group and the control group (χ2=0.054, P=0.732). Conclusion Combined with Shuxuening injection and compound coenzyme can improve blood flow of transplanted kidney, reduce proteinuria, reduce blood urea nitrogen and creatinine in patients with CAN after renal transplantation and effectively improve patient's hemodynamic parameters and safety.

Objective: To obtain the high-resolution dose distribution for the single source channel of Leksell 4C gamma knife. Methods: A parallel computing platform based on the Message Passing Interface (MPI) and Monte Carlo Code MCNPX was established. The ring-shaped detector and two pre-validated variance reduction techniques (emission direction-biased sampling of source and termination of electron tracking in partial structures) were adopted to derive the high-resolution dose distribution for the single source channel of Leksell 4C gamma knife. The effect of cut-off energy for both photon and electron on the accuracy of simulation outcomes was evaluated and statistically compared. Results: Compared with previous findings, the spatial resolution of the dose distribution for the single source channel obtained in this study was higher (radial resolution=0.1 mm) with less statistical error (<1%). The calculation time was acceptable (approximately 24 h). For the 4-, 8-, 14-and 18-mm variable collimators, the penumbra and full width at the half maximum (FWHM) for single side were 1.0, 1.1, 1.2, 1.3 mm and 2.2, 4.3, 7.3, 9.3 mm, respectively, which were consistent with previous studies. The difference of the simulation results was extremely small between different cut-off energy for photon (1 keV vs.10 keV). However, the simulation results significantly differ between 1 and 521 keV electronic cut-off energy. Conclusions The MCNPX parallel computing platform based on the MPI environment can be utilized to derive highly accurate dose distribution with high resolution in acceptable calculation time. The cut-off energy of the photon and electron should be cautiously set up during simulation.