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Xiaoxia Ding,1 Shisong Rong,2 Yu Wang,1 Dong Li,1 Liang Wen,1 Bo Zou,1 Dongxiao Zang,1 Kemi Feng,3 Yuanbo Liang,3 Fenghua Wang,4 Gang Zhai1 1Department of Ophthalmology, Fushun Eye Hospital, Fushun, Liaoning, People’s Republic of China; 2Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA, USA; 3Department of Ophthalmology, the Affiliated Eye Hospital, School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Department of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Science Key Laboratory, Beijing, People’s Republic of ChinaCorrespondence: Gang Zhai, Fushun Eye Hospital, No. 1 Hupo Street, Xinfu District, Fushun, Liaoning, 113008, People’s Republic of China, Email fsgangzhai@163.comAim: To report the prevalence of depression and its association with vision-related quality of life and social support in a type 2 diabetes mellitus (T2DM) population.Methods: Patients were recruited from a community-based study, Fushun Diabetic Retinopathy Cohort Study (FS-DIRECT), conducted between July 2012 and May 2013 in China. Depression was assessed using the Centre for Epidemiological Studies Depression Scale (CES-D). Vision-related quality of life was evaluated using the Visual Function Questionnaire-25 (VFQ-25). Social support was captured with the Social Support Rating Scale (SSRS). Generalized linear models were used to estimate the individual and joint association of VFQ-25 composite score (VFQCS) and SSRS score (SSRSS) with depression.Results: A total of 1618 subjects (60.9% female) aged 61.69 ± 8.72 years in an urban district of Jiangjun Street, Fushun City, Liaoning province, Northeast China from July 2012 to May 2013 were recruited, of which, 23.36% (95% CI: 21.30– 25.42%) were identified with depression. Every 14.1 increase in VFQ-25 composite score decreased the risk of depression by half (OR = 0.5; 95% CI: 0.4– 0.6); with the elevation of 10.0 SSRS score the risk of depression decreased by 40% (OR = 0.6; 95% CI: 0.5– 0.7). Patients with the VFQCS less than 91.3 and SSRSS less than 38.0 had 5.9 times more risk of depression (OR = 5.9; 95% CI: 3.6– 9.7). Age (over 60 years) (OR = 0.6; 95% CI: 0.4– 0.9) and medical history of cardiovascular disease (OR = 1.7; 95% CI: 1.1– 2.5) were independently correlated with depression symptom.Conclusion: The prevalence of depression is high among patients with T2DM in urban district in northeast China. Vision-related quality of life and social support scores are significantly associated with depression. Measures should be taken to screen depressive symptoms in patients with type 2 diabetes patients. These patients need to be intervened with appropriate and effective treatment as early as possible. Meanwhile, behavioral health specialists should guide the patient to get and use social support sources effectively.Keywords: diabetic retinopathy, depression, quality of vision, Visual Function Questionnaire-25, Social Support Rating Scale

Junwu Lin,1,* Hong Qin,2,* Yue Han,3 Xinghua Li,4 YuJuan Zhao,5 Guangsheng Zhai6 1Department of Otolaryngology, Central Hospital, Qingdao, Shandong, People’s Republic of China; 2Department of Otolaryngology, Women and Children’s Hospital, Qingdao, Shandong, People’s Republic of China; 3Department of Urology, Zhangqiu District People’s Hospital, Jinan, Shandong, People’s Republic of China; 4Department of Critical Care Medicine, Zhangqiu District People’s Hospital, Jinan, Shandong, People’s Republic of China; 5Department of Otolaryngology, Rizhao Second People’s Hospital, Rizhao, Shandong, People’s Republic of China; 6Department of Radiotherapy, Zibo Central Hospital, Zibo, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangsheng ZhaiDepartment of Radiotherapy, Zibo Central Hospital, No. 54, Communist Youth League West Road, Zhangdian District, Zibo 255036, Shandong, People’s Republic of ChinaFax +86-18678186986Email guangshengzhai86@163.comBackground: The development of drug resistance leads many NPC patients to experience disease relapse following the completion of chemotherapy. It is thus essential that the mechanistic basis for such chemoresistance be clarified in an effort to identify approaches to sensitizing NPC tumors to treatment with cisplatin and related agents.Methods: A qRT-PCR approach was used to measure the expression of circNRIP1 in NPC, while luciferase assays were used to identify interactions with downstream targets of circNRIP1 activity including miR-515-5p and IL-25. CCK8 assays were also utilized to detect IC50 values for cisplatin and 5-Fu.Results: The expression of circNRIP1 was significantly increased in the serum of chemoresistant NPC patients. At a functional level, we determined that circNRIP1 is able to sequester miR-515-5p, thereby inhibiting its ability to post-transcriptionally suppress IL-25 expression. We observed a significant negative correlation between the expression of miR-515-5p and circNRIP1 in serum samples from chemoresistant NPC patients, consistent with a functional interaction between these two factors. We further found that 5-Fu and CDDP IC50 values in NPC cells in which circNRIP1 had been knocked down were restored following miR-515-5p inhibitor transfection. Similarly, changes in these IC50 values were reversed in NPC cells transfected with miR-515-5p mimics following the overexpression of IL-25 in these same cells.Conclusion: These data highlight the circNRIP1/miR-515-5p/IL-25 as a novel regulator of 5-Fu and cisplatin resistance in NPC, suggesting that this pathway may be amenable to therapeutic targeting as an approach to treating this cancer type.Keywords: circNRIP1, 5-Fu resistance, cisplatin resistance, NPC, miR-515-5p, IL-25

Mengshi Xu,1,* Liang Xu,2,* Huaping Du,1 Wanying Shan,1 Jie Feng,1 Guojie Zhai,1 Xiuyan Yang1 1Department of Neurology, Suzhou Ninth People’s Hospital, Suzhou, Jiangsu 215200, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiuyan Yang; Guojie Zhai Email yangxiuyan335@163.com; 125461985@qq.comBackground and Aims: Decreased serum retinoic acid (RA) levels have been shown to be linked with increased mortality in cardiovascular diseases. This study aimed to investigate the relationship between serum RA and 3-month functional outcome after ischemic stroke.Methods: Between January 2019 and September 2019, we prospectively recruited ischemic stroke patients within 24 hrs of symptom onset. Serum RA levels were measured for all patients at admission. The primary outcome was defined as poor functional outcome (modified Rankin Scale 3– 6) at 90 days. The secondary outcome was defined as early neurological deterioration (END), which is considered as an increase of ≥ 1 point in motor power or total National Institutes of Health Stroke Scale score of ≥ 2 points within 7 days.Results: A total of 217 patients were included in the analysis. The median RA levels were 2.9 ng/mL. Ninety-four (43.3%) and 65 (30.0%) patients experienced 3-month poor outcome and END, respectively. After adjusted for potential confounders, decreased levels of serum RA were associated with a higher risk of poor outcome (P for trend = 0.001) and END (P for trend = 0.002). Adding RA quartile to the existing risk factors improved risk prediction for poor outcome [net reclassification improvement (NRI) = 42.6%, P = 0.001; integrated discrimination improvement (IDI) = 5.7%, P = 0.001] and END (NRI index = 45.4%, P = 0.001; IDI = 4.3%; P = 0.005).Conclusion: Low serum RA levels at baseline were associated with poor prognosis at 90 days after ischemic stroke, suggesting that RA may be a potential prognostic biomarker for ischemic stroke.Keywords: acute ischemic stroke, retinoic acid, early neurological deterioration, functional outcome

Liang Xing,1,2,* Feng Sun,1,2,* Zhendong Wang,1,2 Yan Li,1,2 Zhifang Yang,1,2 Fengshan Wang,1,3 Guangxi Zhai,3 Haining Tan1,2 1National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People’s Republic of China; 2Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Jinan 250012, Shandong, People’s Republic of China; 3School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People’s Republic of China *These authors contributed equally to this work Background: In the past few years, significant progress has been made in inhibiting neovascularization at the tumor site, cutting off the nutrient supply of the tumor, and inhibiting tumor growth and metastasis. However, many proteins/peptides have the disadvantage of poor stability, short half-life, and uncertain targeting ability. Chemical modification can be used to overcome these disadvantages; many polyethylene glycol-modified proteins/peptides have been approved by US FDA. The purpose of this study was to obtain a novel anti-angiogenic chondroitin sulfate (CS)-peptide nanoparticle conjugate with efficient anti-neovascularization and tumor targeting ability and an acceptable half-life. Materials and methods: The CS-ES2-AF nanoparticle conjugate was synthesized and characterized using 1H-nuclear magnetic resonance spectroscopy, transmission electron microscopy, and particle size and zeta potential analyzer. The anti-angiogenic ability was studied using MTT, migration, tube formation, and chick chorioallantoic membrane assays. The targeting ability of CS-ES2-AF was studied by ELISA, surface plasmon resonance, and bioimaging. The pharmacokinetics was also studied.Results: The CS-ES2-AF could self-assemble into stable nanoparticles in aqueous solution, which significantly enhances its anti-neovascularization activity, tumor targeting more explicit, and prolongs its half-life.Conclusion: CS is an effective protein/peptide modifier, and CS-ES2-AF displayed good potential in tumor targeting therapy. Keywords: chondroitin sulfate, ES2-AF, nanoparticles, anti-angiogenesis, targeting

Rui Yang,1 Xin Huang,1 Jinfeng Dou,2 Guangxi Zhai,2 Lequn Su1 1Pharmacy Department, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China; 2Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan, People's Republic of China Abstract: Oleanolic acid is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS) has been developed to enhance the solubility and oral bioavailability of oleanolic acid. The formulation design was optimized by solubility assay, compatibility tests, and pseudoternary phase diagrams. The morphology, droplet size distribution, zeta potential, viscosity, electrical conductivity, and refractive index of a SMEDDS loaded with oleanolic acid were studied in detail. Compared with oleanolic acid solution, the in vitro release of oleanolic acid from SMEDDS showed that the drug could be released in a sustained manner. A highly selective and sensitive high-performance liquid chromatography-mass spectrometry method was developed for determination of oleanolic acid in rat plasma. This method was used for a pharmacokinetic study of an oleanolic acid-loaded SMEDDS compared with the conventional tablet in rats. Promisingly, a 5.07-fold increase in oral bioavailability of oleanolic acid was achieved for the SMEDDS compared with the marketed product in tablet form. Our studies illustrate the potential use of a SMEDDS for delivery of oleanolic acid via the oral route. Keywords: oleanolic acid, self-microemulsifying drug delivery system, formulation design, in vitro release, bioavailability

Runliang Feng,1,* Zhimei Song,1,* Guangxi Zhai2 1Department of Pharmaceutical Engineering, College of Medicine and Life Science, University of Jinan, Jinan, Shandong Province, 2Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan, Shandong Province, People's Republic of China*These authors contributed equally to this workBackground: Curcumin (CUR) has been linked with antioxidant, anti-inflammatory, antimicrobial, anti amyloid, and antitumor effects, but its application is limited because of its low aqueous solubility and poor oral bioavailability.Methods: To improve its bioavailability and water solubility, we synthesized two series of poly (ε-Caprolactone)-poly (ethylene glycol)-poly (ε-Caprolactone) triblock copolymers by ring-opening polymerization of poly (ethylene glycol) and ε-Caprolactone, with stannous 2-ethylhexanoate as the catalyst. Structure of the copolymers was characterized by proton nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, and gel permeation chromatography. The nanoparticles (NPs) were prepared using a probe-type ultrasonic emulsion and solvent evaporation method. To obtain an optimal delivery system, we explored the effect of the length of the copolymers' hydrophilic and hydrophobic chains on the encapsulation of hydrophobic CUR, performing entrapment efficiency and drug loading evaluations, as well as studying the particle distribution and in vitro release using the direct dispersion method. Finally, study of the in vivo pharmacokinetics of the CUR-loaded NPs was also carried out on selected copolymers in comparison with CUR solution formulations.Results: CUR was encapsulated with 94.3% and 95.5% efficiency in biodegradable nanoparticulate formulations based on NP43 and NP63, respectively. Dynamic laser light scattering and transmission electron microscopy indicated a particle diameter of 55.6 nm and 62.4 nm for NP43 and NP63, respectively. Fourier transform infrared spectroscopy and differential scanning calorimetry analysis of the NPs showed that CUR was encapsulated into the NPs. The in vitro release experiments showed that NP63 controlled the release of CUR more effectively, with only 55% of CUR released after 96 hours. In comparison with the free-drug solution in vivo, encapsulation of the CUR in NP63 increased mean residence time from 0.169 to 40.148 hours and the area under the concentration–time curve 4.178-fold.Conclusion: CUR was effectively entrapped by the prepared NPs, which could improve the solubility of CUR and prolong its retention in the systemic circulation.Keywords: nanoparticle, copolymer, solubility, hydrophilic chain, hydrophobic chain

Pore pressure in aquifers confined below a cryosphere will increase as Mars cools and the cryosphere thickens. Increased pore pressure decreases the effective stress and hence promotes seismicity. We calculate the rate of pore pressure change from cooling of Mars's interior and the modulation of pore pressure from solar and Phobos tides and barometric loading. Using the time-varying pressure and tidal stresses, we compute Coulomb stress changes and the expected seismicity rate from a rate-and-state friction model. Seismicity rate will vary by several tens of percent to 2 orders of magnitude if the mean pore pressure is within 0.2 and 0.01 MPa of lithostatic, respectively. Seismic events promoted by high pore pressure may be tremor-like. Documenting (or not) tidally modulated shallow seismicity would provide evidence for (or against) water-filled confined aquifers, that pore pressure is high, and that the state of stress is close to failure—with implications for processes that can deliver water to the Martian surface.

Wastewater injection over the past decade has increased seismicity in the central USA, in some cases accompanied by detectable surface uplift. Here, we use this uplift to constrain subsurface properties and pore pressure evolution. We apply an advanced multitemporal interferometric algorithm to 35 synthetic aperture radar images acquired by ALOS satellite over four years before the 2012 earthquake sequence in east Texas, where large volumes of wastewater are disposed at depths of ∼800 m and ∼1800 m. To solve for the hydraulic diffusivity of the injection layers, we jointly inverted the injected volume and uplift data, considering a poroelastic layered half space. We find diffusivity values of 0.3±0.1 m 2 /s and 0.7±0.15 m 2 /s for shallow and deep injection layers, respectively, which combined with seismically-derived bulk moduli yields permeability values of 5.5±2.6×10 −14 m 2 and 1.9±0.25×10 −13 m 2 for these layers, consistent with permeability range reported for Rodessa formation and well test values. Hydraulic conductivity determines the evolution of pore pressure and thus the origin and location of induced seismicity. This study highlights the value of geodetic observations to constrain key hydrogeological properties of injection layers and to monitor the evolution of the subsurface pressure change.

ObjectivesThe genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.MethodsThe authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent.ResultsNone of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.ConclusionsIdentifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Purpose: Paclitaxel-induced cognitive impairment (PICI) is a frequent and severe adverse reaction of chemotherapy. Increased neuroinflammation related to neutrophil extracellular traps (NETs) may play a key role in PICI. Shaoyao Gancao Decoction (SGD) is a classic Chinese prescription with good neuroprotective activities. However, the action of SGD in PICI remains elusive. Herein, our work was set out to study the potential role and possible mechanism of SGD in PICI through network pharmacology, Mendelian analysis and animal experiments. Methods: First, network pharmacology analysis was performed to identify the potential active compounds and targets of SGD on PICI. Secondly, PICI mice model was established, and the neuroprotective effects of SGD on PICI mice were eveluated by using new object recognition, Morris water maze test and TUNEL staining. The impact of SGD on inflammatory factors, microglia activation and NETs formation were also studied by ELISA and immunofluorescence. The regulation of SGD on PTEN/PI3K/AKT pathway was detected by Western blot. Finally, Mendelian randomization was performed using genome-wide association analysis data of PTEN and cognitive disorders in OpenGWAS database. Results: Network pharmacological analysis revealed 105 active ingredients in SGD, and identified 124 targets associated with SGD and PICI. KEGG pathway analysis implied that PI3K-AKT signaling pathway maight be involved in the protective effect of SGD agianst PICI Animal experiments displayed that SGD significantly alleviated cognitive impairment induced by paclitaxel, and decreased neuronal apoptosis. Furthermore, SGD remarkably reduced IL-1β, TNF-α and microglia activation, while enhanced SOD activity in hippocampus. In addition, SGD could inhibit NETs formation, evidenced by decreasing the level of plasma MPO-DNA complex, as well as MPO and PAD4 expression. Western blotting assay suggested that SGD attenuated the elevated expression of PI3 K, AKT, p-AKT and PKC-α induced by paclitaxel, whereas decreased PTEN expression. The results of Mendelian randomization analysis further confirm that PTEN is an important therapeutic target for improving cognitive function. Conclusion: Collectively, our preliminary findings indicated that SGD can improve cognitive function of PICI mice. SGD may play a neuroprotective role by inhibiting NETs formation via PTEN/PI3K/AKT signaling pathway. SGD may be a potential alternative therapy for PICI.

In order to improve the operational efficiency, search precision, and obstacle avoidance flexibility of the path planning algorithm for coal mine foot robot, a path planning method for coal mine foot robots is proposed, which integrates the improved A* algorithm and the dynamic window approach (DWA). Firstly, the A* algorithm is improved by reducing the length of the planned path through a redundant node removal strategy. The method improves the neighborhood search method and cost function to increase the speed of path planning, and uses segmented second-order Bessel curves for path smoothing. The path nodes planned by the improved A* algorithm are sequentially used as local target points for local path planning DWA for algorithmic fusion. The method filters neighboring obstacle nodes to shorten the path length again, and improves obstacle avoidance performance by adjusting the weight ratio in the DWA cost function. In response to the problem of robots falling into a 'feigned death' state when encountering unavoidable obstacles, the method starts from the current initial point, the fusion algorithm is called up again. The global path planning is carried out again, and the new nodes obtained replace the original local target points, and the subsequent work is carried out according to the new route. The simulation results show that, while ensuring the safety and stability of robot walking, the improved A* algorithm reduces the calculation time by 65%, the path length by 24.1%, and the number of path nodes by 27.65% compared to the traditional A* algorithm, resulting in a smoother path. The fusion algorithm further enhances the global path planning capability, enabling it to bypass newly added dynamic and static obstacles in multi obstacle environments. When the robot encounters an L-shaped obstacle and enters a 'feigned death' state, it reconducts global path planning at the 'feigned death' position, updates its walking path, and successfully reaches the final target point. The experimental results of path planning for JetHexa hexapod robot based on fusion algorithm have verified the effectiveness and superiority of the fusion algorithm.

The forage crop Caragana korshinskii Kom. is of high quality, and the biomechanical properties of its plant system are of great significance for the development of harvesting equipment and the comprehensive utilisation of crop resources. However, the extant research on the biomechanical properties of Caragana korshinskii Kom. is inadequate to enhance and refine the theoretical techniques for mechanised harvesting. In this study, we established a discrete element model of CKS based on the Hertz-Mindlin bonding contact model. By combining physical experiments and numerical simulations, we calibrated and validated the intrinsic and contact parameters. The Plackett-Burman design test was employed to identify the significant factors influencing bending force, and the optimal parameter combination for these factors was determined through response surface analysis. When the shear stiffness per unit area was 3.56×109 Pa, the bonded disk scale was 0.93 mm, the normal stiffness per unit area was 9.68×109 Pa, the normal strength was 5.62×107 Pa, the shear strength was 4.27×107 Pa, the discrete element numerical simulation results for three-point bending, radial compression, axial tension, and shear fracture exhibited a maximum failure force error of 3.32%, 4.37%, 4.87% and 3.74% in comparison to the physical experiments. In the cutting experiments, a smaller radial angle between the tool edge and the stem resulted in less damage to the cutting section, which was beneficial for the smoothness of the stubble after harvesting and the subsequent growth of the stem. The discrepancy in cutting force between the physical and numerical simulations was 3.89%, and the F-x (force versus displacement) trend was consistent. The multi-angle experimental validation demonstrated that the discrete element model of CKS is an accurate representation of the real biomechanical properties of CKS. The findings offer valuable insights into the mechanisms underlying crop-machine interactions.

【Background and Objective】 Pepper is a shallow-rooted cash crop characterized by high leaf area index (LAI) and stomatal conductivity. It is sensitive to soil water change, and excessive or insufficient irrigation could thus inhibit its development, resulting in a decrease in yield and fruit quality. Reducing irrigation amount at different growth stages to maintain soil moisture at optimal levels has been posited as an improved cultivation method to improve yield and quality of the pepper. This paper aims to investigate the effect of water deficit at different growth stages on growth, yield and quality of chili pepper in the middle and low reaches of the Yellow River. 【Method】 The experiment was conducted in a solar greenhouse in Xinxiang, Henan province, with the pepper irrigated by drip irrigation. Three water deficits were imposed at flowering-fruiting stage (K) and fruiting stage (J) at different levels: severe water deficit by keeping the soil moisture content at 55%-65% of the field capacity (K1 and J1), moderate water deficit by keeping soil moisture content at 65%-75% of the field capacity (K2 and J2), sufficient irrigation by keeping soil moisture content at 75%-85% of the field capacity (K3 and J3). In each treatment, we measured plant height, stem diameter, yield and fruit quality of the pepper. 【Result】 ① Water deficit in reproductive stage reduced plant height and stem diameter of the pepper, while a moderate water deficit in flowering-fruiting stage and fruiting stage did not significantly affect plant height and stem diameter. ② The combination of K2 and J3 increased the yield of the pepper, promoted formation of marketable fruits. Compared with the combination of K3 and J3, the combination K2+J3 increased the yield of marketable fruits by 18.9%. ③ The combination of K2 and J3 had the highest soluble sugar content; the combination of K1 and J1 gave the highest dihydrocapsaicin content; the combination of K2 and J2 had the highest capsaicin, soluble protein, and vitamin C content. 【Conclusion】 A moderate water deficit during the flowering - fruiting stage combined with a sufficient irrigation at fruiting stage can improve yield and fruit quality for the greenhouse chili pepper.