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Background: Lineage plasticity in prostate cancer (PCa) has emerged as an important mechanism leading to the onset of therapy- and castration-resistant PCa (t-CRPC), which is closely associated with cancer stem cell (CSC) activity. This study is to identify critical driver(s) with mechanism of action and explore new targeting strategy., Methods: Various PCa cell lines with different genetic manipulations were subjected to in vitro prostasphere assay, cell viability assay and in vivo stemness potential. In addition, bioinformatic analyses such as Ingenuity pathway and Gene Set Enrichment Analysis were carried out to determine clinical relevance. The in vivo anti-tumour activity of JAK or STAT1 inhibitors was examined in clinically relevant t-CRPC model., Results: We demonstrated the role of interferon-related signalling pathway in promoting PCa stemness, which correlated with significant elevation of interferon related DNA damage resistance signature genes in metastatic PCa. Inhibition of JAK-STAT1 signalling suppresses the in vitro and in vivo CSC capabilities. Mechanistically, IFIT5, a unique downstream effector of JAK-STAT1 pathway, can facilitate the acquisition of stemness properties in PCa by accelerating the turnover of specific microRNAs (such as miR-128 and -101) that can target several CSC genes (such as BMI1, NANOG, and SOX2). Consistently, knocking down IFIT5 in t-CRPC cell can significantly reduce in vitro prostasphere formation as well as decrease in vivo tumour initiating capability., Conclusions: This study provides a critical role of STAT1-IFIT5 in the acquisition of PCSC and highlights clinical translation of JAK or STAT1 inhibitors to prevent the outgrowth of t-CRPC., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Chemoresistance is one of the leading causes of therapeutic failure in gastric cancer (GC) treatment. Recent studies have shown lncRNAs play pivotal roles in regulating GC chemoresistance. Nanocarriers delivery of small interfering RNAs (siRNAs) to silence cancer-related genes has become a novel approach to cancer treatment research. However, finding target genes and developing nanosystems capable of selectively delivering siRNAs for disease treatment remains a challenge. In this study, a novel lncRNA TMEM44-AS1 that is related to 5-FU resistance is identified. TMEM44-AS1 has the ability to bind to and sponge miR-2355-5p, resulting in the upregulated PPP1R13L expression and P53 pathway inhibition. Next, a new nanocarrier called chitosan-gelatin-EGCG (CGE) is developed, which has a higher gene silencing efficiency than lipo2000, to aid in the delivery of a si-TMEM44-AS1 can efficiently silence TMEM44-AS1 expression to synergistically reverse 5-FU resistance in GC, leading to a markedly enhanced 5-FU therapeutic effect in a xenograft mouse model of GC. These findings indicate that TMEM44-AS1 may estimate 5-FU therapy outcome among GC cases, and that systemic si-TMEM44-AS1 delivery combined with 5-FU therapy is significant in the treatment of patients with recurrent GC., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objectives: Tetralogy of Fallot (TOF) is the most common deformity combined with the unilateral absence of the mediastinal pulmonary artery (UAMPA), and its treatment strategy remains controversial. In this study, we analyzed the effect of bilateral pulmonary reconstruction in patients with TOF combined with UAMPA., Methods: This was a single-center, retrospective review of 1713 patients with TOF between January 2009 and November 2021. Overall, eight patients were diagnosed with TOF combined with UAMPA. Among them, seven underwent surgery: three underwent one-stage TOF correction with bilateral pulmonary artery reconstruction; three patients underwent bilateral pulmonary artery reconstruction, followed by two-stage TOF correction after several months; and one patient underwent two procedures of left pulmonary artery reconstruction, and the ventral septal defect remained open. The left pulmonary arteries were reconstructed with a Goretex conduit in three cases, direct anastomosis in two cases, and the modified autologous tissue extension technique in two cases., Results: All seven patients survived during the postoperative follow-up and showed good cardiac function and normal oxygen saturation of >97%. During follow-up echocardiography, we noted that the left pulmonary arteries reconstructed with a Goretex conduit or direct anastomosis had thrombosis or stenosis. However, those reconstructed using the modified autologous tissue extension technique was unobstructed., Conclusions: In patients with TOF and UAMPA, if there is a pulmonary artery confluence in the affected hilum, it is feasible to implement bilateral pulmonary artery reconstruction for one-stage TOF correction. The use of the pulmonary artery extension technique and autologous tissue for bilateral pulmonary reconstruction could reduce the incidence of anastomotic stenosis., (© 2022 Wiley Periodicals LLC.)

The accelerometry(AMG) muscle relaxant monitor is the most widely used quantitative muscle relaxant monitor to assess the degree of neuromuscular at present. In this study, the ulnar nerve was stimulated by using train of four stimulation(TOF) mode of the AMG muscle relaxant monitor, and the movement of the adductor pollicis muscle was monitored. In this way, the distribution range of key parameters (acceleration peak value, response time, and TOF ratio) of the adductor pollicis muscle during the use of muscle relaxant in clinical practice is analyzed and will provide a practical basis for the development and improvement of the muscle relaxant monitor.

Introduction: Cigarette and tobacco use is a leading cause of chronic obstructive pulmonary disease, lung cancer, and other malignant tumors. In China, people prefer to engage in mental activities (gambling, overtime work, playing video games, or other mental activities) on the weekends or during spare time, especially in the evening before they prepare for bed. In China, smokers frequently consume tea while smoking. The relationship between smokers who consume tea, engage in mental activities after dinner, or both (drinking tea and engaging in cognitive activities after dinner together), and daily cigarette smoking or nicotine addiction must be clarified., Methods: A total of 438 smokers were included in the study. Age, gender, body mass index (BMI), smoking habits, Fagerström test for nicotine dependence scores, and behaviors, were recorded. The study excluded smokers with a Fagerström score <1 or with a mental disorder diagnosis. The smokers were divided into four groups based on their behaviors: those who did not drink tea, did not engage in mental activities after dinner, those who drank tea only, those who engaged in mental activities only, and those who engaged in both., Results: Only drinking tea or doing mental activities after dinner cannot increase cigarettes per day (22.20 ± 10.143 vs 23.49 ± 11.966, p=0.362; 22.20 ± 10.143 vs 22.66 ± 1.192, p=0.750) or FTND scores [6.0 (4.0; 7.0) vs 6.0 (4.0; 7.75), p=0.941; 6.0 (4.0; 7.0) vs 6.0 (4.25; 7.75), p=0.980]. People who drink tea and engage in mental activities after dinner smoke more (22.20 ± 10.143 vs 30.75 ± 17.264, p<0.0001) and have higher nicotine dependence levels [6.0 (4.0; 7.0) vs 7.0 (5.0; 8.0), p=0.015]., Conclusions: The consumption of tea or a mental activity after dinner is not associated with daily smoking or nicotine dependence. There is an association between the combined behaviors (tea drinking and mental activity after dinner) and the daily consumption of cigarettes, and the degree of nicotine dependence., Competing Interests: The authors have each completed and submitted an ICMJE form for disclosure of potential conflicts of interest. The authors declare that they have no competing interests, financial or otherwise, related to the current work. All the authors report that since the initial planning of the work, the study has been funded by the Affiliated Hospital of Medical School of Ningbo University Youth Talent Cultivation Program (FYQM-LC-202003), Ningbo Social and Scientific Development Fund (2015C50012), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (2020382182), Zhejiang Provincial Health Science and Technology Project (2022RC24 and 2016KYB268), 2021 Ningbo Medical Science and Technology Plan Project (2021Y13), Ningbo Health Youth Technical Key Talents Training Special Project (2020SWSQNGG-05) and the Natural Science Foundation of Ningbo (2018A610271 and 2017A610250). These are all non-profit third parties., (© 2022 Chen Z. et al.)

Nerve agents are highly toxic chemical warfare agents that are easy to synthesize and have recently been applied many times in local wars and terrorist attacks. Fluorescent probes have been widely used in life science and medical research due to their features of short reaction time, high sensitivity and good selectivity. Herein, two fluorescent compounds, NMU-1 and NMU-2, were synthesized for the selective detection of nerve agents. NMU-1 exhibited good detection performance for nerve agents. With increasing nerve agent concentration, the fluorescence signal of NMU-1 at 498 nm gradually decreased with an excellent linear relationship. NMU-1 exhibited a low LOD (4.6 μM for DCP and 8.41 μM for soman), a rapid response (less than 3 min) and a large Stokes shift (98 nm) along with obvious color changes. Due to its high sensitivity and good selectivity, NMU-1 was successfully applied to image nerve agents in living PC12 cells. Furthermore, NMU-1 was used as a key element to develop chemical warfare agent test paper, which exhibited significant fluorescent changes under hand-held 365-nm UV light upon contact with nerve agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Evidence regarding the association between evaluated glomerular filtration rate (eGFR) and non-alcoholic fatty liver disease (NAFLD) is still limited. On that account, the purpose of our research is to survey the link of evaluated eGFR on NAFLD., Methods: This study is a retrospective cohort study. Which consecutively and non-selectively collected a total of 16,138 non-obese participants in a Chinese hospital from January 2010 to December 2014. We then used the Cox proportional-hazards regression model to explore the relationship between baseline eGFR and NAFLD risk. A Cox proportional hazards regression with cubic spline functions and smooth curve fitting (the cubic spline smoothing) was used to identify the non-linear relationship between eGFR and NAFLD. Additionally, we also performed a series of sensitivity analyses and subgroup analyses. Data had been uploaded to the DATADRYAD website., Results: The mean age of the included individuals was 43.21 ± 14.95 years old, and 8,467 (52.47%) were male. The mean baseline eGFR was 98.83 ± 22.80 mL/min per 1.73m 2 . During a median follow-up time of 35.8 months, 2,317 (14.36%) people experienced NAFLD. After adjusting covariates, the results showed that eGFR was negatively associated with incident NAFLD (HR = 0.983, 95%CI: 0.980, 0.985). There was also a non-linear relationship between eGFR and NAFLD, and the inflection point of eGFR was 103.489 mL/min per 1.73 m 2 . The effect sizes (HR) on the left and right sides of the inflection point were 0.988 (0.984, 0.991) and 0.971 (0.963, 0.979), respectively. And the sensitive analysis demonstrated the robustness of our results. Subgroup analysis showed that eGFR was more strongly associated with incident NAFLD in diastolic blood pressure (DBP) < 90 mmHg, fasting plasma glucose (FPG) ≤ 6.1 mmol/L, high-density lipoprotein cholesterol (HDL-c) < 1 mmol/L, and alanine aminotransferase (ALT) ≥ 40 U/L participants. In contrast, the weaker association was probed in those with DBP ≥ 90 mmHg, ALT < 40 U/L, FPG > 6.1 mmol/L, and HDL-c ≥ 1 mmol/L., Conclusion: This study demonstrates a negative and non-linear association between eGFR and incident NAFLD in the Chinese non-obese population. eGFR is strongly related to NAFLD when eGFR is above 103 mL/min per 1.73 m 2 . From a therapeutic perspective, it makes sense to maintain eGFR levels within the inflection point to 130 mL/min/1.73 m 2 ., 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 Cen, Han, Liu and Hu.)

To improve the utilization rate of chlorfenapyr and make the wall material of chlorfenapyr microcapsules easily degradable, polylactide diol, toluene diisocyanate and 1,4-butanediol were used to prepare a chlorfenapyr microcapsule suspension by interfacial polymerization. The product was characterized by the methods of optical microscopy, scanning electron microscopy and Fourier-transform infrared spectroscopy. The results indicated that the microcapsule particles were spherical, with an encapsulation efficiency of 84.20%. The diluted product had good wetting and spreading abilities on cabbage leaves. Compared with other commercial formulations, the slow-release effect of the microcapsule suspension was more obvious and the release mechanisms conform to Fickian diffusion, with the release rate controllable by adjusting the external pH conditions. Furthermore, the wall material of the microcapsules showed good degradation performance in a phosphate-buffered solution. Microencapsulation by this method significantly increased the validity period of chlorfenapyr and the wall material was also degraded easily., Competing Interests: The authors report there are no competing interests to declare., (This journal is © The Royal Society of Chemistry.)

Sildenafil is a prescription drug used to treat pulmonary hypertension and erectile dysfunction. However, the illegal addition of sildenafil to health supplements may be hazardous to human health. Therefore, it is imperative to develop a method for the detection of sildenafil in health products. Solid-phase extraction (SPE) is typically used for the separation, purification, and enrichment of samples, with the aim of reducing the matrix interference of the samples and improving the detection sensitivity. SPE is widely employed in the detection of trace compounds in complex samples. Metal-organic frameworks (MOFs) are hybrid crystalline materials composed of metal ions and organic ligands. MOFs offer the advantages of a large specific surface area, permanent nanopores, good stability, and pore controllability. Owing to their advantages, researchers have attempted to use MOFs for SPE; however, it is difficult to collect MOFs in the powder form when they are directly used in SPE, necessitating the use of a substrate material to fix the MOFs. Hence, this study proposes a novel SPE method with high sensitivity that employs a UiO-66-NH 2 @cellulose hybrid aerogel, for the detection of sildenafil in health products. First, UiO-66-NH 2 was synthesized by a hydrothermal method. Cellulose nanocrystal (CNC) was modified with an aldehyde group to obtain CNC-CHO, and carboxymethyl cellulose (CMC) was modified with a hydrazide group to obtain CMC-NHNH 2 . Subsequently, UiO-66-NH 2 was added to the CNC-CHO solution, mixed with the CMC-NHNH 2 solution, and then crosslinked to load UiO-66-NH 2 and form a hybrid aerogel as a bulk adsorbent. This bulk hybrid aerogel could be collected easily without extra force for use in SPE. The synthesized hybrid aerogel was characterized by X-ray powder diffraction, scanning electron microscopy, Fourier transform-infrared (FT-IR) spectroscopy, and nitrogen gas adsorption/desorption. The results showed that UiO-66-NH 2 was successfully loaded on the pore surface of the hybrid aerogel, which made the pore of aerogel become more regular and a larger surface area. Investigation of the loading amount of UiO-66-NH 2 in the hybrid aerogel revealed that a higher amount of UiO-66-NH 2 could yield better extraction efficiency. The highest amount of UiO-66-NH 2 that could be loaded in the hybrid aerogel was 50%. The experimental conditions affecting the enrichment of sildenafil were optimized, and determined to be the following: pH of the sample, 9.0; extraction time, 60 min; eluent, acetonitrile; elution time, 40 min; elution volume, 3×2 mL; salt ion concentration, 0. Separation was performed on an Agilent Zorbax Eclipse Plus C18 column (150 mm×4.6 mm, 5 μm) with a phosphate solution containing 0.1 mol/L triethylamine (pH=6.50)-acetonitrile (30∶70, v/v) as the mobile phase. The detection wavelength was set at 292 nm. Under the optimal conditions, the UiO-66-NH 2 @cellulose hybrid aerogel was used as an adsorbent to extract sildenafil in different concentrations. The peak area was proportional to the sildenafil concentration in the range of 10-2000 ng/mL, with limit of detection (LOD, S/N =3) of 2.85 ng/mL and enrichment factor of 59.17. The correlation coefficient ( R 2 ) was 0.9950. Compared to previous preconcentration methods for sildenafil, this method offered a wider linear range. Five batches of hybrid aerogels were simultaneously prepared under the same conditions and used to extract sildenafil; the relative standard deviation (RSD, n =3) was 1.71%, indicating that the prepared hybrid aerogels offered good reproducibility. The used composite aerogels were freeze-dried again and reused to extract sildenafil; the recovery was still maintained at 85.23% after five extraction cycles, indicating that the UiO-66-NH 2 @cellulose hybrid aerogel had good regeneration ability. The feasibility of the developed method was verified by analyzing five health products. The results demonstrated the presence of 3.01 μg/g sildenafil in one of the products and no sildenafil in the others. The recoveries of this SPE method ranged from 74.93% to 89.12%, with RSDs in the range of 2.8%-5.3%, proving the feasibility of this analytical method.

Background: The growth and development of the atlas in children has not been studied to date using a large sample size., Objective: To study whether a 3.5-mm screw is suitable for the atlas in children, to explore the anatomical size and development of the atlas in 0-14-year-old children, and to provide morphological basis for lateral mass screw internal fixation., Methods: A Computed Tomography (CT) morphometric analysis was performed on 420 pediatric atlases. In the atlas, D1, D2, D3, D4, and α of the atlas lateral mass were measured. Statistical analysis was performed using one-way ANOVA and Students' t test. The least square method was used for the regression analysis of the change trend in anatomical structure. The curve with the greatest goodness of fit was used as the anatomic trend regression curve., Results: D1, D2, D3, and D4 generally showed an increasing trend with age. The ranges of averages of D1, D2, D3, D4, and α in 0-14 year-old children were as follows: 4.576-9.202 mm, 9.560-25.100 mm, 3.414-10.554 mm, 11.150-27.895, and 12.41°-20.97°, respectively. The trends of the fitting curves of L1 and L3 were power functions, and those of L2 and L4 were logarithmic curves., Conclusions: CT examination could help in preoperative decision-making, and 3.5-mm screw was found to be suitable for lateral mass screw internal fixation in children aging 2 years and older. D1-D4 increased with age. This provided a certain reference to perform posterior atlantoaxial fusion in children and is of great significance to design posterior atlantoaxial screw in children., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (PA/VSD/MAPCAs) is a relatively rare, complex, and heterogeneous congenital heart disease. As one of the effective treatments, the midline unifocalization strategy still remains complicated and challenging due to the diverse forms of MAPCAs and pulmonary arteries. The purpose of this study is to summarize our experience of a novel three-dimensional (3D) visualized operative procedure in the single-stage complete repair with unifocalization and to clarify the benefits it may bring to us., Methods: We described our experience of the 3D visualized operative procedure such as 3D printing, virtual reality (VR), and mixed reality (MR) technology in patients with PA/VSD/MAPCAs who underwent a single-stage complete repair with unifocalization. The data from the patients who underwent this procedure (3D group) and those who underwent the conventional procedure (conventional group) were compared., Results: The conventional and 3D groups included 11 patients from September 2011 to December 2017 and 9 from January 2018 to March 2021, respectively. The baseline characteristics such as age, body weight, preoperative saturation, the anatomy of the pulmonary arteries and MAPCAs, the Nakata index, and TNPAI had no statistical significance. All 9 patients in the 3D group were operated only through a median sternotomy, while 8 cases (72.7%) in the conventional group needed another posterolateral thoracotomy ( p = 0.001). In the 3D group, the CPB time was shorter (93.2 ± 63.8 vs. 145.1 ± 68.4 min, p = 0.099), and the median pre-CPB time per MAPCAs was significantly shorter [25.7 (14.0, 46.3) vs. 65 (41.3, 75.0) min, p = 0.031]. There was no early death in the 3D group, while there were 3 in the conventional group (0 vs. 27.3%, p = 0.218)., Conclusion: The novel 3D visualized operative procedure may help improve the performance of the single-stage complete repair with the midline unifocalization of PA/VSD/MAPCAs and help shorten the dissecting time of the MAPCAs. It may promote the routine and successful application of this strategy in more centers., 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 Qiu, Wen, Ji, Chen, Liu, Li, Teng, Zhang, Liufu, Zhang, Xu, Chen, Huang, Cen and Zhuang.)

There have been no studies with large sample sizes on growth of the pedicle of C2 in children. In the present study we measured the pedicle of C2 through computed tomography (CT) imaging in children aged less than 14 years and evaluated the suitability of the 3.5-mm screw for the pedicle in such children. The study was conducted on CT morphometric images of 420 children in our hospital between June 2018 and June 2020. The width (D1), length (D2), height (D3), inclination angle (α), and tail angle (β) of the C2 pedicle were measured. One-way analysis of variance and Student's t test were used for statistical analyses. The least-square method was used to analyze the curve fitting the trend of anatomical change in the pedicle. The largest degree of goodness of fit determined the best-fitting curve. The size of the pedicle of C2 increased with age. The median ranges of D1, D2, D3, α, and β were 3.312-5.431 mm, 11.732-23.645 mm, 3.597-8.038 mm, 32.583°-36.640°, and 24.867°-31.567°, respectively. The curves fitting the trends of D1 and D3 were power functions, whereas D2 was fitted by a logarithmic curve. However, no curve fitted α or β. A 3.5-mm screw can be placed in the pedicle of C2 in children aged more than 1 year. The growth and development trend of this pedicle can provide an anatomical reference for deciding on posterior cervical surgery and for selecting and designing pedicle screws for children., (© 2022 American Association for Clinical Anatomists and the British Association for Clinical Anatomists.)

Objective: Studies on the association between urinary protein-to-creatinine ratio (UPCR) and chronic kidney disease (CKD) progression are limited. This study aimed to investigate the relationship between UPCR and CKD progression in a Japanese population., Methods: The present research was a secondary analysis of a prospective cohort study. Eight hundred and ninety-six subjects from the research of CKD-ROUTE in Japan were included. All the patients were new visitors or first referred to the participating centers of nephrology between October 2010 and December 2011. The target-independent variable was UPCR measured at baseline. The dependent variable was CKD progression and the estimated glomerular filtration rate (eGFR) changes during follow-up. We used Cox proportional hazards regression to investigate the association between UPCR and CKD progression risk. To address UPCR and CKD progression's non-linearity, a multivariate Cox proportional hazards regression analysis with cubic spline functions model and smooth curve fitting (penalized spline method) were conducted. We further used a generalized linear mixed model to explore the relationship between UPCR and the changes of eGFR., Result: The mean age of the included patients was 67.2 ± 13.4 years old. Two hundred and thirty-four people occurred CKD progression during follow-up. The present study showed that UPCR was independently associated with CKD progression in the multivariate analysis [HR = 1.164, 95% CI (1.116, 1.215)]. The non-linear relationship between UPCR and CKD progression was explored in a dose-dependent manner, with an obvious inflection point of 1.699. Furthermore, our findings indicated that the tendency of the effect sizes on both the left and right sides of the inflection point was not consistent [left HR: 4.377, 95% CI (2.956, 6.483); right HR: 1.100, 95% CI (1.049-1.153)]. Using the linear mixed-effects regression model, we found that UPCR was an independent predictor of the longitudinal changes in eGFR ( p < 0.001 for the interaction term with time)., Conclusion: This study demonstrates a nonlinear positive relationship between UPCR and CKD progression in the Japanese population. UPCR is also an independent predictor of the longitudinal changes in eGFR., 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 Qin, Hu, Cen, Wang, Wan and Wei.)

Purpose: To investigate the changes in choroidal vascular structures after exercise in patients with glaucoma using an image binarisation algorithm with enhanced-depth imaging optical coherence tomography. Methods: Thirty-four eyes of 19 patients with primary open-angle glaucoma and 40 eyes of 20 normal subjects were included in the glaucoma and control groups, respectively. All subjects were evaluated before, immediately after, and 30 min after 20-min running at moderate speed. The subfoveal choroidal area was segmented into the luminal area (LA) and stromal area (SA), and the choroidal vascularity index (CVI) was measured by calculating the ratio of LA to the total choroidal area (TCA). The mean intraocular pressure (IOP), subfoveal choroidal thickness, CVI, SA, CA, and TCA were compared within and between both groups. The correlation between CVI, IOP, and other vascular indexes was investigated. Results: In the glaucoma group, a significantly lower CVI was found immediately after exercise and recovered 30 min after exercise. Higher TCA and LA levels were demonstrated 30 min after exercise compared to immediately after exercise. In both groups, IOP decreased immediately after exercise but was restored after a 30-min rest. In the glaucoma group, there was a higher correlation between CVI and other choroidal vascular parameters than in the control group. There was no difference in IOP or choroidal parameters between the groups at different time points. Conclusion: In patients with glaucoma, CVI decreased significantly immediately after exercise, indicating that the choroidal layer is affected by exercise and an unhealthy vascular regulatory mechanism., 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 Cheng, Fang, Gao, Wu, Qiao, Ruan, Lian, Cen, Fu, Shen and Nie.)

Aiming at the lack of feature extraction ability of rumor detection methods based on the deep learning model, this study proposes a rumor detection method based on deep learning in social network big data environment. Firstly, the scheme of combining API interface and third-party crawler program is adopted to obtain Weibo rumor information from the Weibo "false Weibo information" public page, so as to obtain the Weibo dataset containing rumor information and nonrumor information. Secondly, the distributed word vector is used to encode text words, and the hierarchical Softmax and negative sampling are used to improve the training efficiency. Finally, a classification and detection model based on the combination of semantic features and statistical features is constructed, the memory function of Multi-BiLSTM is used to explore the dependency between data, and the statistical features are combined with semantic features to expand the feature space in rumor detection and describe the distribution of data in the feature space to a greater extent. Experiments show that when the word vector dimension is 300, compared with the compared literature, the accuracy of the proposed method is improved by 4.232% and 1.478%, respectively, and the F1 value of the proposed method is improved by 5.011% and 1.795%, respectively. The proposed method can better extract data features and has better rumor detection ability., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Junjie Cen and Yongbo Li.)

This paper focuses on the finite-time generalized synchronization problem of non-identical fractional order chaotic (or hyper-chaotic) systems by a designing adaptive sliding mode controller and its application to secure communication. The effects of both disturbances and model uncertainties are taken into account. A novel fractional order integral sliding mode surface is designed and its stability to the origin is proved in a given finite time. By the aid of the fractional Lyapunov stability theory, a robust controller with adaptive update laws is proposed and its finite-time stability for generalized synchronization between two non-identical fractional-order chaotic systems in the presence of model uncertainties and external disturbances is derived. Numerical simulations are provided to demonstrate the effectiveness and robustness of the presented approach. All simulation results obtained are in good agreement with the theoretical analysis. According to the proposed generalized finite-time synchronization criterion, a novel speech cryptosystem is proposed to send or share voice messages privately via secure channel. Security and performance analyses are given to show the practical effect of the proposed theories., Competing Interests: The authors have declared that no competing interests exist.

The mechanisms underlining pathogenesis of polycystic ovary syndrome (PCOS) remain largely unknown. Dysfunction of ovarian granulosa cells plays an important role. The present study performed the lncRNA and mRNA profiling by whole genome transcriptomic sequencing of ovary granulosa cells from women with PCOS and investigated the potential role of differentially expressed gens (DEGs) in the pathomechanism of PCOS. In total, 1,936 DEGs (30 upregulated and 1,906 downregulated mRNAs and lncRNAs) were identified in the ovary granulosa cells between control and PCOS group. Functional enrichment analysis showed that DEGs were mainly associated with cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and olfactory transduction. qRT-PCR validated the upregulation of DLGAP5 mRNA in ovary from PCOS group when compared to control group. Immunostaining and TUNEL assays showed that DLGAP5 protein level was increased while apoptosis was decreased in follicles of ovary in PCOS group. In vitro functional assays showed that DLGPA5 knockdown repressed viability and proliferation, but enhanced apoptosis and disrupted cell cycle in granulosa cells; while DLGAP5 overexpression had the opposite effects in granulosa cells. In conclusion, the study showed differentially expressed lncRNA and mRNA profile in the granulosa cells in ovaries of PCOS. Functional results demonstrated that DLGAP5 is a dysregulated candidate gene in the pathogenesis of PCOS, especially granulosa cell apoptosis and proliferation., 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 Deng, Li, Song, Cen, Zhang, Sui, Cui, Li, Xu, Wang, Chung and Tang.)

Herein, a novel Ru-doped bimetal phosphide (Ru-NiCoP) heterostructure electrocatalyst on Ni foam is successfully synthesized through a multi-step hydrothermal reaction, ion exchange, and phosphorization method for efficient overall water splitting in alkaline media. The doping of Ru and P can effectively optimize the electronic structure and expose more active sites. The unique 3D interconnected nanowires not only ensures the uniform distribution of Ru coupled with NiCoP, but also endows the Ru-NiCoP/NF with the large ECSA, the fast electron transport and the favorable reaction kinetics attributes. Benefiting from the compositional and structural advantages, Ru-NiCoP/NF catalyst exhibits significantly enhancedcatalytic activities along with excellent stability, only needing 32.3 mV at 10 mA cm -2 for HER and 233.8 mV at 50 mA cm -2 for OER. In particular, when Ru-NiCoP/NF is employed as both cathode and anode electrodes,a small voltage of 1.50 V is required to reach 30 mA cm -2 for overall water splittingwith an impressive stability. This study provides an alternative strategyon the design and development of high performance catalysts foroverall water splittingand other energy conversion fields., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To establish an optimal model to predict the teicoplanin trough concentrations by machine learning, and explain the feature importance in the prediction model using the SHapley Additive exPlanation (SHAP) method., Methods: A retrospective study was performed on 279 therapeutic drug monitoring (TDM) measurements obtained from 192 patients who were treated with teicoplanin intravenously at the First Affiliated Hospital of Army Medical University from November 2017 to July 2021. This study included 27 variables, and the teicoplanin trough concentrations were considered as the target variable. The whole dataset was divided into a training group and testing group at the ratio of 8:2, and predictive performance was compared among six different algorithms. Algorithms with higher model performance (top 3) were selected to establish the ensemble prediction model and SHAP was employed to interpret the model., Results: Three algorithms (SVR, GBRT, and RF) with high R 2 scores (0.676, 0.670, and 0.656, respectively) were selected to construct the ensemble model at the ratio of 6:3:1. The model with R 2 = 0.720, MAE = 3.628, MSE = 22.571, absolute accuracy of 83.93%, and relative accuracy of 60.71% was obtained, which performed better in model fitting and had better prediction accuracy than any single algorithm. The feature importance and direction of each variable were visually demonstrated by SHAP values, in which teicoplanin administration and renal function were the most important factors., Conclusion: We firstly adopted a machine learning approach to predict the teicoplanin trough concentration, and interpreted the prediction model by the SHAP method, which is of great significance and value for the clinical medication guidance., 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 Ma, Liu, Gu, Dai, Gan, Cen, Shang, Liu and Chen.)

Endoplasmic reticulum (ER)-plasma membrane (PM) contacts are sites of lipid exchange and Ca2+ transport, and both lipid transport proteins and Ca2+ channels specifically accumulate at these locations. In pancreatic β-cells, both lipid and Ca2+ signaling are essential for insulin secretion. The recently characterized lipid transfer protein TMEM24 (also known as C2CD2L) dynamically localizes to ER-PM contact sites and provides phosphatidylinositol, a precursor of phosphatidylinositol-4-phosphate [PI(4)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], to the PM. β-cells lacking TMEM24 exhibit markedly suppressed glucose-induced Ca2+ oscillations and insulin secretion, but the underlying mechanism is not known. We now show that TMEM24 only weakly interacts with the PM, and dissociates in response to both diacylglycerol and nanomolar elevations of cytosolic Ca2+. Loss of TMEM24 results in hyper-accumulation of Ca2+ in the ER and in excess Ca2+ entry into mitochondria, with resulting impairment in glucose-stimulated ATP production., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

The unique permselectivity of cellular membranes is of crucial importance to maintain intracellular homeostasis while adapting to microenvironmental changes. Although liposomes and polymersomes have been widely engineered to mimic microstructures and functions of cells, it still remains a considerable challenge to synergize the stability and permeability of artificial cells and to imitate local milieu fluctuations. Herein, we report concurrent crosslinking and permeabilizing of pH-responsive polymersomes containing Schiff base moieties within bilayer membranes via enzyme-catalyzed acid production. Notably, this synergistic crosslinking and permeabilizing strategy allows tuning of the mesh sizes of the crosslinked bilayers with subnanometer precision, showing discriminative permeability toward maltooligosaccharides with molecular sizes of ~1.4-2.6 nm. The permselectivity of bilayer membranes enables intravesicular pH oscillation, fueled by a single input of glucose. This intravesicular pH oscillation can further drive the dissipative self-assembly of pH-sensitive dipeptides. Moreover, the permeabilization of polymersomes can be regulated by intracellular pH gradient as well, enabling the controlled release of encapsulated payloads., (© 2022. The Author(s).)

The goal of this study was to investigate the association between total epinephrine dosage during resuscitation and acute kidney injury after return of spontaneous circulation in patients with cardiac arrest. We performed a secondary analysis of previously published data on the resuscitation of cardiac arrest patients. Bivariate, multivariate logistic regression, and subgroup analyses were conducted to investigate the association between total epinephrine dosage during resuscitation and acute kidney injury after return of spontaneous circulation. A total of 312 eligible patients were included. The mean age of the patients was 60.8 ± 15.2 years. More than half of the patients were male (73.4%) and had an out-of-hospital cardiac arrest (61.9%). During resuscitation, 125, 81, and 106 patients received ≤2, 3 - 4, and ≥5 mg epinephrine, respectively. After return of spontaneous circulation, there were 165 patients (52.9%) and 147 patients (47.1%) with and without acute kidney injury, respectively. Both bivariate and multivariate analysis showed a statistically significant association between total epinephrine dosage and acute kidney injury. The subgroup analysis showed that the strength of the association between epinephrine dosage and acute kidney injury varied by location of cardiac arrest. Further multivariate regression analysis found that the association between epinephrine dosage and acute kidney injury was only observed in patients with in-hospital cardiac arrest after adjusting for multiple confounding factors. Compared with in-hospital cardiac arrest patients who received ≤2 mg of epinephrine, patients with 3-4 mg of epinephrine or ≥5 mg of epinephrine had adjusted odds ratios of 4.2 (95% confidence interval 1.0-18.4) and 11.3 (95% confidence interval 2.0-63.0), respectively, to develop acute kidney injury. Therefore, we concluded that a higher epinephrine dosage during resuscitation was associated with an increased incidence of acute kidney injury after return of spontaneous circulation in adult patients with in-hospital cardiac arrest., 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 Gao, Mok, Qiu, Cen, Chen and Zhuang.)

Background: Intrauterine adhesions (IUA) develop in up to 20% of women with a history of abortion. After hysteroscopic adhesiolysis, balloon stents are usually placed for seven days to prevent recurrence. The efficacy of prolonged use (30 days) of balloon stents has not been determined., Methods: The trial was conducted from June 2019 to March 2021. Ninety-one patients who underwent hysteroscopic adhesiolysis for moderate or severe IUA were randomized to receive a 30-day placement of a balloon stent (n = 44) or an intrauterine device (IUD) (n = 47). The primary outcomes were the ongoing pregnancy and miscarriage rates assessed at 15-19 months. The secondary outcomes were the recurrence of IUA and the American Fertility Society (AFS) intrauterine adhesion scores at the first and second hysteroscopies, the diagnosis of new chronic endometritis at the second-look hysteroscopy, and the vaginal/uterine microbiome assessed using 16S rRNA sequencing. The trial was registered at Chinese Clinical Trial Registry (ChiCTR1900023306)., Findings: The ongoing pregnancy rates (balloon 56·4% versus IUD 57·1%) and miscarriage rates (balloon 10·3% versus IUD 22·9%) were not significantly different between the groups. No differences in the recurrence of IUA, reduction of AFS scores, or new endometritis rates were detected. The bacterial load in the uterus and vagina increased in the IUD group but not in the balloon group., Interpretation: Balloon placement has a similar effect on ongoing pregnancy rates as intrauterine device (IUD) placement. Patients who underwent balloon placement had a lower miscarriage rate, although the difference was not significant. There were no differences in the recurrence rate of IUA, reduction of American Fertility Society scores, or rate of new chronic endometritis. The balloon stent has less effects on the uterine microbiota., Funding: National Natural Science Foundation of China (81802593)., Competing Interests: The authors report no conflict of interest., (© 2022 The Authors.)

Background: Metabolic disturbance is closely correlated with intrahepatic cholangiocarcinoma (IHCC), and we aimed to identify metabolic gene marker for the prognosis of IHCC., Methods: We obtained expression and clinical data from 141 patients with IHCC from public databases. Prognostic metabolic genes were selected using univariate Cox regression analysis. Unsupervised cluster analysis was applied to identify IHCC subtypes, and CIBERSORT was used for immune infiltration analysis of different subtypes. Then, the metabolic gene signature was screened using multivariate Cox regression analysis and the LASSO algorithm. The prognostic potential and regulatory network of the metabolic gene signature were further investigated., Results: We screened 228 prognosis-related metabolic genes. Based on their expression levels, IHCC samples were divided into two subtypes, which showed significant differences in survival and immune cell infiltration. After LASSO analysis, eight metabolic genes including CYP19A1, SCD5, ACOT8, SRD5A3, MOGAT2, PFKFB3, PPARGC1B, and RPL17 were identified as the optimal genes for the prognosis signature. The prognostic model had excellent predictive abilities, with areas under the receiver-operating characteristic curves over 0.8. A nomogram model was also established based on two independent prognostic clinical factors (pathologic stage and prognostic model), and the generated calibration curves and c-indexes determined its excellent accuracy and discriminative ability to predict 1- and 5-year survival status (c-indexes>0.7). Finally, we found that miR-26a-5p, miR-27a-3p, and miR-27b-3p were the upstream regulators that mediate the involvement of gene signatures in metabolic pathways., Conclusion: We developed eight metabolic gene signatures to predict IHCC prognosis and proposed potential upstream regulatory axes of gene signatures., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Introduction: Imiquimod plays an important role in the management of condyloma and premalignant lesions. Successively, an increase of hypopigmented lesions following imiquimod application has been reported. However, the mechanisms of imiquimod on melanocytes remain unclear. This study was designed to assess the effect of Imiquimod on the functions of melanocytes in vitro., Methods: Primary cultured melanocytes were isolated from normal control skin tissue. After incubation with imiquimod for 48 h in vitro, cell viability was analyzed by cell counting kit-8 assay. Apoptosis was detected using the Annexin V-fluorescein-5-isothiocyanate flow cytometry assay. Melanin content and tyrosinase activity in melanocytes were measured by colorimetric method and the modified dopachrome method. The production of inflammatory cytokine interleukin 8 (IL-8), IL-6, and soluble ICAM-1 (soluble Intercellular Adhesion Molecule-1[sICAM-1]) in melanocytes were measured by enzyme-linked immunosorbent assay (ELISA). Toll-like receptor 7 (TLR7), toll-like receptor 9 (TLR9) protein, and autophagy-related proteins microtubule-associated protein 1A/1B-light chain 3 (LC3-II), p62, mechanistic target of rapamycin (mTOR), and Atg5 were assessed using western blot analysis., Results: Imiquimod significantly inhibited the activity of tyrosinase activity and decreased melanin content in melanocytes and significantly increased apoptosis and IL-6, IL-8, and sICAM-1 production in melanocytes. Moreover, the expression of TLR7 and TLR9 proteins were significantly increased, and the expression of mTOR, p62 protein were markedly decreased, but the expression of LC3II/I and Atg5 protein were significantly increased in melanocytes after incubating with imiquimod., Conclusions: This study shows that imiquimod directly inhibits melanogenesis and increases melanocyte apoptosis rates. These effects combined with the upregulation of TLR7 and TLR9 together with increased autophagy activity and inflammatory cytokines production, might be the main reasons leading to hypopigmented lesions after imiquimod application., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Inborn errors of mitochondrial fatty acid oxidation (FAO), such as medium-chain acyl-CoA dehydrogenase deficiency (MCAD) and very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) affects cellular function and whole-body metabolism. Carnitine uptake deficiency (CUD) disturbs the transportation of fatty acids into the mitochondria, but when treated is a mild disease without significant effects on FAO. For improved clinical care of VLCAD in particular, estimation of FAO severity could be important. We have investigated whether the oxygen consumption rate (OCR) of peripheral blood mononuclear cells (PBMCs) obtained from patients with MCAD, VLCAD, and CUD can be used to study cellular metabolism in patients with FAO defects and to determine the severity of FAO impairment. PBMCs were isolated from patients with VLCAD (n = 9), MCAD (n = 5-7), and CUD (n = 5). OCR was measured within 6-hours of venous puncture using the Seahorse XFe96. The PBMCs were exposed to glucose alone or with caprylic acid (C8:0) or palmitic acid (C16:0). OCR was significantly lower in cells from patients with β-oxidation deficiencies (MCAD and VLCAD) compared to CUD at basal conditions. When exposed to C16:0, OCR in VLCAD cells was unchanged, whereas OCR in MCAD cells increased but not to the levels observed in CUD. However, C8:0 did not increase OCR, as would be expected, in VLCAD cells. There was no clear relationship between clinical severity level and OCR. In patients with β-oxidation deficiencies, changes of mitochondrial respiration in PBMCs are detectable, which indicate that PBMCs have translational potential for studies of β-oxidation defects. However, further studies are warranted., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Photodynamic therapy (PDT) of tumor has achieved good results, but the treatment efficiency is not high due to the lack of effective photosensitizers and tumor hypoxia. In this study, iridium dioxide nanoparticles (IrO 2 NPs) with excellent photothermal/photodynamic effects and catalase like activity were synthesized by a simple method. The combination of glucose oxidase (GOx) and IrO 2 NPs is formed by hyaluronic acid (HA), which have the activities of glucose oxidase and catalase, can target tumor sites and form in situ amplifiers in tumor microenvironment (IrO 2 -GOx@HA NPs). Firstly, GOx convert the high levels of glucose in the tumor to hydrogen peroxide (H 2 O 2 ), and then IrO 2 NPs convert H 2 O 2 to oxygen (O 2 ), which can enhance the type II of PDT. IrO 2 NPs also can be used as a thermosensitive agent for photothermal therapy (PTT). In cancer cells, IrO 2 -GOx@HA NPs-mediated amplifier enhances the effect of type II of PDT, aggravating the apoptosis of breast cancer (4T1) cells and cooperating with its own PTT to further improve the overall treatment effect. Under simulated hypoxic conditions of tumor tissue, it was found that IrO 2 -GOx@HA NPs treatment can effectively relieve hypoxia inside tumor tissue. In addition, the results in vivo further proved that, IrO 2 -GOx@HA NPs can enhance the role of II PDT and cooperate with PTT to treat breast cancer effectively. The results highlight the prospect of IrO 2 -GOx@HA NPs in controlling and regulating tumor hypoxia to overcome the limitations of current cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Acute exacerbation of chronic obstructive pulmonary disease (COPD) resulting in hospitalization is significantly associated with the increased morbidity and mortality, but there is a lack of an effective method to assess it. This study aimed to compare the ability of peak expiratory flow (PEF) and COPD assessment test (CAT) to assess COPD exacerbations requiring hospitalization., Methods: A cohort of 110 patients with moderate to severe COPD was studied over a period of 12 months, and their daily morning PEFs and CAT scores were recorded throughout the study., Results: After 12 months of follow-up, 72 patients experienced 156 COPD exacerbations, 74 (47%) that resulted in hospitalization and 82 (53%) that did not result in hospitalization. Change in CAT score from baseline to exacerbation was significantly related to change in PEF and Spearman's rho =0.375 (95% CI, 0.227 to 0.506; p < .001). Change in PEF and CAT score from baseline to hospitalized exacerbation was significantly larger than that from baseline to non-hospitalized exacerbation (p < .05). Multivariable analysis indicated that ΔPEF (OR 1.11, 95% CI 1.06-1.16, p < .001) and ΔCAT (OR 1.64 95% CI 1.18-2.27, p = .003) were independently associated with risk of hospitalized exacerbation. ROC analysis indicated that the optimal cutoff value of ΔPEF for identifying hospitalized exacerbation was 49 L/min (27% from baseline), with a sensitivity and specificity of 82.7% and 76.7% (area under the curve [AUC] = 0.872 (95% CI 0.80-0.944, p < .05). The optimal cutoff value of ΔCAT score for identifying hospitalized exacerbation was 10.5 (63% from baseline), with a sensitivity and specificity of 67.3% and 77.4% [AUC]=0.763 (95% CI 0.67-0.857, p < .05). The AUC of ΔPEF and ΔCAT combined for the identification of hospitalized exacerbation was 0.900 (95% CI 0.841-0.959, p < .05), which was larger than that of ΔCAT or ΔPEF., Conclusions: ΔPEF and ΔCAT were independently associated with risk of hospitalized exacerbation. Compared with CAT, PEF was superior to identify hospitalized exacerbation. Identification via PEF and CAT combined is more effective than using PEF or CAT alone. These results help to assess the severity of COPD exacerbation and provide valuable information for clinical decision-making.

Several clinical trials have shown promising efficacy of pegylated interferon (Peg-IFN) in the first- and second-line polycythemia vera (PV) and essential thrombocythemia (ET). However, the efficacy and safety of Peg-IFN in the real world have rarely been reported. Hence, we conducted a prospective, single-center, single-arm, open exploratory study, which aimed to explore the hematologic response, molecular response, safety, and tolerability of patients with PV and ET treated with Peg-IFN in the real world. This study included newly diagnosed or previously treated patients with PV and ET, aged 18 years or older, admitted to the Department of Hematology of the First Affiliated Hospital of Soochow University from November 2017 to October 2019. The results revealed that complete hematological response (CHR) was achieved in 66.7% of patients with PV and 76.2% of patients with ET, and the molecular response was obtained in 38.5% of patients with PV and 50% of patients with ET after 48 weeks of Peg-IFN treatment. Peg-IFN is safe, effective and well tolerated in most patients. In the entire cohort, 4 patients (9.1%) discontinued treatment due to drug-related toxicity. In conclusion, Peg-IFN is a promising strategy in myeloproliferative neoplasms (MPNs), and Peg-IFN alone or in combination with other drugs should be further explored to reduce treatment-related toxicity and improve tolerability., 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 © 2021 Sun, Cai, Cen, Zhu, Pan, Wang, Wu and Chen.)

Previous studies have reported beneficial effects of NADPH oxidase 4 (NOX4) inhibition on beta-cell survival in vitro and in vivo. The mechanisms by which NOX4 inhibition protects insulin producing cells are, however, not known. The aim of the present study was to investigate the effects of a pharmacological NOX4 inhibitor (GLX7013114) on human islet and EndoC-βH1 cell mitochondrial function, and to correlate such effects with survival in islets of different size, activity, and glucose-stimulated insulin release responsiveness. We found that maximal oxygen consumption rates, but not the rates of acidification and proton leak, were increased in islets after acute NOX4 inhibition. In EndoC-βH1 cells, NOX4 inhibition increased the mitochondrial membrane potential, as estimated by JC-1 fluorescence; mitochondrial reactive oxygen species (ROS) production, as estimated by MitoSOX fluorescence; and the ATP/ADP ratio, as assessed by a bioluminescent assay. Moreover, the insulin release from EndoC-βH1 cells at a high glucose concentration increased with NOX4 inhibition. These findings were paralleled by NOX4 inhibition-induced protection against human islet cell death when challenged with high glucose and sodium palmitate. The NOX4 inhibitor protected equally well islets of different size, activity, and glucose responsiveness. We conclude that pharmacological alleviation of NOX4-induced inhibition of beta-cell mitochondria leads to increased, and not decreased, mitochondrial ROS, and this was associated with protection against cell death occurring in different types of heterogeneous islets. Thus, NOX4 inhibition or modulation may be a therapeutic strategy in type 2 diabetes that targets all types of islets.

Aims: To investigate genotype and phenotype of congenital nephrogenic diabetes insipidus caused by AVPR2 mutations, which is rare and limitedly studied in Chinese population., Methods: 88 subjects from 28 families with NDI in a department (Beijing, PUMCH) were screened for AVPR2 mutations. Medical records were retrospectively reviewed and characterized. Genotype and phenotype analysis was performed., Results: 23 AVPR2 mutations were identified, including six novel mutations (p.Y117D, p.W208R, p.L313R, p.S127del, p.V162Sfs*30 and p.G251Pfs*96). The onset-age ranged from 1 week to 3 years. Common presentations were polydipsia and polyuria (100%) and intermittent fever (57%). 21% and 14% of patients had short stature and mental impairment. Urine SG and osmolality were decreased, while serum osmolality and sodium were high. Urological ultrasonography results showed hydronephrosis of the kidney (52%), dilation of the ureter (48%), and thickened bladder wall or increased residual urine (32%), led to intermittent urethral catheterization (7%), cystostomy (11%) and binary nephrostomy (4%). Urological defects were developed in older patients. Genotype and phenotype analysis revealed patients with non-missense mutations had higher levels of serum sodium than missense mutations., Conclusion: In the first and largest case series of NDI caused by AVPR2 mutations in Chinese population, we established genetic profile and characterized clinical data, reporting six novel mutations. Further, we found genotype was associated with phenotype. This knowledge broadens genotype and phenotype spectrum of rare congenital NDI caused by AVPR2 mutations, and provides basis for studying molecular biology of AVPR2., (© 2021. Italian Society of Endocrinology (SIE).)

Fermented golden pomfret (Trachinotus ovatus) is appreciated by local consumers owing to its distinct flavor. Electronic nose (E-nose) and gas chromatography-ion mobility spectrometry (GC-IMS) technologies were used to analyze the changes in volatile compounds responsible for evolution of the golden pomfret odor profile during fermentation. Forty-five ion peaks were detected using GC-IMS. Although aldehydes represented the major initial volatile compound group, their levels decreased as fermentation proceeded. Between 3 and 15 days, increased levels of esters contributed to a stable volatile organic compounds profile. After 18 days, high levels of indole and pyrazines were detected. Eleven key volatile compounds were screened based on partial least squares discriminant analysis (PLS-DA). Back propagation artificial neural network (BP-ANN) predicted the fermentation stage enabling the development of better strategies to regulate golden pomfret fermentation. This study provided a theoretical basis for real-time monitoring and quality control of Chinese fermented golden pomfet., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Particulate matter with 10 μm or less in diameter (PM 10 ) exposure is a major threat to health and environment around the world. Even though a number of clinical and experimental studies have focused on the cardiopulmonary effects of PM 10 , its impact on neurovascular development and the underlying toxicity is relatively less studied. The present study is therefore undertaken to evaluate the potential toxic effects of PM 10 on neurodevelopment and the associated gene expression profiles in the zebrafish embryo/larvae. During 2017-2018, PM 10 samples (24 h sampling, 180 sampling days) were collected in an urban downtown site of Jinan, Shandong province, China. To delineate the potential toxic effects of PM 10 during neurodevelopment, zebrafish embryos/larvae were exposed to different concentrations viz., 25, 50, 100, 200, and 400 μg/mL of PM 10 solution for 24-120 h post-fertilization (hpf) and the effects on the mortality, morphology, swimming behavior, electroencephalogram discharges, growth of dopaminergic neurons, neurovasculature development and gene expression profiles of dopaminergic and neurodevelopment-related genes using qRT-PCR were studied. A significant increase in the mortality rate and morphological abnormalities were observed in 200 μg/mL of the PM 10 treated group at 120 hpf. High concentrations (≥100 μg/mL) of PM 10 exposure reduced locomotor behavior, caused abnormal electroencephalogram discharges, degeneration of dopaminergic neurons, inhibition of neurovascular development, cerebral hemorrhage, and significant changes in the expression pattern of genes involved in dopaminergic pathway and neurodevelopment such as (th1, dat, drd1, drd2a, drd3, drd4b, syn2a, gap43, α1-tubulin, gfap, map2, elavl3, eno2, neurog1, sox2, shha, and mbp). Taken together, all these parameters collectively imply developmental neurotoxicity and dysfunction of the dopaminergic neurons which provides the first evidence of PM 10 -induced neurodevelopmental toxicity in the zebrafish embryo/larvae., (Copyright © 2021. Published by Elsevier B.V.)

Cells of the tumor microenvironment exert a vital influence on sarcoma prognosis. This study aimed to analyze and identify differentially expressed genes (DEGs) related to immunity and their significance as immune biomarkers for the accurate prediction of overall survival of patients with sarcoma. The Cancer Genome Atlas was adopted for obtaining sarcoma gene microarray and corresponding clinical information. ESTIMATE algorithm was used to calculate tumor immune microenvironment indices. Immune-associated DEGs were identified using the limma packages and were further analyzed using the ClusterProfiler package and STRING website. Based on the results of these analyses, we constructed a prognostic model. Furthermore, we assessed the prognosis prediction model through functional evaluation and analysis of GSE17674. The functional analysis revealed that the upregulated immune DEGs were related to immune-related aspects. Chemokine ligands/receptors and immune-related genes were found to be vital for sarcoma formation and progression. We established a prognostic signature of seven genes, which indicated that high-risk cases exhibit poor prognostic outcome. The prognostic signature constructed in this study can accurately predict the overall prognosis in patients with sarcoma. Moreover, the novel immune gene expression analysis may provide clinical guidance for predicting prognosis in patients with sarcoma.

Background: To evaluate trends in the in-hospital mortality rate for pediatric cardiac surgery procedures between 2005 and 2017 in our center, and to discuss the mortality characteristics of children's CHD after thoracotomy., Methods: This retrospective data were collected from medical records of children underwent CHD surgery between 2005 and 2017., Results: A total of 19,114 children with CHD underwent surgery and 444 children died, with the in-hospital mortality was 2.3%. Complex mixed defect CHD had the highest fatality rate (8.63%), left obstructive lesion CHD had the second highest fatality rate (4.49%), right to left shunt CHD had the third highest mortality rate (3.51%), left to right shunt CHD had the lowest mortality rate (χ2 = 520.3,P < 0.05). The neonatal period has the highest mortality rate (12.17%), followed by infant mortality (2.58%), toddler age mortality (1.16%), and preschool age mortality (0.94%), the school age and adolescent mortality rate was the lowest (χ2 = 529.3,P < 0.05). In addition, the fatality rate in boys was significantly higher than that in girls (2.77% versus 1.62%, χ2 = 26.4, P < 0.05)., Conclusions: The mortality rate of CHD surgery in children decreased year by year. The younger the age and the more complicated the cyanotic heart disease, the higher the mortality rate may be., (© 2021. The Author(s).)

Controlled polypeptide synthesis via α -amino acid N -carboxylic anhydride (NCA) polymerization using conventional primary amine initiators encounters two major obstacles: (i) normal amine mechanism (NAM) and activated monomer mechanism (AMM) coexist due to amine basicity and nucleophilicity and (ii) NCA is notoriously sensitive towards moisture and heat and unstable upon storage. We serendipitously discover that N -phenoxycarbonyl-functionalized α -amino acid (NPCA), a latent NCA precursor, could be polymerized solely based on NAM with high initiating efficiency by using primary amine hydrochloride as an initiator. The polymerization affords well-defined polypeptides with narrow polydispersity and high-fidelity terminal functionalities, as revealed by the clean set of MALDI-TOF MS patterns. We further demonstrate successful syntheses of random and block copolypeptides, even under open-vessel conditions. Overall, the integration of moisture-insensitive and air-tolerant NPCA precursors with stable primary amine hydrochloride initiators represents a general strategy for controlled synthesis of high-fidelity polypeptides with sophisticated functions., Competing Interests: The authors declare no competing financial interest., (Copyright © 2021 Lei Li et al.)

Background: Recent developments in surgical techniques and hospital care have led to improved outcomes following repair of total anomalous pulmonary venous connection (TAPVC). However, surgical repair of neonatal TAPVC remains associated with a high risk of postoperative mortality and pulmonary venous obstruction (PVO). We conducted this retrospective study to identify risk factors associated with surgical outcomes in the neonatal population. Methods: A retrospective review was conducted for all 127 neonates who underwent operations for isolated TAPVC from January 2009 to January 2019. Results: Preoperative PVO occurred in 33 (26.0%) of the 127 patients. Fifty patients (39.4%) required tracheal intubation before the operation. Twenty-three patients (18.1%) underwent emergency surgery. There were 11 (8.7%) early deaths. Significant risk factors were prolonged cardiopulmonary bypass (CPB) time ( p = 0.013) and increased postoperative central venous pressure (CVP, p = 0.036). There were 5 (4.3%) late deaths within 1 year of repair. The risk factors for overall death were preoperative acidosis ( p = 0.001), prolonged CPB time ( p < 0.001) and increased postoperative CVP ( p = 0.007). In particular, mortality was significantly higher ( p = 0.007) with a postoperative CVP > 8 mmHg. With an increase in use of sutureless techniques ( p = 0.001) and decrease in deep hypothermic circulatory arrest ( p = 0.009) over the past 5 years, postoperative mortality greatly decreased (21.2%: 6.7%, p = 0.016). Postoperative PVO occurred in 15 patients (11.8%). Risk factors were mixed TAPVC ( p = 0.037), preoperative acidosis ( p = 0.001) and prolonged CPB time ( p = 0.006). Conclusion: Although postoperative mortality of neonatal TAPVC has dropped to 6.7% over the past 5 years, it is still relatively high. Risk factors for postoperative death include preoperative acidosis, prolonged CPB time and increased postoperative CVP. Mortality was significantly higher for neonates with an average CVP > 8 mmHg 24 h after surgery., 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 © 2021 Ji, Qiu, Liu, Xie, Liufu, Liu, Chen, Wen, Li, Cen and Zhuang.)

Background: To explore whether opening the external urethral orifice in the coronal sulcus can reduce the incidence of epididymitis after operating on hypospadias with prostatic utricle cyst (PUC) connecting to the vas deferens. Group A consisted of 3 patients with severe hypospadias and PUC undergoing cystostomy, hypospadias correction and urethroplasty, along with the relocation of the external orifice of the urethra to the coronal sulcus. Group B consisted of 4 patients having initial hypospadias repaired with meatus in the orthotopic position in the glans, presenting with multiple epididymitis after hypospadias surgery and unsuccessful conservative treatment. MR confirmed that all the Group B patients had PUC connecting to the vas deferens. Group B patients underwent urethral dilatation along with urethral catheterization, cutting of the original corpus cavernosum that encapsulated the urethra, and extension of the position of the external urethral orifice to the coronal sulcus., Results: In group A, 3 children underwent bladder fistula removal 2 weeks after the operation. The penis developed normally without any complications. Four children in group B underwent stent removal 12 weeks after operation, and one patient was still stenosed and dilated again. All patients in group B were followed without epididymitis recurrence., Conclusions: For patients with hypospadias complicating with a PUC, connecting to one side of the vas deferens, the positioning of the external urethral orifice in the coronary sulcus would be helpful to reduce the occurrence of epididymitis., (© 2021. The Author(s).)

Firms should deploy exploration and exploitation to foster organizational adaptation. Previous research on exploration and exploitation lacked a focus on disruption implications in different contexts. This study aims to empirically test a moderation model including disruption events, exploration, exploitation, and organizational adaptation and enable a deeper understanding of organizational learning and innovation theory to yield competitive advantage and sustainability of innovative firms. Our results reveal that exploration is more effective during outside disruption events. The results do not support the concept that exploitation is more effective during inside disruptions. Disruptions also moderate the combined effect of exploration and exploitation. Although they are generally complementary in facilitating organizational adaptation, a singular focus on either exploration or exploitation is as effective as is combining exploration and exploitation during inside and outside disruption events. The results of an event study using seven Chinese international firms, including Alibaba, Meituan, Dianping, Baidu, Beibei, TP-link, and Maxio, provided 132 completed and usable questionnaires that supported our hypotheses. Our study contributes to a better understanding of disruption, exploration, exploitation, and related performance implications., 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 © 2021 Xiao, Cen and Soberg.)

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), which is characterized by the reciprocal t (15;17) (q24; q21) translocation, resulting in PML-RARA gene fusion. Therapy-related AML (t-AML) is a serious complication after cytotoxic and/or radiation therapy in many malignant diseases. In this report, MLL/KMT2A-MON2, with balanced chromosomal translocation t (11;12) (q23; q14), was identified as a novel fusion in a child transformed to t-AML after successful treatment of APL. This study emphasized that clinical monitoring with an integrated laboratory approach is essential for the diagnosis and treatment of t-AML., (© 2021 Wiley Periodicals LLC.)

Dynamin is recognized as a crucial regulator for membrane fission and has three isoforms in mammals. But the expression patterns of dynamin isoforms and their roles in non-neuronal cells are incompletely understood. In this study, the expression profiles of dynamin isoforms and their roles in endocytosis was investigated in brain endothelial cells. We found that Dyn2 was expressed at highest levels, whereas the expression of Dyn1 and Dyn3 were far less than Dyn2. Live-cell imaging was used to investigate the effects of siRNA-mediated knockdown of individual dynamin isoforms on transferrin uptake, and we found that Dyn2, but not Dyn1 or Dyn3, is required for the endocytosis in brain endothelial cells. Results of dextran uptake assay showed that dynamin isoforms are not involved in the clathrin-independent fluid-phase internalization of brain endothelial cells, suggesting the specificity of the role of Dyn2 in clathrin-dependent endocytosis. Immunofluorescence and electron microscopy analysis showed that Dyn2 co-localizes with clathrin and acts at the late stage of vesicle fission in the process of endocytosis. Further results showed that Dyn2 is necessary for the basolateral-to-apical internalization of amyloid-β into brain endothelial cells. We concluded that Dyn2, but not Dyn1 or Dyn3, mediates the clathrin-dependent endocytosis for amyloid-β internalization particularly from basolateral to apical side into brain endothelial cells., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To study the surgical effects of medial rectus recession (MRR) on divergence insufficiency esotropia (DIE)., Methods: Nine DIE patients who were admitted to and had MRR at Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University between December 2017 and June 2020 were included in this retrospective study. All patients were followed up for 1 year at least. The postoperative esodeviation, near-distant disparity (NDD) and visual function were observed and compared., Results: The mean age of the 9 patients was 28.8 years old (10-49 yr.), including 3 adolescent patients (≤18 yr.). The mean preoperative esodeviation was (19.8±13.2) PD for near and (32.6±15.3) PD at distance, while, the mean postoperative esodeviation 1 year after MMR was (-0.2±3.5) PD for near and (6.0±2.2) PD at distance, showing significant improvement over the mean preoperative esodeviation ( P =0.012, P =0.007). NDD dropped from (12.8±2.4) PD before the surgery to (6.0±2.2) PD 1 year after the surgery, showing significant improvement ( P =0.008), and remained stable 1 year after the surgery ( F =0.075, P =0.900). There was no significant improvement of near stereopsis ( P =0.306). Binocular function at distance was significantly improved after surgery (Worth 4 dots test : P =0.017; Bagolini striated glasses: P =0.035). The patients were divided into two groups, the adolescent group (age≤18 yr., n =3) and the adult group (age>18 yr., n =6). Prior to the operation, the mean spherical diopter of the adolescent group (OD -1.75 D, OS -1.92 D) was lower than that of the adult group (OD -6.17 D, OS -6.04 D) ( P =0.012). The average value of preoperative AC/A of the adolescent group was 4.33. It was 2.33 in the adult group, which was lower than the normal value, and significantly lower than that of the adolescent group ( P =0.12). There was no significant difference in esodeviation or NDD between the adolescent group and the adult group before and after operation., Conclusions: Medial rectus muscle recession can effectively improve the NDD and the binocular function at distance of patients with divergence insufficiency esotropia. Postoperative esodeviations both for near and at distance tend to regress after the surgery. Therefore, it is recommended that the amount of MRR be increased in the treatment of DIE., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of non-obese diabetic (NOD) mice with imatinib resulted in increased beta-cell AMP-activated kinase (AMPK) phosphorylation. Imatinib activated AMPK also in vitro, resulting in decreased ribosomal protein S6 phosphorylation and protection against islet amyloid polypeptide (IAPP)-aggregation, thioredoxin interacting protein (TXNIP) up-regulation and beta-cell death. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) mimicked and compound C counteracted the effect of imatinib on beta-cell survival. Imatinib-induced AMPK activation was preceded by reduced glucose/pyruvate-dependent respiration, increased glycolysis rates, and a lowered ATP/AMP ratio. Imatinib augmented the fractional oxidation of fatty acids/malate, possibly via a direct interaction with the beta-oxidation enzyme enoyl coenzyme A hydratase, short chain, 1, mitochondrial (ECHS1). In non-beta cells, imatinib reduced respiratory chain complex I and II-mediated respiration and acyl-CoA carboxylase (ACC) phosphorylation, suggesting that mitochondrial effects of imatinib are not beta-cell specific. In conclusion, tyrosine kinase inhibitors modestly inhibit mitochondrial respiration, leading to AMPK activation and TXNIP down-regulation, which in turn protects against beta-cell death., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Neuroinflammation is considered as an important mechanism of vascular dementia (VaD). Our primary study showed that the bisindole analogue (2-(2-(bis(5-chloro-1H-indol-3-yl)methyl)phenoxy)aniline, compound 4ae) had great anti-inflammation in zebrafish. Rat model of permanent occlusion of the bilateral common carotid arteries (2-vessel occlusion, 2VO) was utilized to evaluate the neuroprotective effect of 4ae. Our results showed that 4ae treatment effectively reduced Iba-1 positive microglia cells in cerebral cortex and hippocampus after cerebral ischemia. Compared with the model group, neuroinflammation characterized by Interleukin (IL)-6 and tumor necrosis factor (TNF)-α, oxidative stress characterized by reactive oxygen species (ROS) and superoxide dismutase (SOD) were both improved significantly after treatment with 4ae. Moreover, 4ae treatment significantly reversed ischemia-induced ACE enhancement, while notably increased the level of ACE2. To further elucidate the role of 4ae on neuroinflammation, we investigated the effects of 4ae on lipopolysaccharide (LPS)-induced inflammation in BV2 microglia cells, a kind of innate immune cells in central nervous system. The results demonstrated that the expressions of CD11b, TNFα and IL-6 and the level of ROS were up-regulated after treatment with LPS. More importantly, 4ae was able to block the activation of BV2 by reducing ROS production and the expression of inflammatory cytokines. In addition, our results suggested that 4ae inhibited the inflammatory response mediated by microglia cells by inhibiting NF-κB. This anti-inflammatory effect on microglia may be a potential mechanism for the neuroprotective effect of 4ae in VaD., (Copyright © 2021. Published by Elsevier B.V.)

Multifunctional nanoagents integrating multiple therapeutic and imaging functions hold promise in the field of non-invasive and precise tumor therapies. However, the complex preparation process and uncertain drug metabolism of nanoagents loaded with various therapeutic agents or imaging agents greatly hinder its clinical applications. Developing simple and effective nanoagents that integrate multiple therapeutic and imaging functions remain a huge challenge. Therefore, a novel strategy based on in situ hydrogen release is proposed in this work: aminoborane (AB) was loaded onto mesoporous polydopamine nanoparticles (MPDA NPs) as a prodrug for hydrogen production, and then, PEG was modified on the surface of nanoparticles (represented as AB@MPDA-PEG). MPDA NPs not only act as photothermal agents (PTA) with high photothermal conversion efficiency (808 nm, η = 38.72%) but also as the carriers of AB accumulated in the tumor through enhanced permeability and retention (EPR) effect. H 2 gas generated by AB in the weak acid conditions of the tumor microenvironment (TME) not only was used to treat tumors via a combination of hydrogen and photothermal therapies but also serves as a US and CT contrast agent, providing accurate guidance for tumor treatment. Finally, in vivo and in vitro investigation suggest that the designed multifunctional nanosystem not only showed excellent properties such as high hydrogen-loading capacity, long-lasting sustained hydrogen release ability and excellent biocompatibility but also achieve selective PTT/hydrogen therapies and US/CT bimodal imaging functions, which can effectively guide antitumor therapies. The proposed hydrogen gas-based strategy for combination therapies and bimodal imaging integration holds promise as an efficient and safe tumor treatment for future clinical translation.

Aims/hypothesis: ZBED6 (zinc finger, BED-type containing 6) is known to regulate muscle mass by suppression of Igf2 gene transcription. In insulin-producing cell lines, ZBED6 maintains proliferative capacity at the expense of differentiation and beta cell function. The aim was to study the impact of Zbed6 knockout on beta cell function and glucose tolerance in C57BL/6 mice., Methods: Beta cell area and proliferation were determined in Zbed6 knockout mice using immunohistochemical analysis. Muscle and fat distribution were assessed using micro-computed tomography. Islet gene expression was assessed by RNA sequencing. Effects of a high-fat diet were analysed by glucose tolerance and insulin tolerance tests. ZBED6 was overexpressed in EndoC-βH1 cells and human islet cells using an adenoviral vector. Beta cell cell-cycle analysis, insulin release and mitochondrial function were studied in vitro using propidium iodide staining and flow cytometry, ELISA, the Seahorse technique, and the fluorescent probes JC-1 and MitoSox., Results: Islets from Zbed6 knockout mice showed lowered expression of the cell cycle gene Pttg1, decreased beta cell proliferation and decreased beta cell area, which occurred independently from ZBED6 effects on Igf2 gene expression. Zbed6 knockout mice, but not wild-type mice, developed glucose intolerance when given a high-fat diet. The high-fat diet Zbed6 knockout islets displayed upregulated expression of oxidative phosphorylation genes and genes associated with beta cell differentiation. In vitro, ZBED6 overexpression resulted in increased EndoC-βH1 cell proliferation and a reduced glucose-stimulated insulin release in human islets. ZBED6 also reduced mitochondrial JC-1 J-aggregate formation, mitochondrial oxygen consumption rates (OCR) and mitochondrial reactive oxygen species (ROS) production, both at basal and palmitate + high glucose-stimulated conditions. ZBED6-induced inhibition of OCR was not rescued by IGF2 addition. ZBED6 reduced levels of the mitochondrial regulator PPAR-γ related coactivator 1 protein (PRC) and bound its promoter/enhancer region. Knockdown of PRC resulted in a lowered OCR., Conclusions/interpretation: It is concluded that ZBED6 is required for normal beta cell replication and also limits excessive beta cell mitochondrial activation in response to an increased functional demand. ZBED6 may act, at least in part, by restricting PRC-mediated mitochondrial activation/ROS production, which may lead to protection against beta cell dysfunction and glucose intolerance in vivo., (© 2021. The Author(s).)