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Yuxiang Deng,1,* Jianhong Peng,1,* Yujie Zhao,1 Qiaoqi Sui,1 Ruixia Zhao,2 Zhenhai Lu,1 Miaozhen Qiu,3 Junzhong Lin,1 Zhizhong Pan1 1Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Public Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: Recent studies have suggested that the lymph node ratio (LNR) is a prognostic indicator for various malignancies. However, LNR has not been evaluated in colorectal liver-only metastasis (CRLM). This study aimed to investigate the prognostic value of LNR in patients with CRLM after curative resection. Patients and methods: We retrospectively investigated the clinicopathologic features of 154 CRLM patients who underwent curative resection between 2005 and 2015. We classified patients into low and high groups based on their LNR by using the X-tile software. Survival curves were plotted through Kaplan–Meier method and compared by log-rank test. Cox proportional hazards analysis was performed to identify the factors associated with recurrence-free survival (RFS) and overall survival (OS). Results: The patients were divided into two groups in which 124 patients were identified as LNR ≤0.33 and 30 patients as LNR >0.33. Compared to low LNR, high LNR was significantly associated with poor 3-year RFS (47.2% vs 16.7%, P=0.001) and OS (72.8% vs 45.3%, P=0.003) rates. Multivariate analysis indicated that the LNR was an independent predictor for 3-year RFS (hazard ratio, 2.124; 95% CI, 1.339–3.368; P=0.001) and OS (HR, 2.287; 95% CI, 1.282–4.079; P=0.005). However, the node (N) stage and lymph node distribution were not significantly associated with the 3-year RFS (P=0.071, P=0.226) or OS (P=0.452, P=0.791) in patients with CRLM. Conclusion: This study demonstrated that LNR was an independent predictor for 3-year RFS and OS in patients with CRLM who underwent curative resection and that its prognostic value was superior to that of N stage and lymph node distribution. Keywords: colorectal cancer, liver metastases, lymph node ratio, N stage, prognosis

Patients taking atypical antipsychotics (AAPs), especially clozapine, are often associated with hyperglycaemia. Here, clozapine served as a representative agent for investigating how AAPs induce hyperglycaemia. In normal mice and mice fed a high fat diet (HFD), clozapine impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS) following intraperitoneal glucose administration and increased plasma 5-HT levels. Intraperitoneal 5-HT administration also impaired glucose tolerance and GSIS in mice. In INS-1 cells, high 5-HT levels impaired GSIS, which was attenuated by the 5-HTR 3 antagonist tropisetron or by silencing 5-HTR 3a . The 5-HTR 2a agonist TCB2 attenuated clozapine-induced GSIS impairment. Silencing 5-HTR 2a or the 5-HTR 2a antagonist ketanserin impaired GSIS. In mice, 5-HT administration impaired GSIS, which was attenuated by tropisetron but aggravated by clozapine. Clozapine increased plasma [ 2 H]5-HT exposure following intravenous administration to mice. In HEK293-OCT1 cells, clozapine inhibited [ 2 H]5-HT and MPP + uptake. Clozapine or OCT1 silencing impaired 5-HT metabolism in mouse primary hepatocytes, demonstrating that clozapine increased plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Liver-specific silencing of OCT1 increased plasma [ 2 H]5-HT exposure and 5-HT levels and impaired GSIS and glucose tolerance in mice. In conclusion, clozapine impaired GSIS and glucose tolerance by increasing plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Increased 5-HT impaired GSIS by activating islet 5-HTR 3a . The antagonistic effect of clozapine on islet 5-HTR 2a also contributed to GSIS impairment. The finding that clozapine-induced GSIS impairment was attributed to increased 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake may partly explain hyperglycaemia caused by other AAPs., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Thyroid hormone resistance syndrome complicated with papillary thyroid cancer is clinically rare.Madelung's disease is a rare disorder of lipid metabolism.We analyzed the clinical data of a case of thyroid hormone resistance syndrome complicated with papillary thyroid carcinoma and Madelung's disease,performed whole-exon sequencing for the patient's peripheral blood samples,and retrospectively analyzed the relevant literature.This review is expected to provide experience for clinical diagnosis and treatment.

The Self-Attention Mechanism (SAM) excels at distilling important information from the interior of data to improve the computational efficiency of models. Nevertheless, many Quantum Machine Learning (QML) models lack the ability to distinguish the intrinsic connections of information like SAM, which limits their effectiveness on massive high-dimensional quantum data. To tackle the above issue, a Quantum Kernel Self-Attention Mechanism (QKSAM) is introduced to combine the data representation merit of Quantum Kernel Methods (QKM) with the efficient information extraction capability of SAM. Further, a Quantum Kernel Self-Attention Network (QKSAN) framework is proposed based on QKSAM, which ingeniously incorporates the Deferred Measurement Principle (DMP) and conditional measurement techniques to release half of quantum resources by mid-circuit measurement, thereby bolstering both feasibility and adaptability. Simultaneously, the Quantum Kernel Self-Attention Score (QKSAS) with an exponentially large characterization space is spawned to accommodate more information and determine the measurement conditions. Eventually, four QKSAN sub-models are deployed on PennyLane and IBM Qiskit platforms to perform binary classification on MNIST and Fashion MNIST, where the QKSAS tests and correlation assessments between noise immunity and learning ability are executed on the best-performing sub-model. The paramount experimental finding is that the QKSAN subclasses possess the potential learning advantage of acquiring impressive accuracies exceeding 98.05% with far fewer parameters than classical machine learning models. Predictably, QKSAN lays the foundation for future quantum computers to perform machine learning on massive amounts of data while driving advances in areas such as quantum computer vision.

Anthropogenic hydrological regulation is profoundly altering the structure and function of wetland ecosystems. Due to the scarcity of long-term monitoring records, the responses of wetland ecosystems to anthropogenic hydrological regulation remain unclear. We reconstructed past ecohydrological changes in Dajiuhu Wetland during the last 40 years and explored the driving forces, based on multiproxy records of a 44-cm-length sediment core collected from Wuhaohu Lake of Dajiuhu Wetland in Shennongjia, Hubei. The results showed that the diatom community in Wuhaohu Lake had experienced three major stages, including the dominance of benthic diatoms between 1980 and 2008, the rapid increase in planktonic diatoms between 2008 and 2016, and the dominance of small-sized fragilarioid species after 2016. Results of redundancy analysis showed that change in diatom assemblage was significantly correlated with total organic carbon, total nitrogen and the ratios of Mn to Fe. Diatom floral changes after 2008 indicated the shift of Wuhaohu Lake from an early organic-rich peatland to a shallow lake, mainly in response to an increase in water table driven by damming. From 2016, the increases in benthic and epiphytic diatoms responded to the expansion of aquatic plants and improved light penetration after the relocation of local population. Sedimentary diatom records revealed the process of environmental changes, and hence would provide a scientific basis for the environmental protection of wetlands.

Network Meta-analysis and multi-criteria decision analysis(MCDA) model were performed to evaluate the benefit-risk of Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules in the adjuvant treatment of primary liver cancer(PLC). The randomized controlled trial(RCT) of Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules in treating PLC were retrieved from CNKI, Wanfang, VIP, Web of Science, PubMed, and Cochrane Library. R 4.2 was employed to conduct a network Meta-analysis, on the basis of which the effect values of the three medicines were obtained by indirect comparison. MCDA was performed to establish the value tree based on the benefit-risk indexes. Hiview 3.2 was used to calculate the benefit values, risk values, and benefit-risk values of the three medicines in treating PLC, and a sensitivity analysis was carried out to evaluate the robustness of the results. Oracle Crystal Ball 11.1 was employed to optimize the evaluation results by Monte Carlo simulation. A total of 39 RCTs were included. The results showed that Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules combined with transcatheter arterial chemoembolization(TACE) had the benefit values of 45, 51 and 45, the risk values of 59, 47, and 41, and the benefit-risk values of 52, 49, and 43, respectively. The benefit-risk differences and [95%CI] of Compound Cantharis Capsules vs Huisheng Oral Solution, Compound Cantharis Capsules vs Jinlong Capsules, and Huisheng Oral Solution vs Jinlong Capsules were 3.00[-13.09, 21.82], 9.00[-4.39, 24.62], and 6.00[-8.84, 20.28], respectively. Based on the results of MCDA, Huisheng Oral Solution, Jinlong Capsules, and Compound Cantharis Capsules combined with TACE had the greatest benefit, the greatest risk, and the best overall benefit, respectively. Considering the efficacy and safety, the priority of the three oral Chinese patent medicines combined with TACE for treating PLC followed the trend of Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules.

Objective: To evaluate the benefit-risk of 3 commonly used Chinese medicine injections, Aidi Injection (ADI), Cinobufagin Injection (CINI) and Compound Kushen Injection (CKI), in the treatment of primary liver cancer (PLC), so as to provide a reference for clinical decision-making., Methods: Randomized controlled trials (RCTs) of ADI, CINI and CKI in the treatment of PLC published in the databases of China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal Database, SinoMed, PubMed, Cochrane Library, and Web of Science were retrieved from January 2020 to October 2022. The data of benefit and risk indicators were combined to obtain the effect value. The multi-criteria decision analysis (MCDA) model was applied to build the decision tree. The benefit value, risk value and benefit risk value of the 3 injections in PLC treatment were calculated. Monte Carlo simulation was carried out to calculate the 95% confidence interval and probability of differences among the 3 injections, so as to optimize the evaluation results., Results: A total of 71 RCTs were included. The benefit values of ADI, CINI and CKI combined with transcatheter arterial chemoembolization (TACE) were 42, 38 and 36, respectively. The risk values were 42, 25 and 37, respectively. The benefit risk values were 42, 31 and 37, respectively. The benefit risk differences of ADI vs. CINI, ADI vs. CKI, and CKI vs. CINI were 11 (-0.86, 17.75), 5 (-5.01, 11.09), and 6 (-1.87, 12.63), respectively. The probability that ADI superior to CINI, ADI superior to CKI, and CKI superior to CINI was 96.26%, 77.27%, and 92.62%, respectively., Conclusion: Based on the results of MCDA model, CINI combined with TACE has the greatest risk in the treatment of the PLC. Considering the efficacy and safety, the possible priority of the 3 Chinese medicine injections combined with TACE in the treatment of PLC is ADI, CKI and CINI., (© 2023. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Lead halide perovskite nanocrystals (PNCs) have attracted intense attention due to their excellent optoelectronic properties. In this work, a series of water-stable CsPb(Br/I) 3 PNCs fluorescent probes were prepared using an anion exchange method. It was found that the PNCs probes could be used to detect ascorbic acid (AA) in water, and interestingly, the FL spectra of the PNCs probes can be adjusted by controlling the concentration of KI in anion exchange to improve the detection selectivity of AA. The high sensitivity and selectivity make CsPb(Br/I) 3 PNCs an ideal material for AA sensing. The concentration of AA can be linearly measured in the range from 0.01 to 50 μ M, with a detection limit of 4.2 nM. The reason for the enhanced FL of CsPb(Br/I) 3 PNCs was studied, and it is considered that AA causes the aggregation of CsPb(Br/I) 3 PNCs. This strategy of improving the selectivity of the probe to the substrate by adjusting the spectrum will significantly expand the application of PNCs in the field of analysis and detection., (© 2024 IOP Publishing Ltd.)

Appropriate Ca 2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca 2+ signal, serves significant roles in physiological function of pancreatic β cells. To maintaining ER homeostasis, Ca 2+ movement across the ER membrane is always accompanied by a simultaneous K + flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca 2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic β-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 β-cell-specific knockout (βKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca 2+ store was overloaded in islets of βKO mice, which contributed to ER stress and ER stress-induced apoptosis in β cells. Next, we verified that ethanol treatment induced increases in ER Ca 2+ store and apoptosis in pancreatic β cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in βKO mice, restored ER Ca 2+ overload and attenuated ER stress in β cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca 2+ stores and protect β cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes., (© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Objective: Genome-scale CRISPR-Cas9 knockout coupled with single-cell RNA sequencing (scRNA-seq) has been used to identify function-related genes. However, this method may knock out too many genes, leading to low efficiency in finding genes of interest. Insulin secretion is controlled by several electrophysiological events, including fluxes of K ATP depolarization and K + repolarization. It is well known that glucose stimulates insulin secretion from pancreatic β-cells, mainly via the K ATP depolarization channel, but whether other nutrients directly regulate the repolarization K + channel to promote insulin secretion is unknown., Methods: We used a system involving CRISPR-Cas9-mediated knockout of all 83 K + channels and scRNA-seq in a pancreatic β cell line to identify genes associated with insulin secretion., Results: The expression levels of insulin genes were significantly increased after all-K + channel knockout. Furthermore, Kcnb1 and Kcnh6 were the two most important repolarization K + channels for the increase in high-glucose-dependent insulin secretion that occurred upon application of specific inhibitors of the channels. Kcnh6 currents, but not Kcnb1 currents, were reduced by one of the amino acids, lysine, in both transfected cells, primary cells and mice with β-cell-specific deletion of Kcnh6., Conclusions: Our function-related CRISPR screen with scRNA-seq identifies Kcnh6 as a lysine-specific channel., Competing Interests: Declaration of competing interest All authors declared that no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Several barriers exist in Alberta, Canada to providing accurate and accessible diagnoses for patients presenting with acute knee injuries and chronic knee problems. In efforts to improve quality of care for these patients, an evidence-informed clinical decision-making tool was developed. Forty-five expert panelists were purposively chosen to represent stakeholder groups, various expertise, and each of Alberta Health Services' 5 geographical health regions. A systematic rapid review and modified Delphi approach were executed with the intention of developing standardized clinical decision-making processes for acute knee injuries, atraumatic/overuse conditions, knee arthritis, and degenerative meniscus. Standardized criteria for screening, history-taking, physical examination, diagnostic imaging, timelines, and treatment were developed. This tool standardizes and optimizes assessment and diagnosis of acute knee injuries and chronic knee problems in Alberta. This project was a highly collaborative, province-wide effort led by Alberta Health Services' Bone and Joint Health Strategic Clinical Network (BJH SCN) and the Alberta Bone and Joint Health Institute (ABJHI)., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Herein, a CuNiFe LDHs/BiO 2- x composite photocatalyst was successfully synthesized using a hydrothermal method and applied to activate peroxymonosulfate to degrade ciprofloxacin under visible light irradiation. Owing to the synergistic effect of photocatalysis and PMS activation, a high removal efficiency of CIP up to 88.3% was achieved. The prepared photocatalysts were characterized using XRD, FT-IR, SEM, XPS, UV-Vis DRS, and other methods. The optimal loading amount of CuNiFe LDHs was determined, and the effects of PMS dosage, initial pH value, and inorganic anions (Cl - , CO 3 2- , and NO 3 - ) on the degradation were investigated. Electron paramagnetic resonance and free radical trapping experiments demonstrated that·OH and h + were the main active species for degrading CIP, and the possible degradation mechanism of the system was proposed.

The microbial community of a sequencing batch reactor operated under feast and famine conditions for production of polyhydroxyalkanoates (PHAs) was characterized through high-throughput sequencing and metagenomic analysis. The fermented food waste and chemically-enhanced primary sludge was fed in this bioreactor. After acclimation, the PHA yield achieved as high as 0.60-0.69 g COD PHA /g COD S . The complete changes of microbial community structure were found during shifts of feedstock. A synthesis of SCL/MCL-PHAs pathway was established for PHA-producing bioreactor in this mixed-culture system. The structure-performance relationship of PHA-producing microbial community and feedstock composition was investigated. The results showed that microbial community tends to be decentralized and prefer team work for PHA synthesis to consume the multiple substrates and digest inevitable non-VFA contents in fermented liquor. This study also discovered unreported potential PHA producers (e.g., genera Tabrizicola, Nannocystis, Ga0077539, Ga0077559, JOSHI-001, SNC69-320 and UBA2334) subsisting on municipal organic wastes and expands the current knowledge about mixed-culture system that the PHA synthesis pathway is widely existed in activated sludge., 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 © 2023 Elsevier Ltd. All rights reserved.)

Objective: To study the effects of cadmium on autophagy in germ cells (GC-2 spd cells) through Ca2+ and IRE1 pathway., Methods: The viability of GC-2 spd cells was determined using a CCK-8 assay to establish the concentration of cadmium treating . MDC staining was employed to assess autophagosome formation. Laser confocal microscopy and flow cytometry were utilized to measure cytoplasmic and endoplasmic reticulum (ER) Ca2+ levels. Western blot was conducted to evaluate the expression levels of proteins associated with the IRE1 signaling pathway and autophagy., Results: As the concentration of cadmium increased, cell viability gradually decreased. The concentrations of cadmium were determined to be 2.5, 5, and 10 μmol/L. Compared with the control group, the IOD values of MDC fluorescence intensity within the cadmium group were all elevated (P<0.05), accompanied by elevated ratios of autophagy markers LC3-II/LC3-I and up-regulation of Beclin-1 protein expression (P<0.05). Cytoplasm Ca2+ levels gradually increased, while ER Ca2+ levels decreased (P<0.05). The expression of IP3R protein, the ER Ca2+ release pathway, was up-regulated (P<0.05). Additionally, the expressions of IRE1, XBP1s, CHOP, and GRP78 were up-regulated in the cadmium group (P<0.05)., Conclusion: Cadmium exposure can induce dysregulation of calcium homeostasis in GC-2spd cells, activates the ER stress-induced IRE1 signaling pathway, and ultimately induces the occurrence of autophagy in GC-2spd cells.

The current study explored the slide-lengthening potentials of double and triple hemisections and the biomechanical effects of different inter-hemisection distances. Forty-eight porcine flexor digitorum profundus tendons were divided into double- and triple-hemisection groups (Groups A and B) and a control group (Group C). Group A was divided into Group A1 (distance between hemisections were the same as Group B) and Group A2 (distance between hemisections corresponded to the greatest distance between hemisections in Group B). Biomechanical evaluation, motion analysis, and finite element analysis (FEA) were performed. Failure load of intact tendon was significantly highest among groups. When the distance was 4 cm, the failure load of Group A increased significantly. When the distance between the hemisections was 0.5 or 1 cm, the failure load of Group B was significantly lower than Group A. Tendon elongation and failure load of Group B were significantly lower than those in Group A when the greatest distance between hemisections was the same. Consequently, Double hemisections had a similar lengthening ability to that of triple hemisections with the same distance, but better when the distances between extreme hemisections matched. However, the driving force for the initiation of lengthening may be greater., (© 2023. The Author(s).)

Graves' ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves' disease (GD), can lead to a significant decline in the quality of life in patients. Exosomes, which contain proteins, lipids and DNA, play important roles in the pathological processes of various diseases. However, their roles in Graves' ophthalmopathy are still unclear. We aimed to isolate exosomes and analyze the different exosomal proteins. Tear fluids were collected from twenty-four GO patients, twenty-four GD patients and sixteen control subjects. The numbers of tear exosomes were assayed using nanoparticle tracking analysis. A Luminex 200 kit and ELISA kit were used to confirm the different cytokine concentrations in serum. Extraocular muscle from GO patients and controls was extracted, and western blotting was used to assay the levels of Caspase-3 and complement C4A. Our study demonstrated that the number of tear exosomes differ from GD patients and control. The expression levels of cytokines, including IL-1 and IL-18, were significantly increased in the tear exosomes and serum from GO patients compared with GD patients and controls. The levels of the exosomal proteins Caspase-3, complement C4A and APOA-IV were significantly increased in GO patients compared to GD patients and controls. Orbital fibroblasts from GO patients showed significantly higher levels of Caspase-3 and complement C4A than those from controls. The levels of serum APOA-IV in GO patients were significantly higher than those in GD patients and controls. Specific proteins showed elevated expression in tear exosomes from GO patients, indicating that they may play important roles in GO pathogenesis., 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 Shi, Zhao, Xin, Hou, Wang, Xie, Li and Yang.)

Mutations in KCNH6 has been proved to cause hypoinsulinemia and diabetes in human and mice. Cisapride is a stomach-intestinal motility drug used to treat gastrointestinal dysfunction. Cisapride has been reported to be a potential inhibitor of the KCNH family, but it remained unclear whether cisapride inhibited KCNH6. Here, we discovered the role of cisapride on glucose metabolism, focusing on the KCNH6 potassium channel protein. Cisapride reduced blood glucose level and increased serum insulin secretion in wild-type (WT) mice fed standard normal chow/a high-fat diet or in db/db mice, especially when combined with tolbutamide. This effect was much stronger after 4 weeks of intraperitoneal injection. Whole-cell patch-clamp showed that cisapride inhibited KCNH6 currents in transfected HEK293 cells in a concentration-dependent manner. Cisapride induced an increased insulin secretion through the disruption of intracellular calcium homeostasis in a rat pancreatic β-cell line, INS-1E. Further experiments revealed that cisapride did not decrease blood glucose or increase serum insulin in KCNH6 β-cell knockout (Kcnh6-β-KO) mice when compared with WT mice. Cisapride also ameliorated glucose-stimulated insulin secretion (GSIS) in response to high glucose in WT but not Kcnh6-β-KO mice. Thus, our data reveal a novel way for the effect of KCNH6 in cisapride-induced hypoglycemia., 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 Lu, Shi, Yuan, Xie, Zhao, Zhu and Yang.)

KCNH6 has been proven to affect glucose metabolism and insulin secretion both in humans and mice. Further study revealed that Kcnh6 knockout (KO) mice showed impaired glucose tolerance. However, the precise function of KCNH6 in the liver remains unknown. Mitochondria have been suggested to maintain intracellular Ca 2+ homeostasis; ROS generation and defective mitochondria can cause glucose metabolism disorders, including type 2 diabetes (T2D). Here, we found that Kcnh6 attenuated glucose metabolism disorders by decreasing PEPCK and G6pase abundance and induced Glut2 and IRS2 expression. Overexpression of Kcnh6 increased hepatic glucose uptake and glycogen synthesis. Kcnh6 attenuated intracellular and mitochondrial calcium levels in primary hepatocytes and reduced intracellular ROS and mitochondrial superoxide production. Kcnh6 suppressed oxidative stress by inhibiting mitochondrial pathway activation and NADPH oxidase expression. Experiments demonstrated that Kcnh6 expression improved hepatic glucose metabolism disorder through the c-Jun N-terminal kinase and p38 MAPK signaling pathways. These results were confirmed by experiments evaluating the extent to which forced Kcnh6 expression rescued metabolic disorder in KO mice. In conclusion, KCNH6 enhanced hepatic glucose metabolism by regulating mitochondrial Ca 2+ levels and inhibiting oxidative stress. As liver glucose metabolism is key to T2D, understanding KCNH6 functions may provide new insights into the causes of diabetes., Competing Interests: The authors declare that they have no duality of interest with the contents of this article., (Copyright © 2022 Ying-Chao Zhang et al.)

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence of variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered that the S protein contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 and CS-2). Both sites are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed that CTSL cleavage promoted S to adopt receptor-binding domain (RBD) "up" activated conformations, facilitating receptor-binding and membrane fusion. We confirmed that CTSL cleavage is essential during infection of all emerged SARS-CoV-2 variants (including the recently emerged Omicron variant) by pseudovirus (PsV) infection experiment. Furthermore, we found CTSL-specific inhibitors not only blocked infection of PsV/live virus in cells but also reduced live virus infection of ex vivo lung tissues of both human donors and human ACE2-transgenic mice. Finally, we showed that two CTSL-specific inhibitors exhibited excellent In vivo effects to prevent live virus infection in human ACE2-transgenic mice. Our work demonstrated that inhibition of CTSL cleavage of SARS-CoV-2 S protein is a promising approach for the development of future mutation-resistant therapy., (© 2022. The Author(s).)

Ethnic Pharmacological Relevance: Plant materials are used as complementary and alternative therapies all over the world for the treatment of various diseases. Ulcerative colitis (UC), a chronic nonspecific inflammatory bowel disease listed as one of the modern refractory diseases by the World Health Organization, has a long course, is challenging to cure, and is prone to cause cancer. Recent years have witnessed a growing trend of applying traditional Chinese medicine (TCM) to UC., Aim of This Review: This review presents an overview of the pathogenesis of UC and reports the therapeutic effect of TCM on UC (including TCM prescriptions, single TCM, and treatments using TCM ingredients) to provide a theoretical basis for the use of TCM in treating UC., Methods: We performed a collection and collation of relevant scientific articles from different scientific databases regarding TCM and its usefulness in treating UC. In this paper, the therapeutic effect of TCM is summarized and analyzed according to the existing experimental and clinical research., Results: There are positive signs that TCM primarily regulates inflammatory cytokines, intestinal flora, and the immune system, and also protects the intestinal mucosa. Hence, it can play a role in treating UC., Conclusion: TCM has a definite curative effect in the treatment of UC. It can alleviate and treat UC in a variety of ways. We should take syndrome differentiation and treatment differentiation as the basis. With the help of modern medicine, TCM's clinical curative effects can be enhanced for the treatment of UC., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Computational medicine is an emerging discipline that uses computer models and complex software to simulate the development and treatment of diseases. Advances in computer hardware and software technology, especially the development of algorithms and graphics processing units (GPUs), have led to the broader application of computers in the medical field. Computer vision based on mathematical biological modelling will revolutionize clinical research and diagnosis, and promote the innovative development of Chinese medicine, some biological models have begun to play a practical role in various types of research. This paper introduces the concepts and characteristics of computational medicine and then reviews the developmental history of the field, including Digital Human in Chinese medicine. Additionally, this study introduces research progress in computational medicine around the world, lists some specific clinical applications of computational medicine, discusses the key problems and limitations of the research and the development and application of computational medicine, and ultimately looks forward to the developmental prospects, especially in the field of computational Chinese medicine., (© 2021. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Nano drug delivery systems are a research hotspot in the field of tumor therapy. In this work, molybdenum disulfide (MoS 2 ) nanosheets were selected as the base material and a natural red blood cell membrane (RBC membrane) was camouflaged on the nanosheets to enhance their dispersibility and tumor targeting profile. The camouflaged molybdenum disulfide nanocomposites (MoS 2 -RBC) were successfully prepared by incubation. This nanomaterial has good stability and biocompatibility with a good immune evasion ability. MoS 2 has a large specific surface area and unique layered structure, which provides favorable conditions for the loading of anticancer drugs. Adriamycin hydrochloride (DOX) was used as the model drug and the drug loading capacity was 98.98%. In the tumor microenvironment, the red cell membrane modified MoS 2 drug delivery system (MoS 2 -RBC-DOX) showed obvious pH-dependent release behavior. In addition, the excellent photothermal properties of MoS 2 are conducive to the release of drugs, thus improving the efficacy. According to the cell tests, MoS 2 -RBC had no cytotoxicity toward tumor cells, while DOX loading induced dose-dependent cytotoxicity. Furthermore, MoS 2 -RBC has a favorable photothermal effect, and chemotherapy combined with photothermal therapy is more effective than any single therapy. In vivo fluorescence imaging and in vivo photothermal imaging experiments confirmed the promoted accumulation of carrier materials at the tumor site after RBC membrane modification. Finally, in vivo antitumor studies showed that photothermal/chemotherapy combined with MoS 2 -RBC could completely inhibit tumor growth, and the body weights of mice fluctuated within the normal range without significant decrease. In summary, this MoS 2 -RBC drug delivery system provides a safe, rapid and effective option for future treatment of breast cancer.

Background: Graves' orbitopathy (GO) is an autoimmune disease with mechanical impairment of orbital muscles and lacrimal gland dysfunction. The frequently used methods of assessing GO activity include Clinical Activity Score (CAS), CT, and MRI. These approaches are mainly associated with orbital muscles; however, there are not many studies that focus on the lacrimal gland inflammation of GO patients., Objective: The aim of this study is to assess the usefulness of 99mTc-DTPA single-photon emission (SPE) CT/CT in evaluating the lacrimal gland inflammation in GO, as compared with other methods., Methods: A retrospective analysis of 48 patients with active GO compared with 33 controls was conducted. All subjects underwent clinical-endocrinological analyses, CAS evaluation, CT scans, and SPECT/CT examination. Lacrimal gland dimensions were determined and analyzed., Results: The lacrimal glands in patients with GO were significantly larger in all measured dimensions (P < 0.001) on CT scans relative to those in controls. Increased lacrimal gland diethylene triamine pentaacetic acid (DTPA) uptake ratios (P < 0.001) were displayed in active GO patients compared to controls and were also correlated with thyrotropin receptor antibody levels. The cut-off value for discriminating active and inactive disease was calculated to be 1.735, with specificity of 82.6% and sensitivity of 74.2%. SPECT/CT uptake ratios and CAS values were positively correlated in all GO patients. SPECT/CT uptake ratios were also positively correlated with CT measurements including lacrimal gland volume and coronal width in GO patients., Conclusions: These data indicated that lacrimal gland SPECT/CT images can serve as a good tool for assessing the inflammation and disease activity of GO.

Low serum bicarbonate is closely related to type 2 diabetes mellitus. However, the precise role of bicarbonate on glucose homeostasis and insulin secretion remains unknown. In this study, we investigated the effects of bicarbonate concentration on pancreatic β-cells. It was observed that the high bicarbonate concentration of the cell culture medium significantly increased the glucose-induced insulin secretion (GSIS) levels in mouse islets, MIN6, and the INS-1E β cells. MIN6 cells presented an impaired GSIS; the cells produced a lower bicarbonate concentration when co-cultured with Capan-1 than when with CFPAC-1. NBCe1, a major bicarbonate transporter was observed to block the increasing insulin secretions, which were promoted by a high concentration of bicarbonate. In addition, higher extracellular bicarbonate concentration significantly increased the intracellular cAMP level, pHi, and calcium concentration with a 16.7 mM of glucose stimulation. Further study demonstrated that a low concentration of extracellular bicarbonate significantly impaired the functioning of pancreatic β cells by reducing coupling Ca 2+ influx, whose process may be modulated by NBCe1. Taken together, our results conclude that bicarbonate may serve as a novel target in diabetes prevention-related research., 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.)

Rich experience of clinical diagnosis and treatment has been accumulated in the developmental history of Chinese medicine, and the efficacy has been increasingly accepted by the public. However, the evaluation of clinical efficacy is currently based more on scientific evidence instead of merely the changes of patient symptoms. In Chinese medicine, the changes of major disease indicators, patient symptoms, and pathogenesis are the major criteria for the evaluation of clinical efficacy. The lack of well-accepted and uniform criteria and the uncertainty of subjective evaluation limit the development of clinical Chinese medicine. Evidence-based medicine combines clinical skills with the current best evidence. Narrative medicine, utilizing people's narratives in clinical practice, emphasizes patient feelings, willingness, and value orientation. The introduction of both evidence-based medicine and narrative medicine into the evaluation of clinical efficacy refers to the construction of the clinical efficacy evaluation system in a paradigm of participatory diagnosis and treatment. It can fully reflect the characteristics of Chinese medicine, respect the values of patients, and achieve universal clinical evidence. Therefore, it helps to improve the diagnosis and treatment, the relationship between doctors and patients, patients' life quality and decision-making awareness, and finally the new evaluation model of clinical efficacy of Chinese medicine.

Background: The prevalence of Fabry disease (FD) in Chinese patients with hypertrophic cardiomyopathy (HCM) is unclear. We aimed to evaluate the prevalence, clinical characteristics, and outcomes of FD in Chinese patients with HCM., Methods: Of 217 patients with HCM, FD probands were screened by next-generation sequencing at Fuwai Hospital. Medical data from α-galactosidase A activity, electrocardiography, echocardiography, coronary angiography, cardiac magnetic resonance, pathological examination, and follow up was analyzed., Results: Two FD probands were observed (0.93% of patients with HCM), both of which were diagnosed with symptomatic obstructive HCM at 49 years of age. One proband had a GLA mutation (c.887T>C [p.M296T]) with a late-onset cardiac variant, which was characterized by dual ventricular hypertrophy and conduction disease with a permanent pacemaker. The other patient had a GLA mutation (c.758T>C [p.I253T]) with a classic phenotype and dual ventricular hypertrophy, atrioventricular block, renal failure, and recurrent cerebral infarction. Both probands had late gadolinium enhancement mainly in the basal segment of the inferolateral wall. Follow up revealed no exertional symptoms or outflow obstruction after surgical septal myectomy in the two probands, and stable renal function was observed after 6 months of migalastat therapy in the later one. A family study revealed six female carriers and three sudden cardiac deaths., Conclusions: FD is not uncommon in Chinese patients with HCM. Multiple organic involvement, dual ventricular hypertrophy, and conduction disease provide clinical clues for suspected FD, and early genetic screening is necessary. Surgical septal myectomy and migalastat improve the long-term prognosis of patients with FD., (Copyright © 2021. Published by Elsevier Inc.)

Background and Purpose: Motoric cognitive risk syndrome (MCR) is characterized by slow walking speed and subjective memory complaints (SMCs). This study investigated the prevalence and potential risk factors of MCR and its association with falls in Chinese community-dwelling older adults., Methods: The analysis was based on data from the Rugao Longevity and Aging Study (RuLAS). MCR was defined as the presence of both SMCs and slow walking speed in participants free of major neurocognitive disorders. SMCs were determined according to a positive answer to the question 'Do you feel you have more problems with memory than most?' in the 15-item Geriatric Depression Scale. Slow walking speed was defined as one standard deviation or more below the mean value for patients' age and sex. Data on falls were derived from a standardized questionnaire., Results: The prevalence of SMCs, slow walking speed and MCR in the RuLAS cohort (N = 1592) was 51.9%, 15.6% and 8.3%, respectively. After adjusting for other covariates, an occupation of farming (odds ratio [OR] 2.358, 95% confidence interval [CI] 1.007-5.521, p = 0.048), history of cerebrovascular disease (OR 2.215, 95% CI 1.032-4.752, p = 0.041) and hospitalization (OR 2.008, 95% CI 1.120-3.602, p = 0.019) were risk factors for MCR. Binary logistic regression analysis indicated that the risk of falls was increased by MCR (OR 1.547, 95% CI 1.009-2.371), SMC (OR 1.308, 95% CI 1.003-1.707) and slow walking speed (OR 1.442, 95% CI 1.030-2.017)., Conclusions: Early identification of potential risk factors of MCR can prevent the occurrence of adverse health events such as falls in the elderly., (© 2021 European Academy of Neurology.)

The present study aimed to explore the correlation between agronomic traits and quality indexes of Dendrobium nobile and its application value in agricultural breeding. The cultivated strains of D. nobile in Hejiang-Chishui producing areas were extensively collected,and the main agronomic traits and quality indexes were measured. The agronomic traits with significant correlation with quality indexes were screened out by the correlation analysis,and then the parental lines and self-bred F&#95;1 generation plants were furtherverified. Among 96 lines of D. nobile,the content of soluble polysaccharides showed a significant negative correlation with dendrobine( P &lt; 0. 01),and no significant correlation with agronomic traits in stems and leaves. The content of dendrobine exhibited a significant positive correlation with the stem width-thickness ratio( at the largest cross section; P &lt; 0. 01),and no significant correlation with other agronomic traits. Regression analysis further verified the positive correlation between dendrobine content and stem width-thickness ratio( R2&gt; 0. 9). Two lines,JC-10 and JC-35,with significant differences in stem width-thickness ratio were screened out( P &lt;0. 05). The corresponding F1 generation plants by self-pollination both showed that the dendrobine content was higher with greater stem width-thickness ratio( P &lt; 0. 01). The experimental results suggested that within a certain range,the dendrobine content was higher in D. nobile with flatter stem. Therefore,in the breeding of D. nobile,this specific trait could be used for screening plants with high content of quality indexes such as dendrobine.

A glutathione stabilized Au nanoclusters (GSH-Au NCs) was synthesized here and used to selective detection of cobalt ion. The as-prepared GSH-Au NCs had strong green light emission around 500 nm, and the features of the NCs have been systematically characterized by UV-vis absorption, X-ray photoelectronic spectroscopic, Fourier transform infrared spectroscopy and transmission electron microscope characterization. The interactions between the GSH-Au NCs and metal ions was studied, and the results indicated that the fluorescence of the GSH-Au NCs could be quenched in the presence of Co 2+ ion at pH of 6.0. The quenching ratio was linear with the concentration of Co 2+ ions, and the calibration curve was I 0 /I = 0.1187c co  + 0.6085 in the Co 2+ concentration ranges from 2.0 to 50.0 μM with correlation coefficient (R 2 ) of 0.9950 and the limit of detection (LOD, 3σ) of 0.124 μM. In addition, we collected environmental water samples to test the reliability of the method and demonstrated this method is simple, rapid, and selective., 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 B.V. All rights reserved.)

Under adverse conditions, such as sustained or chronic hyperglycemia or hyperlipidemia, ROS (reactive oxygen species) or/and ER-stress (endoplasmic reticulum stress) will be induced in pancreatic β cells. ROS or ER-stress damages β-cells even leads to apoptosis. Previously we found ROS or ER-stress resulted in JNK activation in β cells and overexpressing NR4A1 in MIN6 cells reduced JNK activation via modulating cbl-b expression and subsequent degrading the upstream JNK kinase (MKK4). To search other possible mechanisms, we found the mRNA level and protein level of MKP7 (a phosphatase for phospho-JNK) were dramatic reduced in pancreatic β cells in the islets from NR4A1 KO mice compared with that from wild type mice. To confirm what we found in animals, we applied pancreatic β cells (MIN6 cells) and found that the expression of MKP7 was increased in NR4A1-overexpression MIN6 cells. We further found that knocking down the expression of MKP7 increased the p-JNK level in pancreatic β cells upon treatment with TG or H 2 O 2 . After that, we figured out that NR4A1 did enhance the transactivation of the MKP7 promoter by physical association with two putative binding sites. In sum, NR4A1 attenuates JNK phosphorylation incurred by ER-stress or ROS partially via enhancing MKP7 expression, potentially decreases pancreatic β cell apoptosis induced by ROS or ER-stress. Our finding provides a clue for diabetes prevention.

Cysteine is widely used as a stabilizer for the preparation of fluorescent gold nanoclusters (Au NCs) with different fluorescence properties. Herein, by using cysteine as a stabilizer and controlling the synthesis conditions, a new non-fluorescent cysteine stabilized gold nanocluster (Cys-Au NCs) probe was prepared and a new strategy for "turning on" the fluorescence of the Cys-Au NCs was studied for rapid and selective detection of silver ions. In this strategy, the addition of silver ions to non-fluorescent Cys-Au NCs solution could quickly induce a visible fluorescence "turn on" phenomenon in 30 s. Further studies indicated that this fluorescence "turn on" phenomenon is specific for silver ions and the "turn on" fluorescence intensity has a linear relationship with the amount of silver ions in the range from 3.0 to 30.0 μM. Therefore, the non-fluorescent Cys-Au NCs were applied to the detection of silver ions in environmental water samples and a limit of detection (LOD) of 0.26 μM was obtained. This research sheds light on new applications of Au NCs and proposes a simple, rapid, sensitive, and visual method for the detection of metal ions.

Network Meta-analysis was used to evaluate the efficacy and safety of different oral Chinese patent medicines combined with transcatheter arterial chemoembolization(TACE) in the treatment of primary liver cancer. Randomized controlled trials of oral Chinese patent medicines for primary liver cancer were retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library and EMbase databases from inception to May 2020. According to the Cochrane recommendation standard, the quality of the included articles was evaluated, and the data were analyzed by RevMan, R software and GeMTC software. A total of 10 kinds of oral Chinese patent medicines and 68 RCTs were included. Network Meta-analysis results showed that: as compared with TACE alone, 10 kinds of oral Chinese patent medicines combined with TACE showed advantages in effective rate, 1-year survival rate, 2-year survival rate, KPS score improvement rate and reduced adverse reaction incidence. In the pairwise comparison of oral Chinese patent medicines, the results showed that Cidan Capsules were superior to Jinlong Capsules and Xihuang Pills in 1-year survival rate. According to the probabi-lity ranking results: Shenyi Capsules and Ganfule were more obvious in improving the effective rate; Cidan Capsules and Shenyi Capsules were more effective in improving the 1-year survival rate; Pingxiao Capsules and Shenyi Capsules had better efficacy in improving 2-year survival rate; Huaier Granules and Shenyi Capsules had better efficacy in improving the quality of life; Huisheng Oral Liquid and Ganfule were more effective in reducing the incidence of adverse reactions(such as nausea, vomiting and leukocytosis). The current evidence showed that oral Chinese patent medicine combined with TACE was superior to TACE alone in efficacy and safety. In terms of the effective rate, 1-year survival rate, 2-year survival rate, KPS score improvement rate and reduced adverse reaction incidence, the optimal treatment measures were Shenyi Capsules, Cidan Capsules, Pingxiao Capsules, Huaier Granules and Huisheng Oral Liquid in turn. However, due to the limitations of the research, the current level of evidence is not high, and clear conclusions and evi-dence strength still need to be further verified and improved by high-quality researches.

Background: A previous study indicated that gut microbiota changed notably in Graves' orbitopathy (GO) patients as compared to controls. However, the characteristics of intestinal bacteria in Graves' disease (GD) and GO are unclear., Objective: The present study aimed to identify specific intestinal bacteria of GD and GO, respectively., Methods: The gut microbial communities of the fecal samples of 30 GD patients without GO, 33 GO subjects, and 32 healthy subjects were analyzed and compared by 16S rRNA gene sequencing., Results: At the phylum level, the proportion of Deinococcus-Thermus and Chloroflexi was decreased significantly in GO patients as compared to GD. At the genus level, the proportion of Subdoligranulum and Bilophila was increased while that of Blautia, Anaerostipes, Dorea, Butyricicoccus, Romboutsia, Fusicatenibacter, unidentified&#95; Lachnospiraceae, unidentified&#95;Clostridiales, Collineslla, Intestinibacter, and Phascolarctobacterium was decreased in the GO group as compared to the GD group. Random forest analysis was used for the identification of specific intestinal microbiota, and Deinococcus-Thermus, Cyanobacteria and Chloroflexi were ranked in the top ten according to their contributions to sample classification. Moreover, compared to the control, there were multiple gut bacterial enrichment metabolic pathways in GO and GD patients, including nucleotide metabolism, enzyme family, and energy metabolism. Compared to GO, the only enrichment metabolic pathway found in GD was the viral protein family., Conclusions: This study highlighted the significant differences in the intestinal microbiota and predictive functions of GD with GO, thereby providing new insights into the role of the gut bacteria that might contribute to the development of GO in GD patients.

To systematically evaluate the efficacy and safety of Huaier Granules in the adjuvant treatment of primary liver cancer. The databases of CNKI, Wanfang, VIP, CBMdisc, PubMed, Cochrane Library and EMbase were searched by computer to screen out the randomized controlled trial on Huaier Granules combined with Western medicine in the treatment of primary liver cancer from the establishment of the databases to January 2020. Data extraction and quality evaluation were conducted for the included literature. Meta-analysis was conducted with RevMan 5.3 software, and evidence quality evaluation was conducted for the outcomes by GRADE profiler software. A total of 24 articles were included, with a total sample size of 2 664 cases. Meta-analysis showed that as compared with Western medicine alone, Huaier Granules combined with Western medicine could improve the objective remission rate(RR=1.38, 95%CI[1.26, 1.51], P&lt;0.000 01), disease control rate(RR=1.29, 95%CI[1.10, 1.52], P=0.002) and 6-month survival rate(RR=1.20, 95%CI[1.10, 1.32], P&lt;0.000 1), 1-year survival rate(RR=1.39, 95%CI[1.23, 1.58], P&lt;0.000 01), 2-year survival rate(RR=1.95, 95%CI[1.28, 2.96], P=0.002), KPS score(MD=17.15, 95%CI[6.47, 27.83], P=0.002) and the improvement rate of KPS score(RR=2.02, 95%CI[1.47, 2.77], P&lt;0.000 1), AFP decline rate(RR=1.40, 95%CI[1.20, 1.62], P&lt;0.000 1), CD3~+(MD=17.34, 95%CI[9.28, 25.40], P&lt;0.000 1), CD4~+(MD=8.62, 95%CI[1.59, 15.64], P=0.02), CD8~+(MD=1.95, 95%CI[-3.93, 7.82], P=0.52), CD4~+/CD8~+(MD=0.42, 95%CI[-0.33, 1.17], P=0.27); reduce the level of AFP(MD=-71.57, 95%CI[-80.42,-62.72], P&lt;0.000 01), recurrence rate(RR=0.76, 95%CI[0.67, 0.85], P&lt;0.000 01), and incidence of adverse reactions(RR=0.60, 95%CI[0.41, 0.89], P=0.01) in patients with primary liver cancer. According to the GRADE system, the evidence for outcome measures was low to very low. The results show that Huaier Granules have certain efficacy and high safety in adjuvant treatment of primary liver cancer, but its effect in reducing adverse reactions and improve immunity remains to be verified. Due to the poor quality of the included studies and evidences, the conclusions still need to be further verified by multi-center, large sample, and randomized double-blind controlled studies.

Sustained hyperglycaemia and hyperlipidaemia incur endoplasmic reticulum stress (ER stress) and reactive oxygen species (ROS) overproduction in pancreatic β-cells. ER stress or ROS causes c-Jun N-terminal kinase (JNK) activation, and the activated JNK triggers apoptosis in different cells. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an inducible multi-stress response factor. The aim of this study was to explore the role of NR4A1 in counteracting JNK activation induced by ER stress or ROS and the related mechanism. qPCR, Western blotting, dual-luciferase reporter and ChIP assays were applied to detect gene expression or regulation by NR4A1. Immunofluorescence was used to detect a specific protein expression in β-cells. Our data showed that NR4A1 reduced the phosphorylated JNK (p-JNK) in MIN6 cells encountering ER stress or ROS and reduced MKK4 protein in a proteasome-dependent manner. We found that NR4A1 increased the expression of cbl-b (an E3 ligase); knocking down cbl-b expression increased MKK4 and p-JNK levels under ER stress or ROS conditions. We elucidated that NR4A1 enhanced the transactivation of cbl-b promoter by physical association. We further confirmed that cbl-b expression in β-cells was reduced in NR4A1-knockout mice compared with WT mice. NR4A1 down-regulates JNK activation by ER stress or ROS in β-cells via enhancing cbl-b expression., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose transcription activity is regulated by small compounds provided by diet, xenobiotics, and metabolism. It has been proven to be involved in energy homeostasis and inflammation in most recent years. Epidemiologically, exposure to xenobiotic AHR ligands contributes to obesity and type 2 diabetes (T2D). AHR is also the critical transcription factor determining the lineage commitment of pro-inflammatory Th17 and Th22 cells from naïve CD4+ T lymphocytes. It has been well-illustrated in animal models that IL-22, the major effector cytokine of Th17 and Th22 cells, played a major role in the interaction of metabolism and gut microbiota. But there were still missing links between gut microbiota, IL-22, and metabolism in humans. Our previous findings indicated that elevated circulating levels of IL-22 and frequencies of Th22 cells were associated with insulin resistance in both patients with obesity and T2D. Additionally, the hyperactive Th17 and Th22 cells phenotype also correlate with islets β-cell dysfunction in T2D. In this study, we made efforts to determine AHR expressions in peripheral blood mononuclear cells (PBMCs) from patients with T2D and metabolically healthy obesity (MHO). Correlation analyses were conducted to assess the possible link between AHR and the metabolic and inflammatory context. We revealed that mRNA expression of AHR was up-regulated and correlated with the percentage of Th17, Th22 as well as Th1 cells. Elevated plasma levels of IL-22 and IL-17 also correlated with increased AHR transcripts in PBMCs from both MHO and T2D patients. The transcription factor AHR may thus have a plausible role in the interaction between metabolism and pro-inflammatory status of patients in the development of obesity and T2D., (Copyright © 2020 Zhao, He, Sha, Song, Qin, Liu, Sun, Sun, Hou and Chen.)

Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.

Objective: To investigate the expression of CD8(+)CD25(+)T cells in peripheral blood of patients with rheumatoid arthritis (RA) and its correlation with clinical indicators of rheumatoid arthritis. Methods: Peripheral blood was collected from 38 patients with RA, and 20 healthy control subjects, RA patients admitted to Peking University people's hospital from May to October 2018, and record the RA patients with the clinical manifestations and laboratory indexes, extraction in the peripheral blood lymphocytes, using flow cytometry to analyse the percentage of CD8(+)CD25(+)T cells in peripheral blood, by using the software SPASS20 and Prism6 to analyze its correlation with clinical and laboratory indices. Results: The expression of CD8(+)CD25(+)T cells in peripheral blood of RA patients was significantly increased, which was statistically different from that of healthy patients ( P< 0.05). CD8(+)CD25(+)T cells in peripheral blood of RA patients showed significant positive correlation with ESR( r= 0.352, P= 0.030), CCP( r= 0.312, P= 0.047) and DAS28( r= 0.330, P= 0.043), and negatively correlated with C3 ( r= -0.354, P= 0.046) and C4( r= -0.440, P= 0.010).No significant correlation was found in other indicators. In RA patients, there were statistically significant differences in CD8(+)CD25(+)T cells between the low-disease active group and the high-disease active group( P< 0.05), but CD8(+)CD25(+)T cells between the low-disease active group and the moderate-disease active group, or between the moderate-disease active group and the high-disease active group had no significant statistical difference. Conclusion: CD8(+)CD25(+)Tcells in peripheral blood of patients with RA are significantlyincreased, and aresignificantly correlated with laboratory and clinical indicators, which may play an important role in the pathogenesis of rheumatoid arthritis.

Background: Treatment of Crohn's disease (CD) remains to be a challenge due to limited insights for its pathogenesis. We aimed to determine the role of O-Linked β-N-acetylglucosamine (O-GlcNAc) in the development of CD and evaluate therapeutic effects of O-GlcNAc inhibitors on CD., Methods: O-GlcNAc in intestinal epithelial tissues of CD, adherent-invasive Escherichia coli (AIEC) LF82-infected cells and mice was determined by immunoblot and immunohistochemistry. AIEC LF82 and dextran sulfate sodium were administrated into C57BL/6 mice for estabolishing inflammatory bowel disease model and for therapeutic study., Findings: O-GlcNAc was increased in intestinal epithelial tissues of CD patients and AIEC LF82-infected mice. Infection of AIEC LF82 up-regulated the level of UDP-GlcNAc and increased O-GlcNAc in human colon epithelial HCT116 and HT-29 cells. We identified that IKKβ and NF-κB were O-Glycosylated in AIEC LF82-treated cells. Mutations of IKKβ (S733A) and p65 (T352A) abrogated the O-GlcNAc in IKKβ and NF-κB and inhibited AIEC LF82-induced activation of NF-κB. Application of 6-diazO-5-oxO-L-norleucine, an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAc, inactivated NF-κB in AIEC LF82-infected cells, enhanced the formation of autophagy, promoted the removal of cell-associated AIEC LF82, alleviated intestinal epithelial inflammation, and improved the survival of the colitis mice., Interpretation: Intestinal inflammation in CD is associated with increased O-GlcNAc modification, which is required for NF-κB activation and suppression of autophagy. Targeting O-GlcNAc could be an effective therapy for inflammatory bowel disease., Funding: National Natural Science Foundation of China (Nos. 81573087 and 81772924) and International Cooperation Foundation of Jilin Province (20190701006GH)., Competing Interests: Declaration of competing interest The authors have declared that no competing of interest exists., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The intestinal microbiota was linked to autoimmune diseases. Graves' orbitopathy (GO) is an autoimmune disease that is usually associated with Graves' disease. However, information on the microbiome of GO patients is yet lacking., Objectives: To investigate whether GO patients differ from healthy controls in the fecal microbiota., Design: A cross-sectional study., Setting: 33 patients with severe and active GO and 32 healthy controls of Han nationality were enrolled between March 2017 and March 2018., Methods: The Gut microbial communities of the fecal samples of GO patients and healthy controls were analyzed and compared by 16S rRNA gene sequencing., Results: Community diversity (Simpson and Shannon) was significantly reduced in fecal samples from patients with GO as compared to controls (p < 0.05). The similarity observed while assessing the community diversity (PCoA) proposed that the microbiota of patients with GO differ significantly from those of controls (p < 0.05). At the phyla levels, the proportion of Bacteroidetes increased significantly in patients with GO (p < 0.05), while at the genus and species levels, significant differences were observed in the bacterial profiles between the two groups (p < 0.05)., Limitations: Single-centered study design and limited fecal samples., Conclusions: The present study indicated distinctive features of the gut microbiota in GO patients. The study provided evidence for further exploration in the field of intestinal microbiota with respect to the diagnosis and treatment of GO patients by modifying the microbiota profile.

Objective: The study was conducted to evaluate the effects of night light regimen on growth performance, antioxidant status and health of Lingnan Yellow broiler chickens from 1 to 21 days of age., Methods: A completely randomized factorial design involved 2 photoperiods (constant lighting [CL], 24 L:0 D and intermittent lighting [INL], 17 L:3 D:1 L:3 D)×2 light intensities (10 lx and 30 lx). A total of one thousand six hundred and eighty 1-d-old Lingnan Yellow broiler chicks were randomly divided into 4 treatments with 6 replicates (70 birds per replicate). The experiment lasted for 21 d., Results: Photoperiods and light intensities had no effect on average daily gain, feed conversion ratio, and mortality of the broiler chickens (p>0.05). The INL had a significant effect on average daily feed intake (p<0.05) of broiler chickens compared with CL. Photoperiod and light intensity had an interactive effect on melatonin (MT) concentration (p<0.05). At CL, reducing light intensity increased MT concentration; INL birds had higher MT but MT concentration was not affected by light intensity. There was an interactive effect on glutathione peroxidase (GPx) and catalase (CAT) in serum and total antioxidant capability (T-AOC) in liver between photoperiod and light intensity. With the decrease of light intensity, the activities of GPx and CAT in serum and T-AOC in liver increased in CL group (p<0.05). Broiler chickens reared under INL had better antioxidant status and 10 lx treatments had higher activities of CAT in serum than 30 lx (p<0.05). Different photoperiods and light intensities had no effect on malondialdehyde. There was an interaction between photoperiod and light intensity on serum creatine kinase (CK) concentration (p<0.05). At CL, the elevated light intensity resulted in an increase in CK content; INL birds had lower CK concentration especially in low light intensity group. Besides, INL and low light intensity significantly reduced the concentration of serum corticosterone and heat shock protein 70 (p<0.05). Serum immunoglobulin M contents were increased in broiler chickens reared under the INL compared with CL group (p<0.05)., Conclusion: Results above suggest that the night light regimen of INL and 10 lx could be beneficial to the broiler chickens from 1 to 21 days of age due to the better health status and electricity savings.

N , N -Dimethylformamide hydrochloric acid/XMCl n ([HDMF]Cl/XMCl n , M = Zn or Fe, n = 2 or 3) was synthesized by stirring the mixture of [HDMF]Cl and metal chloride. [HDMF]Cl-based DES was characterized by FT-IR spectroscopy, ESI-MS and 1 H-NMR spectroscopy. The oxidative desulfurization activity was investigated using [HDMF]Cl/0.2FeCl 3 and [HDMF]Cl/ZnCl 2 as the extractant and catalyst, and hydrogen peroxide (H 2 O 2 ) as the oxidant. The desulfurization rate can reach up to 98.08% and 99.2% for DBT using [HDMF]Cl/0.2FeCl 3 and [HDMF]Cl/ZnCl 2 , respectively. After recycling for 7 times, the removal rate of DBT still can reach more than 97%., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The study was conducted to evaluate the effects of different stocking densities on growth performance, antioxidant capacity, and immunity of broilers. One thousand four hundred and forty 22-day-old Lingnan Yellow broilers were randomly allotted to five different stocking density groups (8, 10, 12, 14, and 16 birds per m 2 ). Each group consisted of three replicates. The results showed that 8 and 10 birds/m 2 groups had higher average daily feed intake (ADFI) than the others (p < 0.05). Heat shock protein 70 (HSP 70 ) in the group of 16 birds/m 2 had the highest levels (p < 0.05). The group of 16 birds/m 2 had the lowest total antioxidant capability (T-AOC) and total superoxide dismutase (T-SOD) activities in blood serum (p < 0.05), and significantly increased interleukin-1β (IL-1β) and interleukin-4 (IL-4) concentration compared to the groups of 8 and 10 birds/m 2 (p < 0.05). In liver, the group of eight birds/m 2 had higher T-AOC levels than that of 12, 14, and 16 birds/m 2 (p < 0.05) and also higher catalase (CAT) activities than that of 14 and 16 birds/m 2 (p < 0.05); the group of 10 birds/m 2 had the highest T-SOD activities among all groups (p < 0.05). In conclusion, the above results suggest that stocking density of broilers up to 8 or 10 birds/m 2 can prevent the negative effects on growth performance and welfare parameters in broilers., (© 2019 Japanese Society of Animal Science.)

Dendrobium denneanum have been used for a long time as rare medicinal herbs in traditional Chinese medicine. Our previous works found that ether extract of D. denneanum had higher anticancer activities than alcohol or water extract,thus with better development prospects. Quantitative proteomics based on SILAC technique was used to investigate the anticancer mechanism of D. denneanum on lung tumor cell line A549,and 4 855 proteins were detected in A549 cells. Quantitative proteomics experiments found that 193 proteins of A549 cells were up-regulated,and 44 proteins were down-regulated by ether extract of D. denneanum. Those proteins are associated with synthesis,transport and metabolism of biological macromolecules,chaperone,DNA repair,oxidoreductase,cell adhesion,cell cycle,apoptosis and autophagy. Through the function analysis of differentially expressed proteins,it was inferred that ether extract of D. denneanum caused cell protein metabolism disorder,endoplasmic reticulum stress response,abnormal self-repair mechanism of cells,damage of cell adhesion and proliferation; besides,it caused a dramatic increase in ROS level in A549 cells,and upset the balance of intracellular oxidation reduction system. Affected by the above factors,lung cancer cells initiated apoptosis and autophagy,which accelerated cell death. This research explains the anticancer mechanism of D. denneanum from the perspective of quantitative proteomics,and lays a foundation for future research and development of new anticancer drugs based on ether extract of D. denneanum.

Objective: This study was conducted with the objectives to examine the impacts of inorganic selenium (Se) and different types and levels of organic selenium on the serum and tissues Se status and antioxidant capacity in broiler breeders., Methods: Five hundred and forty 48-wk-old Lingnan Yellow broiler breeders were randomly assigned to 6 dietary treatments, provided same basal diet (0.04 mg/kg of Se) with 0.15 mg/kg, or 0.30 mg/kg of Se from sodium selenite (SS) or from selenium-enriched yeast (SY) or from selenomethionine (SM). The broiler breeders were slaughtered after an 8-wk experiment., Results: The results showed that SM was better than SY and SS, 0.30 mg/kg level was better than 0.15 mg/kg level in Se deposition (p<0.05) in serum, liver, kidney, pancreas and muscle; in antioxidant status, organic selenium had better effects than SS in broiler breeders (p<0.05), but SM and SY had a similar result, and 0.15 mg/kg level was better than 0.30 mg/kg (p<0.05)., Conclusion: The results demonstrated the evident advantage of supplementation of broiler breeders with 0.15 mg/kg SM, which improved tissue Se concentrations and antioxidant status, and can be considered as the best selenium source.

Main Conclusion: This review summarizes current knowledge of chromosome characterization, genetic mapping, genomic sequencing, quality formation, floral transition, propagation, and identification in Dendrobium. The widely distributed Dendrobium has been studied for a long history, due to its important economic values in both medicine and ornamental. In recent years, some species of Dendrobium and other orchids had been reported on genomic sequences, using the next-generation sequencing technology. And the chloroplast genomes of many Dendrobium species were also revealed. The chromosomes of most Dendrobium species belong to mini-chromosomes, and showed 2n = 38. Only a few of genetic studies were reported in Dendrobium. After revealing of genomic sequences, the techniques of transcriptomics, proteomics and metabolomics could be employed on Dendrobium easily. Some other molecular biological techniques, such as gene cloning, gene editing, genetic transformation and molecular marker developing, had also been applied on the basic research of Dendrobium, successively. As medicinal plants, insights into the biosynthesis of some medicinal components were the most important. As ornamental plants, regulation of flower related characteristics was the most important. More, knowledge of growth and development, environmental interaction, evolutionary analysis, breeding of new cultivars, propagation, and identification of species and herbs were also required for commercial usage. All of these studies were improved using genomic sequences and related technologies. To answer some key scientific issues in Dendrobium, quality formation, flowering, self-incompatibility and seed germination would be the focus of future research. And genome related technologies and studies would be helpful.

TP53 mutations frequently occur in head and neck squamous cell carcinoma (HNSCC) patients without human papillomavirus infection. The recurrence rate for these patients is distinctly high. It has been actively explored to identify agents that target TP53 mutations and restore wild-type (WT) TP53 activities in HNSCC. PRIMA-1 (p53-reactivation and induction of massive apoptosis-1) and its methylated analogue PRIMA-1 Met (also called APR-246) were found to be able to reestablish the DNA-binding activity of p53 mutants and reinstate the functions of WT p53. Herein we report that piperlongumine (PL), an alkaloid isolated from Piper longum L., synergizes with APR-246 to selectively induce apoptosis and autophagic cell death in HNSCC cells, whereas primary and immortalized mouse embryonic fibroblasts and spontaneously immortalized non-tumorigenic human skin keratinocytes (HaCat) are spared from the damage by the co-treatment. Interestingly, PL-sensitized HNSCC cells to APR-246 are TP53 mutation-independent. Instead, we demonstrated that glutathione S-transferase pi 1 (GSTP1), a GST family member that catalyzes the conjugation of GSH with electrophilic compounds to fulfill its detoxification function, is highly expressed in HNSCC tissues. Administration of PL and APR-246 significantly suppresses GSTP1 activity, resulting in the accumulation of ROS, depletion of GSH, elevation of GSSG, and DNA damage. Ectopic expression of GSTP1 or pre-treatment with antioxidant N-acetyl-L-cysteine (NAC) abrogates the ROS elevation and decreases DNA damage, apoptosis, and autophagic cell death prompted by PL/APR-246. In addition, administration of PL and APR-246 impedes UMSCC10A xenograft tumor growth in SCID mice. Taken together, our data suggest that HNSCC cells are selectively sensitive to the combination of PL and APR-246 due to a remarkably synergistic effect of the co-treatment in the induction of ROS by suppression of GSTP1.

Certain strains of biocontrol bacterium Pseudomonas fluorescens produce the secondary metabolite 2,4-diacetylphloroglucinol (2,4-DAPG) to antagonize soilborne phytopathogens in the rhizosphere. The gene cluster responsible for the biosynthesis of 2,4-DAPG is named phlACBDEFGH and it is still unclear how the pathway-specific regulator phlH within this gene cluster regulates the metabolism of 2,4-DAPG. Here, we found that PhlH in Pseudomonas fluorescens strain 2P24 represses the expression of the phlG gene encoding the 2,4-DAPG hydrolase by binding to a sequence motif overlapping with the -35 site recognized by σ 70 factors. Through biochemical screening of PhlH ligands we identified the end product 2,4-DAPG and its biosynthetic intermediate monoacetylphloroglucinol (MAPG), which can act as signaling molecules to modulate the binding of PhlH to the target sequence and activate the expression of phlG Comparison of 2,4-DAPG production between the Δ phlH , Δ phlG , and Δ phlHG mutants confirmed that phlH and phlG impose negative feedback regulation over 2,4-DAPG biosynthesis. It was further demonstrated that the 2,4-DAPG degradation catalyzed by PhlG plays an insignificant role in 2,4-DAPG tolerance but contributes to bacterial growth advantages under carbon/nitrogen starvation conditions. Taken together, our data suggest that by monitoring and down-tuning in situ levels of 2,4-DAPG, the phlHG genes could dynamically modulate the metabolic loads attributed to 2,4-DAPG production and potentially contribute to rhizosphere adaptation. IMPORTANCE 2,4-DAPG, which is synthesized by biocontrol pseudomonad bacteria, is a broad-spectrum antibiotic against bacteria, fungi, oomycetes, and nematodes and plays an important role in suppressing soilborne plant pathogens. Although most of the genes in the 2,4-DAPG biosynthetic gene cluster ( phl ) have been characterized, it is still not clear how the pathway-specific regulator phlH is involved in 2,4-DAPG metabolism. This work revealed the role of PhlH in modulating 2,4-DAPG levels by controlling the expression of 2,4-DAPG hydrolase PhlG in response to 2,4-DAPG and MAPG. Since 2,4-DAPG biosynthesis imposes a metabolic burden on biocontrol pseudomonads, it is expected that the fine regulation of phlG by PhlH offers a way to dynamically modulate the metabolic loads attributed to 2,4-DAPG production., (Copyright © 2017 American Society for Microbiology.)

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for HNSCC patients with mutations in the TP53 gene although patients are responsive to surgery, irradiation, and chemotherapy early in the treatment. p53-Reactivation and Induction of Massive Apoptosis-1 (PRIMA-1) and its methylated analogue PRIMA-1 Met (also known as APR-246) are quinuclidine compounds that rescue the DNA-binding activity of mutant p53 (mut-p53) and restore the potential of wild-type p53. In the current report, we demonstrated that inhibition of poly (ADP-ribose) polymerase-1 (PARP-1) with 6(5H)-phenanthridinone (PHEN) and N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N, N-dimethylamino) acetamide hydrochloride (PJ34) sensitizes UMSCC1, UMSCC14, and UMSCC17A, three HNSCC cell lines to the treatment of APR-246. PHEN enhances APR-246-induced apoptosis, but not programmed necrosis or autophagic cell death in HNSCC cells. The PARP-1 inhibition-induced sensitization of HNSCC cells to APR-246 is independent of TP53 mutation. Instead, PARP-1 inhibition promotes APR-246-facilitated inactivation of thioredoxin reductase 1 (TrxR1), leading to ROS accumulation and DNA damage. Overexpression of TrxR1 or application of antioxidant N-acetyl-L-cysteine (NAC) depletes the ROS increase, reduces DNA damage, and decreases cell death triggered by APR-246/PHEN in HNSCC cells. Thus, we have characterized a new function of PARP-1 inhibitor in HNSCC cells by inactivation of TrxR1 and elevation of ROS and provide a novel therapeutic strategy for HNSCC by the combination of PARP-1 inhibitors and APR-246., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.