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Background: Type 2 diabetes (T2DM) is one of the major metabolic diseases and poses a serious challenge to human life and global economic development. Jinqi Jiangtang Tablets (JQJT) is effective in ameliorating the effects of T2DM, but the mechanism of JQJT is unclear., Purpose: This study integrated metabolomics and transcriptomics to reveal the mechanism by which JQJT improves T2DM., Methods: The T2DM mouse model was established, and the effects of JQJT on improving T2DM were evaluated by determining the levels of blood lipids, fasting blood glucose (FBG), insulin metabolism and hepatic lipid accumulation in mice after JQJT administration for 8 weeks. Serum metabolites were detected using ultra-performance liquid chromatography/quadrupole time-of-flight-tandem mass spectrometry (UPLC-Q-TOF-MS) technology, and mouse liver differential genes were detected using transcriptomic technology. Correlation analysis was used to extract metabolites and RNA with correlations, and potential pathways were enriched and constructed using the common pathway analysis function of MetaboAnalyst 5.0. Finally, the expression of key target proteins and genes was verified by Western blot (WB) and Polymerase Chain Reaction (PCR) to further elucidate the mechanism by which JQJT improves T2DM., Results: JQJT reduced FBG and lipid levels, improved insulin resistance (IR) and hepatic lipoatrophy in mice. A total of 35 differentially abundant metabolites were identified by metabolomics, and 328 differential genes were detected by transcriptomics. The integrated metabolomics and transcriptomics results suggested that JQJT may ameliorate T2DM mainly by regulating glucose and lipid metabolic pathways. WB and PCR results showed that JQJT regulates the insulin signaling pathway, involved in fatty acid metabolism, glycogen synthesis and catabolism., Conclusions: JQJT improved IR in T2DM mice by regulating the insulin signaling pathway, improving glycogen synthesis and glycolysis, and increasing hepatic triglyceride and fatty acid metabolism., Competing Interests: Declaration of competing interest The authors declare that there have no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

As a generalized quantum machine learning model, parameterized quantum circuits (PQC) have been found to perform poorly in terms of classification accuracy and model scalability for multi-category classification tasks. To address this issue, we propose a scalable parameterized quantum circuits classifier (SPQCC), which performs per-channel PQC and combines the measurements as the output of the trainable parameters of the classifier. By minimizing the cross-entropy loss through optimizing the trainable parameters of PQC, SPQCC leads to a fast convergence of the classifier. The parallel execution of identical PQCs on different quantum machines with the same structure and scale reduces the complexity of classifier design. Classification simulations performed on the MNIST Dataset show that the accuracy of our proposed classifier far exceeds that of other quantum classification algorithms, achieving the state-of-the-art simulation result and surpassing/reaching classical classifiers with a considerable number of trainable parameters. Our classifier demonstrates excellent scalability and classification performance., (© 2024. The Author(s).)

Context: Qinggong Shoutao Wan (QGSTW) is a pill used as a traditional medicine to treat age-associated memory decline (AAMI). However, its potential mechanisms are unclear., Objective: This study elucidates the possible mechanisms of QGSTW in treating AAMI., Materials and Methods: Network pharmacology and molecular docking approaches were utilized to identify the potential pathway by which QGSTW alleviates AAMI. C57BL/6J mice were divided randomly into control, model, and QGSTW groups. A mouse model of AAMI was established by d-galactose, and the pathways that QGSTW acts on to ameliorate AAMI were determined by ELISA, immunofluorescence staining and Western blotting after treatment with d-gal (100 mg/kg) and QGSTW (20 mL/kg) for 12 weeks., Results: Network pharmacology demonstrated that the targets of the active components were significantly enriched in the cAMP signaling pathway. AKT1, FOS, GRIN2B, and GRIN1 were the core target proteins. QGSTW treatment increased the discrimination index from -16.92 ± 7.06 to 23.88 ± 15.94% in the novel location test and from -19.54 ± 5.71 to 17.55 ± 6.73% in the novel object recognition test. ELISA showed that QGSTW could increase the levels of cAMP. Western blot analysis revealed that QGSTW could upregulate the expression of PKA, CREB, c-Fos, GluN1, GluA1, CaMKII-α, and SYN. Immunostaining revealed that the expression of SYN was decreased in the CA1 and DG., Discussion and Conclusions: This study not only provides new insights into the mechanism of QGSTW in the treatment of AAMI but also provides important information and new research ideas for the discovery of traditional Chinese medicine compounds that can treat AAMI.

Colorectal cancer (CRC) remains a significant global health challenge, marked by increasing incidence and mortality rates in recent years. The pathogenesis of CRC is complex, involving chronic inflammation of the intestinal mucosa, heightened immunoinflammatory responses, and resistance to apoptosis. The suppressor of cytokine signaling (SOCS) family, comprised of key negative regulators within cytokine signaling pathways, plays a crucial role in cell proliferation, growth, and metabolic regulation. Deficiencies in various SOCS proteins can trigger the activation of the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathways, following the binding of cytokines and growth factors to their receptors. Mounting evidence indicates that SOCS proteins are integral to the development and progression of CRC, positioning them as promising targets for novel anticancer therapies. This review delves into the structure, function, and molecular mechanisms of SOCS family members, examining their roles in cell proliferation, apoptosis, migration, epithelial-mesenchymal transition (EMT), and immune modulation. Additionally, it explores their potential impact on the regulation of CRC immunotherapy, offering new insights and perspectives that may inform the development of innovative therapeutic strategies for CRC., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Ultra-high molecular weight polyethylenes (UHMWPEs) are significant engineering plastics for their unique properties, such as high impact resistance, abrasion resistance, weatherability, lubricity, and chemical resistance. Consequently, developing a suitable catalyst is vital in facilitating the preparation of UHMWPE. The late transition metal catalysts have emerged as effective catalysts in producing UHMWPE due to their availability, enhanced tolerance to heteroatom groups, active polymerization characteristics, and good copolymerization ability with polar monomers. In this review, we mainly focus on the late transition metal catalysts, summarizing advancements in their application over the past decade. Four key metals (Ni, Pd, Fe, Co) for generating linear or branched UHMWPE will be primarily explored in this manuscript.

In recent years, deep learning has been widely used in vulnerability detection with remarkable results. These studies often apply natural language processing (NLP) technologies due to the natural similarity between code and language. Since NLP usually consumes a lot of computing resources, its combination with quantum computing is becoming a valuable research direction. In this paper, we present a Recurrent Quantum Embedding Neural Network (RQENN) for vulnerability detection. It aims to reduce the memory consumption of classical models for vulnerability detection tasks and improve the performance of quantum natural language processing (QNLP) methods. We show that the performance of RQENN achieves the above goals. Compared with the classic model, the space complexity of each stage of its execution is exponentially reduced, and the number of parameters used and the number of bits consumed are significantly reduced. Compared with other QNLP methods, RQENN uses fewer qubit resources and achieves a 15.7% higher accuracy in vulnerability detection., (© 2024. The Author(s).)

The direct copolymerization of ethylene with polar monomers to produce functional polyolefins continues to be highly appealing due to its simple operation process and controllable product microstructure. Low-cost nickel catalysts have been extensively utilized in academia for the synthesis of polar polyethylenes. However, the development of high-temperature copolymerization catalysts suitable for industrial production conditions remains a significant challenge. Classified by the resultant copolymers, this review provides a comprehensive summary of the research progress in nickel complex catalyzed ethylene-polar monomer copolymerization at elevated temperatures in the past five years. The polymerization results of ethylene-methyl acrylate copolymers, ethylene- tert -butyl acrylate copolymers, ethylene-other fundamental polar monomer copolymers, and ethylene-special polar monomer copolymers are thoroughly summarized. The involved nickel catalysts include the phosphine-phenolate type, bisphosphine-monoxide type, phosphine-carbonyl type, phosphine-benzenamine type, and the phosphine-enolate type. The effective modulation of catalytic activity, molecular weight, molecular weight distribution, melting point, and polar monomer incorporation ratio by these catalysts is concluded and discussed. It reveals that the optimization of the catalyst system is mainly achieved through the methods of catalyst structure rational design, extra additive introduction, and single-site catalyst heterogenization. As a result, some outstanding catalysts are capable of producing polar polyethylenes that closely resemble commercial products. To achieve industrialization, it is essential to further emphasize the fundamental science of high-temperature copolymerization systems and the application performance of resultant polar polyethylenes.

Coronary microvascular disease (CMVD) is common in patients with cardiovascular risk factors and is linked to an elevated risk of adverse cardiovascular events. Although modern medicine has made significant strides in researching CMVD, we still lack a comprehensive understanding of its pathophysiological mechanisms due to its complex and somewhat cryptic etiology. This greatly impedes the clinical diagnosis and treatment of CMVD. The primary pathological mechanisms of CMVD are structural abnormalities and/or dysfunction of coronary microvascular endothelial cells. The development of CMVD may also involve a variety of inflammatory factors through the endothelial cell injury pathway. This paper first reviews the correlation between the inflammatory response and CMVD, then summarizes the possible mechanisms of inflammatory response in CMVD, and finally categorizes the drugs used to treat CMVD based on their effect on the inflammatory response. We hope that this paper draws attention to CMVD and provides novel ideas for potential therapeutic strategies based on the inflammatory response., 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., (© 2024 Guo, Yang, Song, Li, Xiao, Zhang, Wen, Pan, Xu, Sheng, Jiang, Guo and Wang.)

Since the discovery of α-diimine catalysts in 1995, an extensive series of Brookhart-type complexes have shown their excellence in catalyzing ethylene polymerizations with remarkable activity and a high molecular weight. However, although this class of palladium complexes has proven proficiency in catalyzing ethylene copolymerization with various polar monomers, the α-diimine nickel catalysts have generally exhibited a much worse performance in these copolymerizations compared to their palladium counterparts. Recently, Brookhart et al. reported a notable exception, demonstrating that α-diimine nickel catalysts could catalyze the ethylene copolymerization with some vinylalkoxysilanes effectively, producing functionalized polyethylene incorporating trialkoxysilane (-Si(OR) 3 ) groups. This breakthrough is significant since Pd-catalyzed copolymerizations are commercially less usable due to the high cost of palladium. Thus, the utilization of Ni, given its abundance in raw materials and cost-effectiveness, is a landmark in ethylene/polar vinyl monomer copolymerization. Inspired by these findings, we used density functional theory (DFT) calculations to investigate the mechanistic study of ethylene copolymerization with vinyltrimethoxysilane (VTMoS) catalyzed by Brookhart-type nickel catalysts, aiming to elucidate the molecular-level understanding of this unique reaction. Initially, the nickel complexes and cationic active species were optimized through DFT calculations. Subsequently, we explored the mechanisms including the chain initiation, chain propagation, and chain termination of ethylene homopolymerization and copolymerization catalyzed by Brookhart-type complexes. Finally, we conducted an energetic analysis of both the in-chain and chain-end of silane enchainment. It was found that chain initiation is the dominant step in the ethylene homopolymerization catalyzed by the α-diimine Ni complex. The 1,2- and 2,1-insertion of vinylalkoxysilane exhibit similar barriers, explaining the fact that both five-membered and four-membered chelates were identified experimentally. After the VTMoS insertion, the barriers of ethylene reinsertion become higher, indicating that this step is the rate-determining step, which could be attributed to the steric hindrance between the incoming ethylene and the bulky silane substrate. We have also reported the energetic analysis of the distribution of polar substrates. The dominant pathway of chain-end -Si(OR) 3 incorporation is suggested as chain-walking → ring-opening → ethylene insertion, and the preference of chain-end -Si(OR) 3 incorporation is primarily attributed to the steric repulsion between the pre-inserted silane group and the incoming ethylene molecule, reducing the likelihood of in-chain incorporation.

Amid China's economic shift to high-quality development, addressing environmental challenges like greenhouse gas emissions and manufacturing pollution, there is a crucial demand for sustainable and eco-friendly development strategies. This study aims to investigate the impact of innovation efficiency in the high-tech industry on carbon emissions. It seeks to explore regional differences, mechanisms, and the influence of energy consumption structures in achieving sustainable development goals. Utilizing data from 30 provinces spanning 2009 to 2020, the study employs the DEA-Malmquist index model, spatial and temporal classification evaluation, and a panel measurement model to assess the efficiency of innovation and development in high-tech industries and their relationship with carbon emissions. The results indicate several key findings: (1) The overall operational efficiency of high-tech industry innovation and development in China is steadily increasing. However, there are distinct characteristics observed among provinces and cities, reflecting diverse input and output types. (2) High-tech industry innovation efficiency significantly contributes to carbon emission reduction, and there is regional heterogeneity in this impact. The central and western regions exhibit greater effects compared to other provinces and cities. (3) The optimization of the energy structure is identified as a mechanism through which high-tech industry innovation efficiency reduces carbon emissions. Moreover, different intervals of high-tech industry innovation efficiency yield varying effects on carbon emissions. This research underscores the importance of fostering high-tech industry innovation efficiency as a means to reduce carbon emissions. It also identifies key areas for future policy development and resource allocation, emphasizing the support needed for low-carbon technology research and development., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Experimental investigations and density functional theory (DFT) calculations were carried out to study the comprehensive effect of different 3,5-heptanedioldibenzoate (HDDB) optical isomers as the internal electron donor on the catalytic performance of Ziegler-Natta catalysts. The experimental catalytic activity of HDDB has a positive correlation with the relative content of the mesomer incorporated during catalyst preparation, while the hydrogen response of HDDB displayed a negative correlation with the relative content of the mesomer. In order to apply the DFT calculation results to the macroscopic activity of the catalyst, the content of the active centers of the catalyst was analyzed. Assuming that the content of the active centers is proportional to the internal electron donor content of the catalyst, binary linear regression was carried out, which showed a good linear correlation between experimental activity data and internal electron donor content. Furthermore, the fitted activity of the single active centers aligned well with the calculated activation energies. These results revealed that the catalytic activity of polypropylene (PP) catalysts is dependent on both the active center content and the catalytic activity of an individual active center. Additionally, the lower hydrogen response of HDDB leads to a higher molecular weight of polypropylene obtained from the RS -containing catalyst compared to the SS -containing catalyst. Further study reveals that the hydrogen transfer reactions of 2,4-pentanediol dibenzoate (PDDB)/HDDB are influenced by the orientation of the methyl/ethyl groups in different isomers, which affect the activation energy differences between the hydrogen transfer reaction and the propylene insertion reaction, and finally influence the molecular weight of PP.

Pregnancy-induced hypertension (PIH) is a hypertensive disorder during pregnancy and can induce perinatal death of human infants. MicroRNA (miR)-195-5p was validated to display low expression in severe preeclampsia placentas, but the role of miR-195-5p in pregnancy-induced hypertension (PIH) has not been investigated. The study emphasized on the functions and mechanism of miR-195-5p in PIH. A reduced uterine perfusion pressure (RUPP) rat model was established to mimic PIH in vivo. Adenovirus (Ad)-miR-195-5p agomir and/or Ad-OTX1 were further injected into some model rats. RT-qPCR was conducted to assess the expression of miR-195-5p and orthodenticle homeobox 1 (OTX1) in rat placental tissues, the isolated aortic endothelial cells (AECs), and in serum samples of PIH patients. Western blot analysis was implemented to measure the protein levels of OTX1, VEGFA, and key factors involved in the MAPK signaling pathway. The concentrations of oxidative stress markers (superoxide dismutase, catalase, and lipid hydroperoxide) in AECs and placental tissues of RUPP rats were measured by corresponding kits. The binding relation between miR-195-5p and OTX1 was verified using the dual-luciferase reporter assay. Hematoxylin-eosin staining was conducted to evaluate the pathological features of rat placental tissues. MiR-195-5p was downregulated, while OTX1 was upregulated in rat placental tissues and human serum samples of PIH patients. MiR-195-5p could target OTX1 and inversely regulate OTX1 expression in AECs and rat placental tissues. In addition, miR-195-5p can negatively regulate VEGFA level. Furthermore, miR-195-5p inactivates oxidative stress and the MAPK signaling by downregulating OTX1 in AECs. In vivo experiments revealed that OTX1 overexpression reversed the protective effect of miR-195-5p overexpression on placental damage and oxidative stress. MiR-195-5p alleviates PIH by inhibiting oxidative stress via targeting OTX1 and inactivating MAPK signaling., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This study aimed to explore the occurrence of acute urinary retention (AUR) and urinary tract infection (UTI) in patients undergoing urinary drainage after colorectal resection and analyse the risk factors., Methods: Clinical data of 167 patients with urinary drainage after colorectal resection in Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital from November 2020 to November 2022 were retrospectively analysed. Clinical data included age, gender, diabetes, hypertension, lesion location, surgical method, previous history of abdominal surgery, urinary system diseases (urinary calculi, benign prostatic hyperplasia and urethral stricture), use of antibiotics before surgery, use of analgesic and sedative drugs after surgery, postoperative extubation time and postoperative adhesive intestinal obstruction. The postoperative AUR and UTI in patients were statistically analysed. Univariate and multivariate logistic regression analyses were used to explore the risk factors and odds ratio (OR) for AUR and UTI., Results: The incidences of AUR and UTI were 23.95% (40/167) and 16.77% (28/167). Patients were divided into AUR group (n = 40), non-AUR group (n = 127), UTI group (n = 28) and non-UTI group (n = 139). Logistic regression analysis showed that previous history of abdominal surgery (OR = 3.517, 95% CI: 1.005-12.313), urinary system diseases (OR = 8.253, 95% CI: 2.692-25.303), postoperative extubation time (OR = 0.536, 95% CI: 0.393-0.732) and postoperative adhesive intestinal obstruction (OR = 25.293, 95% CI: 6.747-94.827) were risk factors for AUR in patients with urinary drainage after colorectal resection ( p < 0.05). Female (OR = 21.569, 95% CI: 1.094-425.138), long postoperative extubation time (OR = 26.218, 95% CI: 3.318-207.151) and urinary system diseases (OR = 8.647, 95% CI: 3.425-21.831) were risk factors for UTI in patients undergoing urinary drainage after colorectal resection ( p < 0.05). Age and preoperative use of antibiotics were not key influencing factors for UTI ( p > 0.05)., Conclusions: Clinical attention is paid to high-risk factors and groups. Corresponding interventions are taken as soon as possible to reduce the occurrence of AUR and UTI and further improve the prognosis of patients with urinary drainage after colorectal resection., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s).)

Neuroinflammation is a critical driver in the pathogenesis and progression of neurodegenerative disorders. Dammarane sapogenins (DS), a deglycosylated product of ginsenoside, possess a variety of potent biological activities. The present study aimed to explore the neuroprotective effects of DS in a rat model of neuroinflammation induced by intracerebroventricular injection of lipopolysaccharide (LPS). Our study revealed that DS pretreatment effectively improved LPS-induced associative learning and memory impairments in the active avoidance response test and spatial learning and memory in Morris water maze test. DS also remarkably inhibited LPS-induced neuroinflammation by suppressing microglia overactivation, pro-inflammatory cytok ine release (TNF-α and IL-1β) and reducing neuronal loss in the CA1 and DG regions of the hippocampus. Importantly, pretreatment with DS reversed LPS-induced upregulation of HMGB1 and TLR4 and inhibited their downstream NF-κB signaling activation, as evidenced by increased IκBα and decreased p-NF-κB p65 levels. Furthermore, DS ameliorated LPS-induced synaptic dysfunction by decreasing MMP-9 and increasing NMDAR1 expression in the hippocampus. Taken together, this study suggests that DS could be a promising treatment for preventing cognitive impairments caused by neuroinflammation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Here, we report the development of cobalt(I)-catalyzed regioselective allylic alkylation reactions of tertiary allyl carbonates with 1,3-dicarbonyl compounds. A family of well-defined tetrahedral cobalt(I) complexes bearing commercially available bidentate bis(phosphine) ligands [(P,P)Co(PPh 3 )Cl] are synthesized and explored as catalysts in allylic alkylation reactions. The catalyst [(dppp)Co(PPh 3 )Cl] (dppp=1,3-Bis(diphenylphosphino)propane) enables the alkylation of a large variety of tertiary allyl carbonates with high yields and excellent regioselectivity for the branched product. Remarkably, this methodology is selective for the activation of tertiary allyl carbonates even in the presence of secondary allyl carbonates. This contrasts with the selectivity observed in cobalt-catalyzed allylic alkylations enabled by visible light photocatalysis. Mechanistic insights by means of experimental and computational investigations support a Co(I)/Co(III) catalytic cycle., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The introduction of polar functional groups into polyolefin chain structures creates opportunities to enhance specific properties, such as adhesion, dyeability, printability, compatibility, thermal stability, and electrical conductivity, which widen the range of potential applications for these modified materials. Transition metal catalysts, especially late transition metals, have proven to be highly effective in copolymerization processes due to their reduced Lewis acidity and electrophilicity. However, when compared to the significant progress and summary of synthetic methods, there is a distinct lack of a comprehensive summary of mechanistic studies pertaining to the catalytic systems involved in ethylene copolymerization catalyzed by palladium and nickel catalysts. In this review, we have provided a comprehensive summary of the latest developments in mechanistic studies of ethylene copolymerization with polar monomers catalyzed by late-transition-metal complexes. Experimental and computational methods were employed to conduct a detailed investigation of these organic and organometallic systems. It is mainly focused on ligand substitution, changes in binding modes, ethylene/polar monomer insertion, chelate opening, and β-H elimination. Factors that control the catalytic activity, molecular weight, comonomer incorporation ratios, and branch content are analyzed, these include steric repulsions between ligands and monomers, electronic effects arising from both ligands and monomers, and so on.

Limonoids, a class of abundant natural tetracyclic triterpenoids, present diverse biological activity and provide a versatile platform amenable by chemical modifications for clinical use. Among all of the limonoids isolated from natural sources, obacunone, nomilin, and limonin are the primary hub of limonoid-based chemical modification research. To date, more than 800 limonoids analogs have been synthesized, some of which possess promising biological activities. This review not only discusses the synthesis of limonoid derivatives as promising therapeutic candidates and details the pharmacological studies of their underlying mechanisms from 2002 to 2022, but also proposes a preliminary limonoid synthetic structure-activity relationship (SAR) and provides future direction of limonoid derivatization 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 © 2023 Elsevier Masson SAS. All rights reserved.)

Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK- ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK- ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.

Coronary artery disease has one of the highest mortality rates in the country, and methods such as thrombolysis and percutaneous coronary intervention (PCI) can effectively improve symptoms and reduce mortality, but most patients still experience symptoms such as chest pain after PCI, which seriously affects their quality of life and increases the incidence of adverse cardiovascular events (myocardial ischaemiareperfusion injury, MIRI). MIRI has been shown to be closely associated with circadian rhythm disorders and mitochondrial dysfunction. Mitochondria are a key component in the maintenance of normal cardiac function, and new research shows that mitochondria have circadian properties. Traditional Chinese medicine (TCM), as a traditional therapeutic approach characterised by a holistic concept and evidence-based treatment, has significant advantages in the treatment of MIRI, and there is an interaction between the yin-yang theory of TCM and the circadian rhythm of Western medicine at various levels. This paper reviews the clinical evidence for the treatment of MIRI in TCM, basic experimental studies on the alleviation of MIRI by TCM through the regulation of mitochondria, the important role of circadian rhythms in the pathophysiology of MIRI, and the potential mechanisms by which TCM regulates mitochondrial circadian rhythms to alleviate MIRI through the regulation of the biological clock transcription factor. It is hoped that this review will provide new insights into the clinical management, basic research and development of drugs to treat MIRI., Competing Interests: Declaration of Competing Interest The authors declare that there have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: The efficacy and safety of anti-vascular endothelial growth factor (anti-VEGF) treatment for Coats' disease remains controversial. This study was designed to evaluate the efficacy and safety of anti-VEGF treatment for Coats' disease. Methods: PubMed, Embase, The Cochrane Library, Clinical Trials, CNKI, and WanFang databases were systematically searched for clinical efficacy and safety studies on anti-VEGF treatment for Coats' disease through June 2021. Study selection, data extraction, and quality assessment were independently performed by 2 reviewers. Quality assessments were performed using the Joanna Briggs Institute Critical Appraisal tools and GRADE-CERQual. Results: A total of 1,501 articles were retrieved and reviewed, of which 24 case series involving 378 patients (range: 3-67 patients each with 3-71 eyes) were included in the analysis. No randomized controlled trials, case-controlled studies, or cohort studies were available for analysis. Most patients were male (60.0%-92.9%), aged 1.35-42.3 years, with a median follow-up time ranging from 3 to 63 months. Among the 24 case series, 22 reported changes in the visual acuity (VA) after anti-VEGF treatment and 21 reported safety outcomes. The results showed that VA improved in 73 patients (37.63%), was stable in 89 (45.87%), and worsening VA was observed in 12 cases (6.19%). The most common adverse event was fibrotic changes ( n  = 35). Systemic complications were not observed. Conclusions: The results of this study indicate that anti-VEGF drugs provide an effective and relatively safe treatment strategy for Coats' disease. However, conducting well-designed, prospective, randomized clinical trials are necessary to confirm our findings.

Background: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease that causes multi-organ complications, seriously affecting patients' quality of life and survival. Understanding its pathogenesis remains challenging, with current clinical treatment regimens often proving ineffective., Methods: In this study, we established a mouse model of T2DM and employed 16s rDNA sequencing to detect changes in the species and structure of gut flora. Additionally, we used UPLC-Q-TOF-MS to identify changes in urinary metabolites of T2DM mice, analyzed differential metabolites and constructed differential metabolic pathways. Finally, we used Pearman correlation analysis to investigate the relationship between intestinal flora and differential metabolites in T2DM mice, aiming to elucidate the pathogenesis of T2DM and provide an experimental basis for its clinical treatment., Results: Our findings revealed a reduction in both the species diversity and abundance of intestinal flora in T2DM mice, with significantly decreased levels of beneficial bacteria such as Lactobacillus and significantly increased levels of harmful bacteria such as Helicobacter pylori. Urinary metabolomics results identified 31 differential metabolites between T2DM and control mice, including Phosphatidylcholine, CDP-ethanolamine and Leukotriene A4, which may be closely associated with the glycerophospholipid and arachidonic acid pathways. Pearman correlation analysis showed a strong correlation between dopamine and gonadal, estradiol and gut microbiota, may be a novel direction underlying T2DM., Conclusion: In conclusion, our study suggests that alterations in gut microbiota and urinary metabolites are characteristic features of T2DM in mice. Furthermore, a strong correlation between dopamine, estradiol and gut microbiota, may be a novel direction underlying T2DM, the aim is to provide new ideas for clinical treatment and basic research., 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 © 2023 Song, Yan, Guo, Zhang, Wen, Li, Yang, Chen and Wang.)

Objective: To promote an effective strategy to improve the non-guideline-recommended prescribing (NGRP) of acid suppressive medications for stress ulcer prophylaxis (SUP) in critically ill patients and to evaluate the impact and barriers of a multifaceted intervention on NGRP in critically ill patients., Research Design and Methods: A retrospective, pre- post-intervention study was performed in the medical-surgical ICU. This study included pre-intervention and post-intervention period. There was no SUP guideline and intervention in the pre-intervention period. In the post-intervention period, the multifaceted intervention included five features: a practice guideline, an education campaign, medication review and recommendations, medication reconciliation, and pharmacist rounding with the ICU team., Results: A total of 557 patients were studied (305 in the pre-intervention group and 252 in the post-intervention group). Patients who underwent surgery, stayed in ICU more than 7 days, or used corticosteroids experienced significantly higher rate of NGRP in the pre-intervention group. The average percentage of patient days of NGRP was significantly reduced from 44.2% to 23.5% ( p < .001) by implementing the multifaceted intervention. The percentage of patients with NGRP decreased from 86.7% to 45.5% in terms of all 5 criteria (indication, dosage, IV to PO, duration, and ICU discharge; p  = .003). Per-patient NGRP cost decreased from $45.1 (22.6, 93.0) to $11.3 (11.3, 45.1; p  = .004). The main barrier influencing NGRP was the factors of the patient, including the concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), the number of comorbidities, and undergoing surgery., Conclusion: The multifaceted intervention was effective in improving NGRP. Further studies are needed to confirm whether our strategy is cost-effective.

Objectives: To evaluate the efficacy and safety of anti-vascular endothelial growth factor (anti-VEGF) therapy for myopia choroidal neovascularisation (CNV), and to compare the efficacy of two different anti-VEGF retreatment criteria., Data Sources: PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched from inception to 31 July 2022., Study Selection: Randomised controlled trials (RCTs) comparing anti-VEGF with sham, photodynamic therapy (PDT) or PDT combination therapy in patients with myopia CNV were reviewed and selected. RCTs comparing visual acuity (VA) stabilisation or disease activity as anti-VEGF retreatment criteria were also included in the study., Data Extraction and Synthesis: Two reviewers independently conducted data extraction and quality assessment. We used a random-effects model for all analyses. Primary outcomes included best-corrected visual acuity (BCVA) and central foveal thickness. Secondary outcomes included number of patients who gained more than three lines in BCVA, number of anti-VEGF injections and ocular adverse event (AE)., Results: Seven RCTs involving 1007 patients were included. Compared with sham and PDT therapy, anti-VEGF therapy achieved better BCVA gains of -0.28 logMAR (95% CI -0.36 to -0.20, p<0.00001) and -0.14 logMAR (95% CI -0.17 to -0.10, p<0.00001), respectively. Both ranibizumab and bevacizumab improved patients' vision better than PDT therapy and no definitive increased risk of ocular AE was observed. Analysis of two small RCTs showed that PDT combination therapy had similar visual improvement and needed fewer anti-VEGF injections compared with anti-VEGF monotherapy (weighted mean difference (WMD)=1.30; 95% CI 1.24 to 1.37, p<0.00001). Anti-VEGF retreatment guided by disease activity criteria resulted in comparable visual improvement and reduced anti-VEGF injections compared with retreatment guided by VA stabilisation (WMD=0.83; 95% CI 0.42 to 1.25, p<0.0001)., Conclusions: Anti-VEGF therapy is effective and well-tolerated for myopia CNV patients. Anti-VEGF retreatment guided by disease activity criteria can achieve comparable efficacy and potentially reduce anti-VEGF injections., Prospero Registration Number: CRD42021292806., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Coronary microvascular disease (CMVD) is a high risk factor for many cardiovascular events. Due to the limited understanding of its pathophysiological mechanism, modern medicine still lacks therapeutic drugs for CMVD. Existing clinical studies have shown that traditional Chinese medicine (TCM) can effectively improve the clinical symptoms and quality of life of CMVD patients. As an indispensable part of TCM, Chinese patent medicines (CPMs) are widely used in clinical practice. In the face of numerous oral CPMs for treatment of CMVD, how to choose a reasonable medication regimen is one of the important issues in clinic. Based on this, this paper reviewed the clinical efficacy and recommended level of 12 CPMs in the treatment of CMVD, which are recommended by expert consensus on diagnosis and treatment of coronary microvascular disease with integrated Chinese and Western medicine (WM). In addition, this study also systematically summarized the possible mechanisms of CPMs in the treatment of CMVD by protecting coronary microvascular endothelial cells, improving vascular endothelial function, inhibiting inflammation, reducing oxidative stress, promoting angiogenesis, and improving hemorheology, aiming to provide meaningful information for its clinical application., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Hypertension has become one of the major public health problems in the world. At present, the pathogenesis of hypertension has still not been completely elucidated. In recent years, an increasing evidence shows that intestinal microecology is closely related to hypertension, which provides a new thinking for the prevention and treatment of hypertension. Traditional Chinese medicine (TCM) has unique advantages in the treatment of hypertension. Taking intestinal microecology as the target, it is possible to interpreting the scientific connotation of TCM prevention and treatment of hypertension by updating the treatment concept of hypertension, so as to improve the therapeutic effect. In our study, the clinical evidence for TCM treatment of hypertension was systematicly summarized. And the relationship among TCM, intestinal microecology and hypertension was analyzed. In addition, the methods by which TCM regulates intestinal microecology to prevent and treat hypertension were presented, to provide new research ideas for prevention and treatment of hypertension., 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 © 2023 Yang, Lin, Liu, Song, Ge, Fan, Chen, Bi, Zhao, Wang, Wang and Mao.)

Background: Little evidence exists regarding the prevalence of pathogens in bloodstream infections (BSIs), the mortality risk, and the benefit of combination therapy over monotherapy. This study aims to describe patterns of empiric antimicrobial therapy, and the epidemiology of Gram-negative pathogens, and to investigate the effect of appropriate therapy and appropriate combination therapy on the mortality of patients with BSIs., Methods: This was a retrospective cohort study including all patients with BSIs of Gram-negative pathogens from January 2017 to December 2022 in a Chinese general hospital. The in-hospital mortality was compared between appropriate and inappropriate therapy, and between monotherapy and combination therapy for patients receiving appropriate therapy. We used Cox regression analysis to identify factors independently associated with in-hospital mortality., Results: We included 205 patients in the study, of whom 147 (71.71%) patients received appropriate therapy compared with 58 (28.29%) who received inappropriate therapy. The most common Gram-negative pathogen was Escherichia coli (37.56%). 131 (63.90%) patients received monotherapy and 74 (36.10%) patients received combination therapy. The in-hospital mortality was significantly lower in patients administered appropriate therapy than inappropriate therapy (16.33% vs. 48.28%, p = 0.004); adjusted hazard ratio [HR] 0.55 [95% CI 0.35-0.84], p = 0.006). In-hospital mortality was also not different in combination therapy and monotherapy in the multivariate Cox regression analyses (adjusted HR 0.42 [95% CI 0.15-1.17], p = 0.096). However, combination therapy was associated with lower mortality than monotherapy in patients with sepsis or septic shock (adjusted HR 0.94 [95% CI 0.86-1.02], p = 0.047)., Conclusions: Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to Gram-negative pathogens. Combination therapy was associated with improved survival in patients with sepsis or septic shock. Clinicians need to choose optical empirical antimicrobials to improve survival outcomes in patients with BSIs., (© 2023. The Author(s).)

Purpose: Tangzhiqing formula (TZQ) is a traditional Chinese medicine prescribed to treat lipid metabolism disorders, atherosclerosis, diabetes and diabetic cardiomyopathy. However, some challenges and hurdles remain. TZQ showed promising results in treating diabetes and hyperlipidaemia. However, its effect on and mechanism of action in hyperlipidaemia complicated with myocardial ischaemia (HL-MI) remain unknown., Methods: In this study, a network pharmacology-based strategy integrating target prediction was adopted to predict the targets of TZQ relevant to the treatment of HL-MI and to further explore the involved pharmacological mechanisms., Results: A total of 104 potential therapeutic targets were obtained, including MMP9, Bcl-2, and Bax, which may be related to the apoptosis and PI3K/AKT signalling pathways. Then, we confirmed these potential targets and pathways with animal experimentation. TZQ reduced lipid levels, increased the expression levels of Bcl-2, decreased Bax, caspase-3 and caspase-9 expression levels, and activated the PI3K/AKT signalling pathway., Conclusion: In conclusion, this study provides new insights into the protective mechanisms of TZQ against HL-MI through network pharmacology and pharmacological approaches., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

All species have a physiological need for sleep, and sleep is crucial for the preservation and restoration of many physiological processes in the body. Recent research on the effects of gut microbiota on brain function has produced essential data on the relationship between them. It has been discovered that dysregulation of the gut-brain axis is related to insomnia. Certain metabolites of gut microbiota have been linked to insomnia, and disturbances in gut microbiota can worsen insomnia. Traditional Chinese medicine (TCM) has unique advantages for the treatment of insomnia. Taking the gut microbiota as the target and determining the scientific relevance of TCM to the prevention and treatment of insomnia may lead to new concepts for the treatment of sleep disorders and improve the therapeutic effect of sleep. Taking the gut microbiota as an entry point, this paper reviews the relationship between gut microbiota and TCM, the relationship between gut microbiota and insomnia, the mechanism by which gut microbiota regulate sleep, and the mechanism by which TCM regulates gut microbiota for insomnia prevention and treatment. This review provides new ideas for the prevention and treatment of insomnia through TCM and new ideas for drug development., Competing Interests: Declaration of Competing Interest The authors of manuscript that titled“Gut microbiota: A new target of traditional Chinese medicine for insomnia” declared that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Low-carbon pilot policies are an important way to achieve the goal of "peak carbon neutrality" and are of great significance to China's international commitments. Based on a sample of 282 prefecture-level cities from 2006 to 2020, this paper investigates the impact of low-carbon pilot policies on urban carbon efficiency using a quasi-natural experiment with three batches of low-carbon pilot cities in 2010, 2012, and 2017, respectively. It is found that: (1) low-carbon pilot cities can improve urban carbon emission efficiency, which is still valid after a series of robustness tests such as the parallel trend test, placebo test, PSM-DID, and counterfactual test; (2) low-carbon pilot cities can enhance urban carbon emission efficiency by promoting the level of urban innovation and advanced urban industrial structure; and (3) the impact of low-carbon pilot policies on urban carbon emission efficiency is heterogeneous across cities with different geographical locations, population sizes, and resource endowment types. The findings provide policy insights for the promotion of low-carbon pilot policies and strengthening the construction of low-carbon pilot cities., Competing Interests: The authors declare that they have no competing interests, (Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare, usually indolent CD30+ T-cell lymphoma with tumor cells, often surrounded by eosinophils, expressing IL-13 and pSTAT6., Objectives: The aim of this study was to understand the unique tumor pathology and growth regulation of BIA-ALCL, leading to potential targeted therapies., Methods: We silenced CD30 and analyzed its effect on IL-13 signaling and tumor cell viability. IL-13 signaling receptors of BIA-ALCL cell lines were evaluated by flow cytometry and pSTAT6 detected by immunohistochemistry. CD30 was deleted by CRISPR/Cas9 editing. Effects of CD30 deletion on transcription of IL-13 and IL-4, and phosphorylation of STAT6 were determined by real-time polymerase chain reaction and western blotting. The effect of CD30 deletion on p38 mitogen-activated protein kinase (MAPK) phosphorylation was determined. Suppression of IL-13 transcription by a p38 MAPK inhibitor was tested. Tumor cell viability following CD30 deletion and treatment with a pSTAT6 inhibitor were measured in cytotoxicity assays., Results: BIA-ALCL lines TLBR1 and TLBR2 displayed signaling receptors IL-4Rα, IL-13Rα1 and downstream pSTAT6. Deletion of CD30 by CRISPR/Cas9 editing significantly decreased transcription of IL-13, less so Th2 cytokine IL-4, and phosphorylation of STAT6. Mechanistically, we found CD30 expression is required for p38 MAPK phosphorylation and activation, and IL-13-STAT6 signaling was reduced by an inhibitor of p38 MAPK in BIA-ALCL tumor cells. Tumor cell viability was decreased by silencing of CD30, and a specific inhibitor of STAT6, indicating STAT6 inhibition is cytotoxic to BIA-ALCL tumor cells., Conclusions: These findings suggest reagents targeting the IL-13 pathway, pSTAT6 and p38 MAPK, may become useful for treating BIA-ALCL patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (HL) share a similar cytological and high surface expression of CD30, and novel therapeutic strategies are needed. The EP300 and CREBBP acetyltransferases play essential roles in the pathogenesis of non-Hodgkin B cell lymphoma, but their functions in ALCL and HL are unknown. In the current study, we investigated the physiological roles of EP300 and CREBBP in both ALCL and HL, and exploited the therapeutic potential of EP300/CREBBP small molecule inhibitors that target either the HAT or bromodomain activities. Our studies demonstrated distinct roles for EP300 and CREBBP in supporting the viability of ALCL and HL, which was bolstered by the transcriptome analyses. Specifically, EP300 but not CREBBP directly modulated the expression of oncogenic MYC/IRF4 network, surface receptor CD30, immunoregulatory cytokines IL10 and LTA, and immune checkpoint protein PD-L1. Importantly, EP300/CREBBP HAT inhibitor A-485 and bromodomain inhibitor CPI-637 exhibited strong activities against ALCL and HL in vitro and in xenograft mouse models, and inhibited PD-L1 mediated tumor immune escape. Thus, our studies revealed critical insights into the physiological roles of EP300/CREBBP in these lymphomas, and provided opportunities for developing novel strategies for both targeted and immune therapies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

A dearomatization-dislocation-coupling cascade rapidly transforms aromatic isocyanides into highly functionalized cyclohexadienes. The facile cascade installs an exceptional degree of molecular complexity: three carbon-carbon bonds, two quaternary stereocenters, and three orthogonal functionalities, a cyclohexadiene, a nitrile, and an isocyanide. The tolerance of arylisocyanides makes the method among the mildest dearomatizations ever reported, typically occurring within minutes at -78 °C. Experimental and computational analyses implicate an electron transfer-initiated mechanism involving an unprecedented isocyanide rearrangement followed by radical-radical anion coupling. The dearomatization is fast, proceeds via a complex cascade mechanism supported by experimental and computational insight, and provides complex, synthetically valuable cyclohexadienes., (© 2022. The Author(s).)

Tangzhiqing formula (TZQ) is a traditional Chinese medicine prescribed to treat glucose and lipid metabolism disorders. A significant effect of TZQ on diabetes and hyperlipidemia has been demonstrated, but its effect on atherosclerosis (AS) remains unknown. This study combines pyroptosis with metabolomics to elucidate the effect and mechanism of TZQ on AS. A model of AS was developed using ApoE -/- mice fed a high-fat diet for 8 weeks. After 6 weeks of atorvastatin (Ator) or TZQ treatment, aortic lumen diameter, aortic lesion size, serum lipid profile, cytokines, and Nod-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis were analyzed. Serum metabolomics profiles were obtained to examine the effect of TZQ on AS and the correlation between pyroptosis and metabolites was further analyzed. As a result, TZQ significantly reduced the diameter of the common carotid artery during diastole and the blood flow velocity in the aorta during systole; reduced blood lipid levels, arterial vascular plaques, and the release of inflammatory cytokines; and inhibited the NLRP3 inflammasome-mediated pyroptosis. According to metabolomics profiling, TZQ is engaged in the treatment of AS via altering arachidonic acid metabolism, glycerophospholipid metabolism, steroid hormone production, and unsaturated fatty acid biosynthesis. The cytochrome P450 enzyme family and cyclooxygenase 2 (COX-2) are two major metabolic enzymes associated with pyroptosis., 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 Chen, Chen, Zhou, Song, Feng, Yang, Wang, Li, Ding, Zhang and Wang.)

Intestinal macrophages are the main participants of intestinal immune homeostasis and intestinal inflammation. Under different environmental stimuli, intestinal macrophages can be polarized into classical activated pro-inflammatory phenotype (M1) and alternative activated anti-inflammatory phenotype (M2). Its different polarization state is the "guide" to promoting the development and regression of inflammation. Under normal circumstances, intestinal macrophages can protect the intestine from inflammatory damage. However, under the influence of some genetic and environmental factors, the polarization imbalance of intestinal M1/M2 macrophages will lead to the imbalance in the regulation of intestinal inflammation and transform the physiological inflammatory response into pathological intestinal injury. In UC patients, the disorder of intestinal inflammation is closely related to the imbalance of intestinal M1/M2 macrophage polarization. Therefore, restoring the balance of M1/M2 macrophage polarization may be a potentially valuable therapeutic strategy for UC. Evidence has shown that traditional Chinese medicine (TCM) has positive therapeutic effects on UC by restoring the balance of M1/M2 macrophage polarization. This review summarizes the clinical evidence of TCM for UC, the vital role of macrophage polarization in the pathophysiology of UC, and the potential mechanism of TCM regulating macrophage polarization in the treatment of UC. We hope this review may provide some new enlightenment for the clinical treatment, fundamental research, and research and development of new Chinese medicine of UC., (Copyright © 2022 Yang, Lin, Feng, Liu, Song, Pan, Zhang, Dai, Ding, Chen and Wang.)

As a primary cause of death in patients with hematological malignancies and transplant recipients, invasive aspergillosis (IA) is a condition that warrants attention. IA infections have been increasing, which remains a significant cause of morbidity and mortality in immunocompromised patients. During the past decade, antifungal drug resistance has emerged, which is especially concerning for management given the limited options for treating azole-resistant infections and the possibility of failure of prophylaxis in those high-risk patients. Histone posttranslational modifications (HPTMs), mainly including acetylation, methylation, ubiquitination and phosphorylation, are crucial epigenetic mechanisms regulating various biological events, which could modify the conformation of histone and influence chromatin-associated nuclear processes to regulate development, cellular responsiveness, and biological phenotype without affecting the underlying genetic sequence. In recent years, fungi have become important model organisms for studying epigenetic regulation. HPTMs involves in growth and development, secondary metabolite biosynthesis and virulence in Aspergillus . This review mainly aims at summarizing the acetylation, deacetylation, methylation, demethylation, and sumoylation of histones in IA and connect this knowledge to possible HPTMs-based antifungal drugs. We hope this research could provide a reference for exploring new drug targets and developing low-toxic and high-efficiency antifungal strategies., 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 Li, Song, Wang, Dong, Bai, Wang, Zhu and Zhang.)

Background: Abnormal glycosylation in a variety of cancer types is involved in tumor progression and chemoresistance. Glycosyltransferase C1GALT1, the key enzyme in conversion of Tn antigen to T antigen, is involved in both physiological and pathological conditions. However, the mechanisms of C1GALT1 in enhancing oncogenic phenotypes and its regulatory effects via non-coding RNA are unclear., Methods: Abnormal expression of C1GALT1 and its products T antigen in human bladder cancer (BLCA) were evaluated with BLCA tissue, plasma samples and cell lines. Effects of C1GALT1 on migratory ability and proliferation were assessed in YTS-1 cells by transwell, CCK8 and colony formation assay in vitro and by mouse subcutaneous xenograft and trans-splenic metastasis models in vivo. Dysregulated circular RNAs (circRNAs) and microRNAs (miRNAs) were profiled in 3 pairs of bladder cancer tissues by RNA-seq. Effects of miR-1-3p and cHP1BP3 (circRNA derived from HP1BP3) on modulating C1GALT1 expression were investigated by target prediction program, correlation analysis and luciferase reporter assay. Functional roles of miR-1-3p and cHP1BP3 on migratory ability and proliferation in BLCA were also investigated by in vitro and in vivo experiments. Additionally, glycoproteomic analysis was employed to identify the target glycoproteins of C1GALT1., Results: In this study, we demonstrated upregulation of C1GALT1 and its product T antigen in BLCA. C1GALT1 silencing suppressed migratory ability and proliferation of BLCA YTS-1 cells in vitro and in vivo. Subsets of circRNAs and miRNAs were dysregulated in BLCA tissues. miR-1-3p, which is reduced in BLCA tissues, inhibited transcription of C1GALT1 by binding directly to its 3'-untranslated region (3'-UTR). miR-1-3p overexpression resulted in decreased migratory ability and proliferation of YTS-1 cells. cHP1BP3 was upregulated in BLCA tissues, and served as an miR-1-3p "sponge". cHP1BP3 was shown to modulate migratory ability, proliferation, and colony formation of YTS-1 cells, and displayed tumor-suppressing activity in BLCA. Target glycoproteins of C1GALT1, including integrins and MUC16, were identified., Conclusions: This study reveals the pro-metastatic and proliferative function of upregulated glycosyltransferase C1GLAT1, and provides preliminary data on mechanisms underlying dysregulation of C1GALT1 via miR-1-3p / cHP1BP3 axis in BLCA., (© 2022. The Author(s).)

In the field of network security, although there has been related work on software vulnerability detection based on classic machine learning, detection ability is directly proportional to the scale of training data. A quantum neural network has been proven to solve the memory bottleneck problem of classical machine learning, so it has far-reaching prospects in the field of vulnerability detection. To fill the gap in this field, we propose a quantum neural network structure named QDENN for software vulnerability detection. This work is the first attempt to implement word embedding of vulnerability codes based on a quantum neural network, which proves the feasibility of a quantum neural network in the field of vulnerability detection. Experiments demonstrate that our proposed QDENN can effectively solve the inconsistent input length problem of quantum neural networks and the problem of batch processing with long sentences. Furthermore, it can give full play to the advantages of quantum computing and realize a vulnerability detection model at the cost of a small amount of measurement. Compared to other quantum neural networks, our proposed QDENN can achieve higher vulnerability detection accuracy. On the sub dataset with a small-scale interval, the model accuracy rate reaches 99%. On each subinterval data, the best average vulnerability detection accuracy of the model reaches 86.3%., (© 2022. The Author(s).)

Early diagnosis of rheumatoid arthritis (RA) is crucial to prevent deterioration and improve the prognosis of disease outcome. However, current clinical diagnostic methods are unable to achieve accurate and early detection of RA. In this work, we designed an activatable organic nanoprobe ( ONP-CySe ) capable of specific and real-time imaging of ClO - in early RA. ONP-CySe comprises a near-infrared fluorescent selenomorpholine-caged cyanine dye as the sensing component and an amphiphilic triblock copolymer triphenyl phosphine derivative for mitochondria targeting. Our results showed that ONP-CySe successfully detected elevated levels of ClO - in the mitochondria of macrophages with high selectivity, low limit of detection (31.5 nM), excellent photostability, and good biocompatibility. Furthermore, ONP-CySe can also be used to monitor anti-inflammatory responses and efficacies of RA therapeutics, such as selenocysteine and methotrexate, in BALB/c mouse models. Therefore, our research proposes a universal molecular design strategy for the detection of ClO - , which holds potential for early diagnosis and drug screening for RA.

Purpose: Protocatechualdehyde (PCA) is a phenolic compound found in the roots of Salvia miltiorrhiza with anti-proliferative and antioxidant activities. At present, there are few studies on protocatechualdehyde against diabetic cataract (DC), and there is also lack of systematic research on the mechanism of protocatechualdehyde. Therefore, this study tried to comprehensively clarify the targets and complex mechanisms of PCA against DC from the perspective of network pharmacology., Materials and Methods: Through collecting relevant targets from the databases, GO and KEGG enrichment analysis were performed on the potential targets. Moreover, core genes were identified by topological analysis of protein-protein interaction (PPI) network and gene-phenotype correlation analysis., Results: The results indicated that protocatechualdehyde may be closely related to targets such as AKT1, MAPK3 and HDAC3, as well as signal pathways such as MAPK signaling pathway, PI3K-Akt signaling pathway and AGE-RAGE signaling pathway in diabetic complications., Conclusion: Together, the present study systematically clarified the possible mechanisms of protocatechualdehyde in the treatment of diabetic cataract and provided new ideas for the drug research of this disease., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Cheng et al.)

What Is Known and Objective: Intravenous to oral (IV-PO) antibiotic conversion, one of the critical elements in antimicrobial stewardship (AMS), is not well implemented in China. Studies on the strategy to apply the IV-PO conversion are needed. Our objective was to evaluate the impact and its barriers of a pharmacist-led practice with computerized reminders on IV-PO antibiotic conversion for community-acquired pneumonia (CAP) inpatients., Method: This was a retrospective, observational pre- and post-intervention study. Interventions were introduced in 2 sequential 12-month phases: Phase 1: pharmacists implemented the conventional practice of reviewing patient charts and medication records every 24 h and verbally informed the prescribers on eligible IV-PO conversions; Phase 2: pharmacists implemented a new intervention practice to inform the prescribers with a computerized reminder in electronic medical record system on eligible IV-PO conversions., Main Outcome Measures: The primary outcome was the proportion of patients who converted to oral therapy on the day patients were eligible for the conversion. The secondary outcomes were length of IV antibiotic therapy days, total length of antibiotic therapy days and length of hospital stay., Results: A total of 524 patients were studied (256 in phase 1 and 268 in phase 2). The proportion of patients who converted to oral therapy on the day patients were eligible for the conversion was significantly increased from 34.77% (89/256) in phase 1 to 62.69% (168/268) in phase 2 (p < 0.05). Length of IV antibiotic therapy days in phase 2 was shortened by 1.23 days, which was 5.52 days compared to 6.75 days in phase 1 (p < 0.05). Total length of antibiotic therapy days was 12.05 days in Phase 1, compared to 10.75 days in phase 2 (p > 0.05). Length of hospital stay for patients in phase 2 was significantly shorter, with a difference of 1.38 days (6.02 days vs. 7.40 days, p < 0.05). The most common barrier of not converting IV-PO was the presence of co-morbidity., Conclusion: The pharmacist-led IV-PO antibiotic conversion practice with computerized reminders was successful and feasible in Chinese hospitals. More IV-PO intervention studies in patients with other infections are needed in the future., (© 2021 John Wiley & Sons Ltd.)

Aberrant activation of NF-κB is the most striking oncogenic mechanism in B-cell lymphoma; however, its role in anaplastic large cell lymphomas (ALCL) has not been fully established and its activation mechanism(s) remain unclear. Using ALCL cell line models, we revealed the supporting roles for NFKB2 and the NIK pathway in some ALCL lines. To investigate the detailed activation mechanisms for this oncogenic pathway, we performed specifically designed alternative NF-κB reporter CRISPR screens followed by the RNA-seq analysis, which led us to identify STAT3 as the major mediator for NIK-dependent NF-κB activation in ALCL. Consistently, p-STAT3 level was correlated with NFKB2 nuclear accumulation in primary clinical samples. Mechanistically, we found that in NIK-positive ALK- ALCL cells, common JAK/STAT3 mutations promote transcriptional activity of STAT3 which directly regulates NFKB2 and CD30 expression. Endogenous expression of CD30 induces constitutive NF-κB activation through binding and degrading of TRAF3. In ALK+ ALCL, the CD30 pathway is blocked by the NPM-ALK oncoprotein, but STAT3 activity and resultant NFKB2 expression can still be induced by NPM-ALK, leading to minimal alternative NF-κB activation. Our data suggest combined NIK and JAK inhibitor therapy could benefit patients with NIK-positive ALK- ALCL carrying JAK/STAT3 somatic mutations.

Synthetic methods that utilise iron to facilitate C-H bond activation to yield new C-C and C-heteroatom bonds continue to attract significant interest. However, the development of these systems is still hampered by a limited molecular-level understanding of the key iron intermediates and reaction pathways that enable selective product formation. While recent studies have established the mechanism for iron-catalysed C-H arylation from aryl-nucleophiles, the underlying mechanistic pathway of iron-catalysed C-H activation/functionalisation systems which utilise electrophiles to establish C-C and C-heteroatom bonds has not been determined. The present study focuses on an iron-catalysed C-H allylation system, which utilises allyl chlorides as electrophiles to establish a C-allyl bond. Freeze-trapped inorganic spectroscopic methods ( 57 Fe Mössbauer, EPR, and MCD) are combined with correlated reaction studies and kinetic analyses to reveal a unique and rapid reaction pathway by which the allyl electrophile reacts with a C-H activated iron intermediate. Supporting computational analysis defines this novel reaction coordinate as an inner-sphere radical process which features a partial iron-bisphosphine dissociation. Highlighting the role of the bisphosphine in this reaction pathway, a complementary study performed on the reaction of allyl electrophile with an analogous C-H activated intermediate bearing a more rigid bisphosphine ligand exhibits stifled yield and selectivity towards allylated product. An additional spectroscopic analysis of an iron-catalysed C-H amination system, which incorporates N -chloromorpholine as the C-N bond-forming electrophile, reveals a rapid reaction of electrophile with an analogous C-H activated iron intermediate consistent with the inner-sphere radical process defined for the C-H allylation system, demonstrating the prevalence of this novel reaction coordinate in this sub-class of iron-catalysed C-H functionalisation systems. Overall, these results provide a critical mechanistic foundation for the rational design and development of improved systems that are efficient, selective, and useful across a broad range of C-H functionalisations., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Histone modification is closely associated with several diseases. The aim of the current study was to investigate the associations among histone acetylation, matrix metalloproteinases (MMPs) and premature rupture of membranes (PROM) during pregnancy. A total of 180 puerperants were divided into three groups: i) Preterm-PROM (PPROM), ii) term-PROM (TPROM) and iii) full-term labor (FTL). Enzyme-linked immunosorbent assay (ELISA) kits and western blotting were used to determine the protein concentrations of MMP2, MMP9, histone deacetylase (HDAC)1, HDAC2 and HDAC6, and the protein levels of histone H4 lysine (H4K)5 and H4K8 acetylation, respectively, in three types of fetal membranes. Additionally, human amniotic epithelial cells were used to determine the effects of the HDAC inhibitors droxinostat and chidamide on cell viability, histone acetylation and the levels of MMP2, MMP9, HDAC1, HDAC2 and HDAC6 in vitro , using the Cell Counting Kit-8 assay, western blotting and ELISA, respectively. Furthermore, the effects of droxinostat and chidamide on the invasion and migration abilities of human amniotic epithelial cells were investigated using transwell assays. In fetal membranes, the activities of MMP2 and MMP9 increased in PPROM, but decreased in TPROM. Further, the expression of HDAC1 was decreased and histone hyperacetylation was increased in both PPROM and TRPOM. In vitro experiments revealed that 5 µM droxinostat and 0.5 µM chidamide selectively decreased the level of HDAC and induced acetylation of H4K5 and H4K8. Additionally, the aforementioned HDAC inhibitors reduced human amniotic epithelial cell viability, invasion and migration, and decreased the expression levels of MMP2 and MMP9. The current study revealed a high expression level of MMP2 and MMP9 in PPROM compared with TPROM and FL tissue, which was in accordance with previously published studies. Furthermore, the in vitro tests performed in the current study revealed the effect of histone H4 hyperacetylation on inhibiting MMP2 and MMP9 levels in vitro was similar to that observed in TPROM. The results obtained in the current study may be used as a theoretical guide for clinical treatment of premature rupture of membranes., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Song et al.)

Hydrogen sulfide (H 2 S) is a vital endogenous signal molecule that exerts critical physiological functions such as biological regulation and cytoprotection. Despite significant progress in developing H 2 S donors, site-specific delivery and controllable release of H 2 S in biological systems remain a key challenge. Herein, we develop new Cys-triggered fluorescent H 2 S donor Pro-S that is composed of a dicyanoisophorone-based near-infrared (NIR) fluorescent dye and a thiocarbamate moiety. The H 2 S donor releases H 2 S under the attack of Cys, accompanied by the release of a fluorescent reporter, which enables the real-time capturing of H 2 S by fluorescence spectroscopy or microscopy. Pro-S exhibits strong NIR fluorescence enhancement (70-fold), excellent controllable H 2 S release (30 min), high H 2 S release efficiency (62%), and well live-cell compatibility, allowing for visualization of H 2 S release in cells and zebrafish. Moreover, Pro-S presents a good effect of anti-inflammation in RAW 264.7 cells. This work provides a new idea for the design of H 2 S donors, which may be beneficial to the comprehension of the potential mechanism of inflammation and optimization of treatment strategies.

13 a -( S )-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10- b )-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13 a ( S )-3-hydroxyl-6,7-dimethoxyphenanthro(9,10- b )-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood-brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats' plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15-30 nm), positive charge (5-9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2-6-fold and 1.3-7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously.

Exosomes (a type of nanoscale extracellular vesicle with a size range of 30-100 nm) mediate cell-cell communication by transferring functional biomolecules, and play an important role in various physiological and pathological processes, including tumor development and progression. More new and effective techniques for visualizing and tracking exosomes in cell-cell communication are highly desirable. However, the application of commonly used exosome-labeling probes is limited by the need for specificity and strict pH tolerance. We describe here the construction and testing of a novel exosome labeling fluorescent probe termed as "ExoTracker", which displayed low cytotoxicity and a high fluorescence intensity in acidic environments. ExoTracker was applied for effective tracking of exosomes in cell endocytosis.

More than 70% of Epstein-Barr virus (EBV)-negative Hodgkin lymphoma (HL) cases display inactivation of TNFAIP3 (A20), a ubiquitin-editing protein that regulates nonproteolytic protein ubiquitination, indicating the significance of protein ubiquitination in HL pathogenesis. However, the precise mechanistic roles of A20 and the ubiquitination system remain largely unknown in this disease. Here, we performed high-throughput CRISPR screening using a ubiquitin regulator-focused single-guide RNA library in HL lines carrying either wild-type or mutant A20. Our CRISPR screening highlights the essential oncogenic role of the linear ubiquitin chain assembly complex (LUBAC) in HL lines, which overlaps with A20 inactivation status. Mechanistically, LUBAC promotes IKK/NF-κB activity and NEMO linear ubiquitination in A20 mutant HL cells, which is required for prosurvival genes and immunosuppressive molecule expression. As a tumor suppressor, A20 directly inhibits IKK activation and HL cell survival via its C-terminal linear-ubiquitin binding ZF7. Clinically, LUBAC activity is consistently elevated in most primary HL cases, and this is correlated with high NF-κB activity and low A20 expression. To further understand the complete mechanism of NF-κB activation in A20 mutant HL, we performed a specifically designed CD83-based NF-κB CRISPR screen which led us to identify TAK1 kinase as a major mediator for NF-κB activation in cells dependent on LUBAC, where the LUBAC-A20 axis regulates TAK1 and IKK complex formation. Finally, TAK1 inhibitor Takinib shows promising activity against HL in vitro and in a xenograft mouse model. Altogether, these findings provide strong support that targeting LUBAC or TAK1 could be attractive therapeutic strategies in A20 mutant HL., Competing Interests: The authors declare no competing interest.

Small extracellular vesicles (sEVs) are enriched in glycoconjugates and display specific glycosignatures. Aberrant expression of surface glycoconjugates is closely correlated with cancer progression and metastasis. The essential functions of glycoconjugates in sEVs are poorly understood. In this study, we observed significantly reduced levels of bisecting GlcNAc in breast cancer. Introduction of bisecting GlcNAc into breast cancer cells altered the bisecting GlcNAc status on sEVs, and sEVs with diverse bisecting GlcNAc showed differing functions on recipient cells. Carcinogenesis and metastasis of recipient cells were enhanced by sEVs with low bisecting GlcNAc, and the pro-metastatic functions of sEVs was diminished by high bisecting GlcNAc modification. We further identified vesicular integrin β1 as a target protein bearing bisecting GlcNAc. Metastasis of recipient cells was strongly suppressed by high bisecting GlcNAc levels on vesicular β1. Our findings demonstrate the important roles of glycoconjugates on sEVs. Modification of sEV glycosylation may contribute to development of novel targets in breast cancer therapy., Competing Interests: The authors report no conflict of interest., (© 2020 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Purpose: For patients with refractory/relapsed Hodgkin lymphoma (roughly 20% of total cases), few effective therapeutic options exist. Currently, brentuximab vedotin (BV), a drug-conjugated anti-CD30 antibody, is one of the most effective approved therapy agents for these patients. However, many patients do not achieve complete remission and ultimately develop BV-resistant disease, necessitating a more detailed understanding of the molecular circuitry that drives BV sensitivity and the mechanism of BV resistance., Experimental Design: Here, we established a ubiquitin regulator-focused CRISPR library screening platform in Hodgkin lymphoma and carried out a drug sensitization screen against BV to identify genes regulating BV treatment sensitivity., Results: Our CRISPR library screens revealed the ubiquitin-editing enzymes A20 and RBX1 as key molecule effectors that regulate BV sensitivity in Hodgkin lymphoma line L428. A20 negatively regulates NF-κB activity which is required to prevent BV cytotoxicity. In line with these results, the RNA-seq analysis of the BV-resistant single-cell clones demonstrated a consistent upregulation of NF-κB signature genes, as well as the ABC transporter gene ABCB1. Mechanically, NF-κB regulates BV treatment sensitivity through mediating ABCB1 expression. Targeting NF-κB activity synergized well with BV in killing Hodgkin lymphoma cell lines, augmented BV sensitivity, and overcame BV resistance in vitro and in Hodgkin lymphoma xenograft mouse models., Conclusions: Our identification of this previously unrecognized mechanism provides novel knowledge of possible BV responsiveness and resistance mechanisms in Hodgkin lymphoma, as well as leads to promising hypotheses for the development of therapeutic strategies to overcome BV resistance in this disease., (©2020 American Association for Cancer Research.)

The merger of photoredox and nickel catalysis has enabled the construction of quaternary centers. However, the mechanism, role of the ligand, and effect of the spin state for this transformation and related Ni-catalyzed cross-couplings involving tertiary alkyl radicals in combination with bipyridine and diketonate ligands remain unknown. Several mechanisms have been proposed, all invoking a key Ni(III) species prior to undergoing irreversible inner-sphere reductive elimination. In this work, we have used open-shell dispersion-corrected DFT calculations, quasi-classical dynamics calculations, and experiments to study in detail the mechanism of carbon-carbon bond formation in Ni bipyridine- and diketonate-based catalytic systems. These calculations revealed that access to high spin states (e.g., triplet spin state tetrahedral Ni(II) species) is critical for effective radical cross-coupling of tertiary alkyl radicals. Further, these calculations revealed a disparate mechanism for the C-C bond formation. Specifically, contrary to the neutral Ni-bipyridyl system, diketonate ligands lead directly to the corresponding tertiary radical cross-coupling products via an outer-sphere reductive elimination step via triplet spin state from the Ni(III) intermediates. Implications to related Ni-catalyzed radical cross-couplings and the design of new transformations are discussed.