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Pei Wang,1,2,* Ming-Hao Xu,3,* Wen-Xin Xu,3,* Zi-Ying Dong,4 Ying-Hao Shen,3 Wen-Zheng Qin1 1Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Digestive Medicine, Wuwei People’s Hospital, Wuwei City, Gansu Province, 733000, People’s Republic of China; 3Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 4Department of CT/MRI Center, Wuwei People’s Hospital, Wuwei City, Gansu Province, 733000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen-Zheng Qin, Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China, Tel/Fax +86-21-64041990, Email qin.wenzheng@zs-hospital.sh.cn Ying-Hao Shen, Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, People’s Republic of China, Tel/Fax +86-21-64041990, Email syh12268@163.comBackground: Anti-programmed death-1 (PD1) antibodies have changed the treatment landscape for hepatocellular carcinoma (HCC) and exhibit promising treatment efficacy. However, the majority of HCCs still do not respond to anti-PD-1 therapy.Methods: We analyzed the expression of CXCL9 in blood samples from patients who received anti-PD-1 therapy and evaluated its correlation with clinicopathological characteristics and treatment outcomes. Based on the results of Cox regression analysis, a nomogram was established for predicting HCC response to anti-PD-1 therapy. qRT‒PCR and multiple immunofluorescence assays were utilized to analyze the proportions of N1-type neutrophils in vitro and in tumor samples, respectively.Results: The nomogram showed good predictive efficacy in the training and validation cohorts and may be useful for guiding clinical treatment of HCC patients. We also found that HCC cell-derived CXCL9 promoted N1 polarization of neutrophils in vitro and that AMG487, a specific CXCR3 inhibitor, significantly blocked this process. Moreover, multiple immunofluorescence (mIF) showed that patients with higher serum CXCL9 levels had greater infiltration of the N1 phenotype of tumor-associated neutrophils (TANs).Conclusion: Our study highlights the critical role of CXCL9 as an effective biomarker of immunotherapy efficacy and in promoting the polarization of N1-type neutrophils; thus, targeting the CXCL9-CXCR3 axis could represent a novel pharmaceutical strategy to enhance immunotherapy for HCC.Keywords: CXCL9, anti-PD-1 antibody, N1 polarization of neutrophils, nomogram

Lei Wei,1,* Dong Xu,2,* Yechang Qian,1 Guoyi Huang,1 Wei Ma,1 Fangying Liu,1 Yanhua Shen,1 Zhongfu Wang,1 Li Li,1 Shanfang Zhang,1 Yafang Chen1 1Department of Respiratory Disease, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 2Medical College of Soochow University, Suzhou, People's Republic of China *These authors contributed equally to this work Objective: To investigate the gene-expression profile of chronic obstructive pulmonary disease (COPD) patients and explore the possible therapeutic targets. Methods: The microarray raw dataset GSE29133, including three COPD samples and three normal samples, was obtained from Gene Expression Omnibus. After data preprocessing with the Affy package, Student’s t-test was employed to identify the differentially expressed genes (DEGs). The up- and downregulated DEGs were then pooled for gene-ontology and pathway-enrichment analyses using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The upstream regulatory elements of these DEGs were also explored by using Whole-Genome rVISTA. Furthermore, we constructed a protein–protein interaction (PPI) network for DEGs. The surfactant protein D (SP-D) serum level and HLA-A gene frequency in COPD patients and healthy controls were also measured by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction, respectively. Results: A total of 39 up- and 15 downregulated DEGs were screened. Most of the upregulated genes were involved in the immune response process, while the downregulated genes were involved in the steroid metabolic process. Moreover, we also found that HLA-A has the highest degree in the PPI network. The SP-D serum level and HLA-A gene frequency in COPD patients were significantly higher than those in healthy controls (13.62±2.09 ng/mL vs 10.28±2.86 ng/mL; 62.5% vs 12.5%; P

Background: Optimal dosing of the recombinant tissue-type plasminogen activator (rt-PA) is important in treating pulmonary thromboembolism (PTE). The aim of this study was to compare the efficacy and safety of a 50 mg/2 h rt-PA regimen with a 100 mg/2 h rt-PA regimen in patients with acute PTE.Methods: A prospective, randomized, multicenter trial was conducted in which 118 patients with acute PTE and either hemodynamic instability or massive pulmonary artery obstruction were randomly assigned to receive a treatment regiment of either rt-PA at 50 mg/2 h (n = 65) or 100 mg/2 h (n = 53). The efficacy was determined by observing the improvements of right ventricular dysfunctions (RVDs) on echocardiograms, lung perfusion defects on ventilation perfusion lung scans, and pulmonary artery obstructions on CT angiograms. The adverse events, including death, bleeding, and PTE recurrence, were also evaluated.Results: Progressive improvements in RVDs, lung perfusion defects, and pulmonary artery obstructions were found to be similarly significant in both treatment groups. This is true for patients with either hemodynamic instability or massive pulmonary artery obstruction. Three (6%) patients in the rt-PA 100 mg/2 h group and one (2%) in the rt-PA 50 mg/2 h group died as the result of either PTE or bleeding. Importantly, the 50 mg/2 h rt-PA regimen resulted in less bleeding tendency than the 100 mg/2 h regimen (3% vs 10%), especially in patients with a body weight < 65 kg (14.8% vs 41.2%, P = .049). No fatal recurrent PTE was found in either group.Conclusions: Compared with the 100 mg/2 h regimen, the 50 mg/2 h rt-PA regimen exhibits similar efficacy and perhaps better safety in patients with acute PTE. These findings support the notion that optimizing rt-PA dosing is worthwhile when treating patients with PTE.Trial Registration: clinicaltrials.gov; Identifier: NCT00781378. [ABSTRACT FROM AUTHOR]

Objective: Oxidative stress induced by free fatty acids contributes to the development of cardiovascular diseases in patients with metabolic syndrome. Reducing oxidative stress may attenuate these pathogenic processes. Activation of AMP-activated protein kinase (AMPK) has been reported to reduce intracellular reactive oxygen species (ROS) levels. The thioredoxin (Trx) system is a major antioxidant system. In this study, we investigated the mechanisms involved in the AMPK-mediated regulation of Trx expression and the reduction of intracellular ROS levels.Research Design and Methods: We observed that activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) significantly reduced ROS levels induced by palmitic acid in human aortic endothelial cells. Activation of AMPK increased expression of the antioxidant Trx, which mediated the ROS reduction. RT-PCR showed that AMPK regulated Trx at the transcriptional level.Results: Forkhead transcription factor 3 (FOXO3) was identified as the target transcription factor involved in the upregulation of Trx expression. FOXO3 bound to the Trx promoter, recruited the histone acetylase p300 to the Trx promoter, and formed a transcription activator complex, which was enhanced by AICAR treatment. AMPK activated FOXO3 by promoting its nuclear translocation. We further showed that AICAR injection increased the expression of Trx and decreased ROS production in the aortic wall of ApoE-/- mice fed a high-fat diet.Conclusions: These results suggest that activation of the AMPK-FOXO3 pathway reduces ROS levels by inducing Trx expression. Thus, the AMPK-FOXO3-Trx axis may be an important defense mechanism against excessive ROS production induced by metabolic stress and could be a therapeutic target in treating cardiovascular diseases in metabolic syndrome. [ABSTRACT FROM AUTHOR]

OBJECTIVE.: To test a new survey instrument and determine the acceptance and potential barriers of cervicovaginal self-sampling for high-risk human papillomavirus in rural Chinese women. MATERIALS AND METHODS.: Data from thirteen survey questions assessed acceptance of the self-sampling procedure. Pain, comprehension, and cultural beliefs were potential barriers evaluated by the survey. RESULTS.: A total of 1,560 women were surveyed. The average and mode number of steps of the self-sampling procedure recalled was 5 (out of 7). Ninety-one percent preferred performing the test at a clinic versus their home. The major barrier encountered was related to the educational level of the women. CONCLUSIONS.: The measure performed well in this population. The self-collection brush was well accepted by these women. Education is the largest hurdle to overcome in implementing a self-sampling screening program. [ABSTRACT FROM AUTHOR]

A significant monkeypox (mpox) outbreak occurred in 2022, particularly involving sexual and gender minority (SGM) groups. Stigma and misperceptions have led to fear of being labeled a member of the SGM group when obtaining immunization for mpox. We hypothesized that the most recommended injection site, intradermal injection in the forearm, stresses stigmatization. We conducted an online survey in a medical center in Taiwan between May 2023 and June 2023 among adults who were going to receive the second preexposure vaccination. The questionnaire comprised questions about physical and psychological impacts of the first mpox vaccination and the preference for the second vaccination location and factors influencing the preference. A total of 2,827 individuals (98.4% male) completed the questionnaires. Intradermal injection in the forearm was related to greater physical and psychological impacts of local adverse events, especially discoloration. "Beauty," "scar," and "others' view" were the most significant factors influencing preference for vaccination regimens. Compared to intradermal injection in the forearm, subjects who cared about "others' views" were likely to prefer vaccination in the deltoid. The odds ratio for preferring intradermally injection in the deltoid over in the forearm was 1.88 (95% CI 1.38-2.56). The odds ratio for preferring subcutaneous injection in the deltoid over intradermally injection in the forearm was 1.69 (95% CI 1.23-2.32). The odds ratio for preferring intradermally injection in the deltoid regardless of the route over intradermally injection in the forearm was 2.11 (95% CI 1.53-2.92). This study demonstrated the adverse events of different mpox vaccination regimens and their association with stigma. Recognizing the factors affecting the preference for mpox vaccine regimens is crucial for easing the mental stress of vaccinee., (© 2024. The Author(s).)

Objective: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is caused by an imbalance between pathogens and impaired host immune responses. Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) are the two major pathogens that cause NTM-PD. In this study, we sought to dissect the transcriptomes of peripheral blood immune cells at the single-cell resolution in NTM-PD patients and explore potential clinical markers for NTM-PD diagnosis and treatment., Methods: Peripheral blood samples were collected from six NTM-PD patients, including three MAB-PD patients, three MAC-PD patients, and two healthy controls. We employed single-cell RNA sequencing (scRNA-seq) to define the transcriptomic landscape at a single-cell resolution. A comprehensive scRNA-seq analysis was performed, and flow cytometry was conducted to validate the results of scRNA-seq., Results: A total of 27,898 cells were analyzed. Nine T-cells, six mononuclear phagocytes (MPs), and four neutrophil subclusters were defined. During NTM infection, naïve T-cells were reduced, and effector T-cells increased. High cytotoxic activities were shown in T-cells of NTM-PD patients. The proportion of inflammatory and activated MPs subclusters was enriched in NTM-PD patients. Among neutrophil subclusters, an IFIT1 + neutrophil subcluster was expanded in NTM-PD compared to healthy controls. This suggests that IFIT1+ neutrophil subcluster might play an important role in host defense against NTM. Functional enrichment analysis of this subcluster suggested that it is related to interferon response. Cell-cell interaction analysis revealed enhanced CXCL8-CXCR1/2 interactions between the IFIT1+ neutrophil subcluster and NK cells, NKT cells, classical mononuclear phagocytes subcluster 1 (classical Mo1), classical mononuclear phagocytes subcluster 2 (classical Mo2) in NTM-PD patients compared to healthy controls., Conclusions: Our data revealed disease-specific immune cell subclusters and provided potential new targets of NTM-PD. Specific expansion of IFIT1 + neutrophil subclusters and the CXCL8-CXCR1/2 axis may be involved in the pathogenesis of NTM-PD. These insights may have implications for the diagnosis and treatment of NTM-PD., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We study the electron tunneling (ET) and local Andreev reflection (AR) processes in a quantum dot (QD) coupled to the left and right ferromagnetic leads with noncollinear ferromagnetisms. In particular, we consider that the QD is also side-coupled to a nanowire hosting Majorana bound states (MBSs) at its ends. Our results show that when one mode of the MBSs is coupled simultaneously to both spin-up and spin-down electrons on the QD, the height of the central peak is different from that if the MBS is coupled to only one spin component electrons. The ET and AR conductances, which are mediated by the dot-MBS hybridization, strongly depend on the angle between the left and right magnetic moments in the leads. Interaction between the QD and the MBSs will result in sign change of the angle-dependent tunnel magnetoresistance. This is very different from the case when the QD is coupled to regular fermonic mode, and can be used for detecting the existence of MBSs, a current challenge in condensed matter physics under extensive investigations.

Fuzheng Huayu recipe (FZHYR) is a Chinese patent medicine for the treatment of fibrosis. The effects of FZHYR on pulmonary fibrosis and macrophage polarization were investigated in vitro . FZHYR inhibited pulmonary inflammation and fibrosis and M2 polarization of macrophages in bleomycin-induced pulmonary fibrosis (BPF) of rat model. Differentially expressed genes were screened by high-throughput mRNA sequencing and GSEA showed that oxidative phosphorylation (OXPHOS) was correlated with BPF. FZHYR inhibited expressions of Ndufa2 and Ndufa6 in lung tissues of BPF rats. These findings suggest that OXPHOS pathway serves as a possible target for pulmonary fibrosis therapy by FZHYR.

Reactions between tungsten alkylidyne [ t BuOCO]W≡C t Bu(THF) 2 1 and sulfur containing small molecules are reported. Complex 1 reacts with CS 2 to produce intermediate η 2 bound CS 2 complex [O 2 C( t BuC═)W(η 2 -( S , C )-CS 2 )(THF)] 8 . Heating complex 8 provides a mixture of a monomeric tungsten sulfido complex 9 and a dimeric complex 10 in a 4:1 ratio, respectively. Heating the mixture does not perturb the ratio. Addition of excess THF in a solution of 9 and 10 (4:1) converts 10 to 9 (>96%) with concomitant loss of (CS) x . Both 9 and 10 can be selectively crystallized from the mixture. An alternative synthesis of exclusively monomeric 9 involves the reaction between 1 and PhNCS. Demonstrating ring expansion metathesis polymerization (REMP), tethered tungsten alkylidene 8 polymerizes norbornene to produce cis -selective syndiotactic cyclic polynorbornene ( c -poly(NBE)).

The standout characteristic of the orchid perianth is the transformation of the upper median petal into a distinctively formed lip, which gives orchid flowers their typically zygomorphic symmetry and makes them the most popular ornamental plants worldwide. To study orchid flower development, two WUSCHEL-related homeobox (WOX) genes, PaWOX3 and PaWOX3B, were identified in Phalaenopsis. PaWOX3 and PaWOX3B mRNAs accumulate abundantly during early reproductive development and perianths of young buds, significantly decrease in mature flower and absent in vegetative leaves and roots. PaWOX3 and PaWOX3B virus-induced gene silencing (VIGS) knockdown in Phalaenopsis significantly reduces floral bud numbers, suggesting that PaWOX3/PaWOX3B may be involved in flower initiation. Transgenic Arabidopsis ectopically expressing repressor forms of PaWOX3/PaWOX3B and their Oncidium orthologue, OnPRS, exhibit lateral organ development defects, implicating these genes likely have function in regulating growth and differentiation for lateral organs. Neither PaWOX3, PaWOX3B single nor PaWOX3/PaWOX3B double VIGS Phalaenopsis altered the flower morphology. Interestingly, double silencing of PaWOX3 or PaWOX3B with OAGL6-2, which controlled the identity/formation of lips, altered the symmetry of 'BigLip' produced in OAGL6-2 VIGS. This result indicated that the levels of PaWOX3/PaWOX3B are still sufficient to maintain the symmetry for the OAGL6-2 VIGS 'BigLip'. However, the symmetry of the OAGL6-2 VIGS 'BigLip' can not be maintained once the expression of PaWOX3 or PaWOX3B is further reduced. Thus, in addition to control lip identity, this study further found that OAGL6-2 could cooperate with functionally redundant PaWOX3/PaWOX3B in maintaining the symmetric axis of lip., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and nonresponsive patients with advanced HCC identified SLAMF7 upregulation in immunotherapy-responsive HCC, and patients with HCC who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8+ T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization in vitro. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and CCL2 transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti-PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy., Significance: CCL2 upregulation caused by SLAMF7 deficiency in hepatocellular carcinoma cells induces immunosuppressive macrophage polarization and confers resistance to immune checkpoint blockade, providing potential biomarkers and targets to improve immunotherapy response in patients., (©2024 American Association for Cancer Research.)

Background: Lenvatinib is the most common multitarget receptor tyrosine kinase inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). Acquired resistance to lenvatinib is one of the major factors leading to the failure of HCC treatment, but the underlying mechanism has not been fully characterized. Methods: We established lenvatinib-resistant cell lines, cell-derived xenografts (CDXs) and patient-derived xenografts (PDXs) and obtained lenvatinib-resistant HCC tumor tissues for further study. Results: We found that ubiquitin-specific protease 14 (USP14) was significantly increased in lenvatinib-resistant HCC cells and tumors. Silencing USP14 significantly attenuated lenvatinib resistance in vitro and in vivo . Mechanistically, USP14 directly interacts with and stabilizes calcium- and integrin-binding protein 1 (CIB1) by reversing K48-linked proteolytic ubiquitination at K24, thus facilitating the P21-activated kinase 1 (PAK1)-ERK1/2 signaling axis. Moreover, in vivo adeno-associated virus 9 mediated transduction of CIB1 promoted lenvatinib resistance in PDXs, whereas CIB1 knockdown resensitized the response of PDXs to lenvatinib. Conclusions: These findings provide new insights into the role of CIB1/PAK1-ERK1/2 signaling in lenvatinib resistance in HCC. Targeting CIB1 and its pathways may be a novel pharmaceutical intervention for the treatment of lenvatinib-resistant HCC., Competing Interests: Competing Interests: Hui-Chuan Sun has received speaker fees from Hengrui, Bayer, and Eisai. The other authors declare that they have no known competing financial interests., (© The author(s).)

Background: Hypertension is a major risk factor for cardiovascular disease and stroke, and its prevalence is increasing worldwide. Health education interventions based on the health belief model (HBM) can improve the knowledge, attitudes, and behaviors of patients with hypertension and help them control their blood pressure., Aim: To evaluate the effects of health education interventions based on the HBM in patients with hypertension in China., Methods: Between 2021 and 2023, 140 patients with hypertension were randomly assigned to either the intervention or control group. The intervention group received health education based on the HBM, including lectures, brochures, videos, and counseling sessions, whereas the control group received routine care. Outcomes were measured at baseline, three months, and six months after the intervention and included blood pressure, medication adherence, self-efficacy, and perceived benefits, barriers, susceptibility, and severity., Results: The intervention group had significantly lower systolic blood pressure [mean difference (MD): -8.2 mmHg, P < 0.001] and diastolic blood pressure (MD: -5.1 mmHg, P = 0.002) compared to the control group at six months. The intervention group also had higher medication adherence (MD: 1.8, P < 0.001), self-efficacy (MD: 12.4, P < 0.001), perceived benefits (MD: 3.2, P < 0.001), lower perceived barriers (MD: -2.6, P = 0.001), higher perceived susceptibility (MD: 2.8, P = 0.002), and higher perceived severity (MD: 3.1, P < 0.001) than the control group at six months., Conclusion: Health education interventions based on the HBM effectively improve blood pressure control and health beliefs in patients with hypertension and should be implemented in clinical practice and community settings., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

A unique luminescent lanthanide metal-organic framework (LnMOF)-based fluorescence detection platform was utilized to achieve sensitive detection of vomitoxin (VT) and oxytetracycline hydrochloride (OTC-HCL) without the use of antibodies or biomolecular modifications. The sensor had a fluorescence quenching constant of 9.74 × 10 6  M -1 and a low detection limit of 0.68 nM for vomitoxin. Notably, this is the first example of a Tb-MOF sensor for fluorescence detection of vomitoxin. We further investigated its response to two mycotoxins, aflatoxin B1 and ochratoxin A, and found that their Stern-Volmer fluorescence quenching constants were lower than those of VT. In addition, the fluorescence sensor realized sensitive detection of OTC-HCL with a detection limit of 0.039 μM. In conclusion, the method has great potential as a sensitive and simple technique to detect VT and OTC-HCL in water., (© 2024 John Wiley & Sons Ltd.)

Background: Lymphocyte-related factors were associated with survival outcome of different types of cancers. Nevertheless, the association between lymphocytes-related factors and tumor response of immunotherapy remains unclear., Methods: This is a retrospective study. Eligible participants included patients with unresectable or advanced hepatocellular carcinoma (HCC) who underwent immunotherapy as their first-line treatment. Radiological assessment of tumor response adhered to RECIST 1.1 and HCC-specific modified RECIST (mRECIST) criteria. Univariate and multivariate logistic analyses were employed to analyze clinical factors associated with tumor response. Kaplan-Meier survivial analysis were employed to compare progression-free survival (PFS) and overall survival (OS) across different clinical factors. Furthermore, patients who received treatment with either a combination of bevacizumab and anti-PD-1(L1) antibody (Beva group) or tyrosine-kinase inhibitor (TKI) and anti-PD-1 antibody (TKI group) were examined to explore the relation between clinical factors and tumor response., Results: A total of 208 patients were enrolled in this study. The median PFS and OS were 9.84 months and 24.44 months,respectively. An independent factor associated with a more favorable tumor response to immunotherapy was identified when PLR<100. Patients with PLR<100 had longer PFS than other patients, while OS showed no significant difference. Further analysis revealed that PLR exhibited superior prognostic value in patients of the Beva group as compared to those in the TKI group., Conclusions: There exisits an association between PLR and tumor response as well as survival outcomes in patients receiving immunotherapy, particularly those treated with the combination of bevacizumab and anti-PD-1., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Hui-Chuan Sun has received honorarium or lecture fees from Roche, Bayer, MSD, Eisai, Hengrui, Innovent, TopAlliance, Abbott, Beigene, Gilead, and Zelgen during the last 5 years. Xiao-Dong Zhu has received speaker fees from Bei-Gene, Eisai, MSD, and Roche. The remaining authors have no conflicts of interest.]., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: This study aimed to reveal the unique microenvironment of peri-implantitis through single-cell analysis., Materials and Methods: Herein, we performed single-cell RNA sequencing (scRNA-seq) of biopsies from patients with peri-implantitis (PI) and compared the results with healthy individuals (H) and patients with periodontitis (PD)., Results: Decreased numbers of stromal cells and increased immune cells were found in the PI group, which implies a severe inflammatory infiltration. The fibroblasts were found to be heterogeneous and the specific pro-inflammatory CXCL13 + sub-cluster was more represented in the PI group, in contrast to the PD and H groups. Furthermore, more neutrophil infiltration was detected in the PI group than in the PD group, and cell-cell communication and ligand-receptor pairs revealed most neutrophils were recruited by CXCL13 + fibroblasts through CXCL8/CXCL6-CXCR2/CXCR1. Notably, our study demonstrated that the unique microenvironment of the PI group promoted the differentiation of monocyte/macrophage lineage cells into osteoclasts, which might explain the faster and more severe bone resorption in the progression of PI than PD., Conclusions: Collectively, this study suggests a unique immune microenvironment of PI, which may explain the differences between PI and PD in the clinic. These outcomes will aid in finding new specific and effective treatments for PI., (© 2024 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

A novel approach, to the best of our knowledge, is presented for assessing silicon wafer surface profiles using an interferometer and vertically rotatable wafer holder. This approach significantly enhances precision and reduces costs, and outperforms traditional techniques in measurement consistency and accuracy. It effectively reduces sample distortion and positional shifts owing to the removal and reinstallation of the wafers. Using this method, a global backsurface-referenced ideal range of 0.385 µm, warp of 0.193 µm, and other parameters were obtained, demonstrating its practicality in efficiently capturing key surface profile metrics for silicon wafers. This innovation promises substantial improvements in high-volume wafer surface profile testing, overcoming prevalent technological challenges in this industry.

The preparation of polycyclic aromatic hydrocarbons (PAHs) by the Scholl reaction is typically performed by using superstoichiometric oxidants. Herein, we develop an electrochemical continuous-flow Scholl reaction to access PAHs that features a reduction in the use of supporting electrolytes and easy scale-up without changing the reaction conditions and setups. This reaction allows the synthesis of distorted PAHs containing three [5]helicene units that possess intriguing electronic and optical properties.

Background and Purpose: We present this current study to complement with mesh inlays plausible benefits (UPHOLD-LITE System) on available long-term study amidst FDA's concern on mesh complications. This study aims to assess the medium-term outcomes of UPHOLD-LITE system for treatment of advanced pelvic organ prolapse (POP) and its complications, and lower urinary tract symptoms., Methods: This is a retrospective case series of 53 months follow-up of 123 consecutive patients who underwent UPHOLD-LITE system. Objective outcome measures the anatomical correction of prolapse with POP-Q ≤ Stage 1. Subjective outcome was patient's feedback to questions 2 and 3 of POPDI-6. Secondary outcome measures the quality of life, presence of lower urinary tract symptoms and complications. Quality of life is assessed by validated questionnaires on Urogenital Distress Inventory 6 (UDI-6), Incontinence Impact Questionnaire 7 (IIQ-7), Pelvic Organ Prolapse Distress Inventory 6 (POPDI-6), and Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire 12 (PISQ-12) at 1 and 3 years post-operatively., Results: Objective outcome at 1 and 3 years was at 96.7 % and 95.4 % respectively. The subjective cure was 95.1 % and 91.6 %. Five-year cumulative cure rate maintained at 87.2 %. Secondary outcomes observed improvement on UDI-6, IIQ-7, POPDI-6 and PISQ-12 postoperatively. Bladder outlet obstruction improved while de novo urodynamic stress incontinence (USI) increased slightly post surgically. Mesh erosion rate was 0.8 %., Conclusion: The UPHOLD-LITE system demonstrated good medium term anatomical correction of apical and anterior prolapse, with good subjective cure and improved quality of life. Whilst complication rate was low, slight increase in de novo USI was observed., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The prevalence rates of attention deficit hyperactivity disorder (ADHD), depression, anxiety and suicide are increasing in patients with atopic dermatitis (AD), although no research has systematically examined these trends yet. Here, we explore the prevalence of the occurrence of comorbidities, such as ADHD, depression, anxiety and suicide with AD. We searched seven electronic databases from inception to October 2022 to identify relevant studies, and the Agency for Healthcare Research and Quality (AHRQ) and Newcastle-Ottawa Scale (NOS) tools were used to assess the quality of observational studies. Statistical analysis was performed using R software. Publication bias was evaluated using Egger's and Begg's linear tests. The global prevalence rates of ADHD, depression, anxiety and suicidal ideation in patients with AD were 7%, 17%, 21% and 13%, respectively, between 1998 and October 2022. Among children (aged <18 years), North American children with AD had the highest prevalence rates of ADHD (10%), depression (13%) and anxiety (20%). Among the adult (aged ≥18 years) population, patients with AD in Africa had the highest prevalence rates of depression (36%) and anxiety (44%), while Asian adults with AD had the highest prevalence rates of ADHD (7%) and suicidal ideation (20%). These results highlight the high prevalence and comorbidity rates of mental illnesses with AD, which should be brought to the attention of patients with AD and their physicians., (© 2023 European Academy of Dermatology and Venereology.)

Background & Aims: Nonampullary duodenal neuroendocrine tumors (NAD-NETs) are rare with limited evidence regarding endoscopic treatment. The study aimed to investigate the efficacy and safety of endoscopic resection of well-differentiated NAD-NETs and evaluate long-term outcomes, including local recurrence and metastasis., Methods: A total of 78 patients with NAD-NETs who underwent endoscopic resection between January 2011 and August 2022 were included. The clinicopathologic characteristics and treatment outcomes were collected and analyzed., Results: En bloc resection was achieved for 74 of the tumors (94.9%) and R0 resection was obtained in 68 of the tumors (87.2%). Univariate analysis identified tumors in the second part of the duodenum, tumor size ≥ 10 mm and muscularis propria invasion as risk factors for non-curative resection. Two patients with R1 resection (vertical margin involvement) and two patients with lymphovascular invasion underwent additional surgery. Four patients experienced adverse events (5.1%), including two cases of delayed bleeding and two cases of perforation, all successfully managed conservatively. During a median follow-up period of 62.6 months, recurrence and lymph node metastasis were only detected in one patient with R1 resection 3 months after the original procedure., Conclusion: Endoscopic resection is safe and effective and provides a favorable long-term outcome for patients with well-differentiated NAD-NETs without regional lymph node or distant metastasis., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Gibberellic acid (GA3), produced industrially by Fusarium fujikuroi, stands as a crucial plant growth regulator extensively employed in the agriculture filed while limited understanding of the global metabolic network hinders researchers from conducting rapid targeted modifications. In this study, a small-molecule compounds-based targeting technology was developed to increase GA3 production. Firstly, various small molecules were used to target key nodes of different pathways and the result displayed that supplement of terbinafine improved significantly GA3 accumulation, which reached to 1.08 g/L. Subsequently, lipid and squalene biosynthesis pathway were identified as the key pathways influencing GA3 biosynthesis by transcriptomic analysis. Thus, the strategies including in vivo metabolic engineering modification and in vitro supplementation of lipid substrates were adopted, both contributed to an enhanced GA3 yield. Finally, the engineered strain demonstrated the ability to achieve a GA3 yield of 3.24 g/L in 5 L bioreactor when utilizing WCO as carbon source and feed., 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 © 2024 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Prunella vulgaris L. (PVL) is a perennial herb belonging to the Labiate family, first recorded in the "Shen Nong's Classic of the Materia Medica". PVL can enter the liver and gallbladder channel to show its function in clearing the liver fire, dispersing nodules, dissolving swelling, and improving vision. The traditional use of PVL is to protect liver function and has clinical applications in liver diseases therapy. The modern pharmacological studies have been shown to possess potential hepatoprotection, but its underlying mechanisms against alcoholic liver disease (ALD) in mice remains to be elucidated., Aim of the Study: This study aimed to explore the protective effect and potential mechanism of PVL on alcohol induced liver injury., Materials and Methods: We used Lieber-DeCarli ethanol liquid diet fed Male C57BL/6 mice for four weeks plus a single binge (NIAAA modified model) to establish an ALD model and explored the protective effects of PVL extract against ALD. Western blot, Flow cytometry and RT-qPCR methods were used to detect lipid metabolism disorders and the inflammatory response induced by macrophages in ALD mice, and the gut microbiota composition changes were detected by 16s rRNA to reveal the potential mechanism of PVL against ALD., Results: In ALD mice, PVL can ameliorate excessive alcohol intake-induced liver injury and lipid metabolism disorders associated with improvement of gut microbiota dysbiosis and intestinal barrier damage. PVL reduced the translocation of endotoxin, which subsequently inhibits hepatic inflammation mediated by the TLR4/MyD88 signaling pathway., Conclusion: These findings demonstrated the protective potential of PVL against gut dysbiosis and endotoxin leakage in ALD mice, which provides a theoretical basis for PVL against liver diseases., 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 B.V. All rights reserved.)

Objective: This study aimed at determining the optimal dose combination of alfentanil and propofol for outpatient abortion anesthesia., Patients and Methods: The study was separated into two parts. In the first part, patients were to determine the median effective dose (ED50) and the 95% effective dose (ED95) of alfentanil in combination with 2.5 mg·kg-1 propofol to inhibit body movements during the abortion using the Dixon up-and-down sequential allocation method. In the second part, 170 patients were randomly divided into group C (2.0 mg·kg-1 propofol with alfentanil 12.16 μg·kg-1) and group E (2.5 mg·kg-1 propofol with its ED95) to compare the anesthetic effect. The primary outcome was the sedation level during general anesthesia. The secondary outcomes were circulation, respiratory complications, and postoperative recovery quality., Results: The ED50 and the ED95 values of alfentanil were 3.37 μg·kg-1 (95% CI: 2.58-3.97 μg·kg-1) and 4.68 μg·kg-1 (95% CI: 4.04-9.32 μg·kg-1). The frequency of deep sedation in group E was significantly higher than in group C (76.5% vs. 60%). Patients in group C showed more wakefulness even during the surgery (14.3% vs. 4.4%). The results of our exploratory analyses did not reveal differences in respiratory depression, circulatory depression, postoperative side effects, or recovery outcomes., Conclusions: The combination of 2.5 mg·kg-1 propofol and 4.68 μg·kg-1 alfentanil produces a better sedative effect than the combination of 2.0 mg·kg-1 propofol and 12.16 μg·kg-1 alfentanil without increasing additional risks associated with anesthesia.

Background: Prior studies have shown that, when administered as an intravenous bolus to prevent uterine atony, prophylactic phenylephrine infusion increased the dose requirement of oxytocin and second-line uterotonics. For the prevention of uterine atony, oxytocin should be delivered by continuous infusion. Here, we aimed to determine the ED50 and ED90 parameters (the effective doses for 50 and 90% patients without uterine atony) of oxytocin for co-infusion with prophylactic phenylephrine during cesarean delivery., Methods: In this prospective randomized double-blinded dose-finding study, one hundred patients were divided into four groups to receive 2.5, 5.0, 7.5, or 10 IU/h oxytocin infusion, after the umbilical cord was clamped during the study period. The uterine tone was evaluated and defined as either adequate or inadequate. Probit regression analysis was applied to calculate the ED50 and ED90 of oxytocin infusion. Uterine tone, the percentage of patients who needed additional oxytocin bolus, second-line uterotonics, side effects, estimated blood loss, and neonatal outcomes were monitored., Results: The estimated ED50 and ED90 values of the oxytocin infusion doses for the prevention of uterine atony were 1.9 IU/h (95% CI -4.6-3.8) IU/h and 9.3 IU/h (95% CI 7.3-16.2) IU/h, respectively. Across groups, there was a significant linear trend between the infusion dose and the percentage of patients who required additional oxytocin (p-value = 0.002). No differences were observed in the incidence of side effects and neonatal outcomes., Conclusion: Under the conditions of this study, the ED90 of oxytocin infusion for the prevention of uterine atony was 9.3 IU/h, which is higher than the current recommendation. This finding is helpful for clinical practice, because of the routine use of phenylephrine in cesarean delivery. Further studies are needed to determine the appropriate initial bolus of oxytocin after neonatal delivery., Trial Registration: The study was registered on the Chinese Clinical Trial Register (register no. ChiCTR2200059556 )., (© 2023. The Author(s).)

Objective: To investigate the role of neutrophil extracellular traps (NETs) in immune checkpoint inhibitor-associated myocarditis (ICIAM) with programmed death protein-1 (PD-1) inhibitors involvement, and to explore the therapeutic potential of targeting NETs in the treatment of ICIAM. Methods: Thirty 6-week-old male BALB/c mice were randomly divided into control group ( n =10), myocarditis group ( n =10), and treatment group ( n =10). Apart from the control group, each mouse was subcutaneously injected with 100 μl of complete Freund's adjuvant containing 250 μg of mouse cardiac troponin I peptide on the 1st and 7th day. Starting on the 8th day, PD-1 inhibitor (15 μg/per mouse) was intraperitoneally injected every other day for a total of 5 times. Since 1 day before the beginning of PD-1+TnI injection, the treatment group was injected with PF-1355 (50 mg·kg -1 ·d -1 ) for 16 consecutive days. The mice's general state was observed during the whole process. Real-time fluorescence quantitative PCR (RTFQ-PCR) was carried out to evaluate the transcriptional regulation of neutrophil related chemokines, NETs, pyronecrosis related factors and proinflammatory cytokines. Immunohistochemistry, immunofluorescence and western blot were applied to determine the changes of pyrosis related molecules. Echocardiography showed the differences of main cardiac indexes while cardiac pathology compared the degree of inflammatory infiltration in 3 gruops. Results: The immunofluorescence intensity of myocardial NETs in the myocarditis group was significantly increased compared to the control group mice (2.49±0.08 and 0.99±0.26, P <0.001). The protein expression levels of pyroptosis-related NLRP3, cleaved-Caspase 1, Caspase 1, cleaved-GSDMD, GSDMD, IL-1β and IL-18 in myocardial tissue of the model group were higher than those of the control group (all P <0.05). After treatment with PF-1355, compared to the myocarditis group, the left ventricular ejection fraction (LVEF) (73.58%±5.31% and 58.12%±3.19%, P <0.001) and left ventricular fraction shortening (LVFS) (39.78%±4.31% and 33.89%±2.19%, P <0.001) increased. H-E staining showed a reduction in inflammatory infiltration area in the treatment group compared to the myocarditis group (30.12%±3.57% and 14.92%±2.46%, P <0.001). The immunofluorescence intensity of NETs decreased in the treatment group compared to the myocarditis group (2.52±0.04 and 1.03±0.05, P <0.001). The levels of NLRP3 and other pyroptosis-related molecules were downregulated in the treatment group compared to the myocarditis group (all P< 0.05). Conclusions: NETs lead to myocardial cell pyroptosis by activating the NLRP3 inflammasome in PD-1 inhibitor-associated myocarditis. The specific MPO inhibitor PF-1355 shows a therapeutic potential by regulating the formation of NETs, decreasing NLRP3 level and relieving myocardial pyroptosis, thus reducing myocardial damage.

Objective: To analyze the efficacy and safety of the sodium channel blockers (SCB) antiseizure medication in the treatment of focal epilepsy in infants under 6 months of age. Methods: This was a case series study. Infants with focal epilepsy with onset within 6 months of age and treated with SCB attending the Department of Neurology of Beijing Children's Hospital from June 2016 to April 2022 were collected. The clinical data, auxiliary examinations, SCB application, efficacy, adverse reactions, and prognosis were analyzed retrospectively. Patients were grouped according to type of seizure and epileptic syndrome, age of onset and etiology. Chi square test and Fisher exact test were used to analyze the differences between groups statistically. Results: A total of 118 infants were enrolled, 65 males and 53 females, with an age of epilepsy onset of 56 (4, 114) days. Developmental and epileptic encephalopathy was diagnosed in 60 infants, 39 had self-limited neonatal and (or) infantile epilepsy, and 19 had non-syndromic focal epilepsy. Application of SCB: 106 used oxcarbazepine, 2 used lacosamide, 9 switched from oxcarbazepine to lacosamide or a combination of 2 SCB, and 1 used oxcarbazepine, lacosamide, and lamotrigine successively; oxcarbazepine was the first choice in 46 cases. The age at which SCB was applied was 103 (53, 144) days. The children were followed up for 6 months to 6 years. SCB was effective in 89 cases (75.4%), including 70 cases (59.3%) who achieved seizure freedom. The seizure-free rate was higher in the focal epilepsy only group than in the group with other seizure types (64.4% (65/101) vs. 4/17, χ ²=9.99, P <0.05). The responder and seizure-free rates were all higher in the group with the onset age of >3-6 months than the group >1-3 months (84.4% (38/45) vs. 62.5% (20/32), 73.3% (33/45) vs. 46.9% (15/32), χ ²=4.85 and 5.58, both P <0.05). With the exception of variants in the PRRT2 gene, those with variants in sodium or potassium channels had higher responder and seizure-free rates than those with variants in other genes(86.2% (25/29) vs. 45.5% (10/22), 62.1% (18/29) vs. 22.7% (5/22), χ ²=9.65 and 7.82,both P <0.05). The most common adverse event was transient hyponatremia, which happened in 66 cases (55.9%). There were 9 cases of rash, which subsided in 6 cases after discontinuing oxcarbazepine and switching to lacosamide, and 7 cases of electrocardiogram abnormalities, which improved after withdrawing oxcarbazepine and changing to lacosamide in 1 case. Conclusion: SCB are effective and tolerable in the treatment of focal epilepsy in infants under 6 months of age, with better efficacy in patients with genetic variants of the sodium or potassium channel, focal seizures only, and seizure onset >3-6 months of age.

Tetracycline (TC), which is ubiquitous in the aquatic environment, can cause ecological imbalance and adversely affect human health. Therefore, a quick, inexpensive, and easy method for the detection of TC in water systems is highly desirable. This study reports the development of a novel electrochemical sensor from waste peanut shell for the quick detection of TC in water. Raman and TEM lattice mapping analyses confirmed the successful preparation of graphene -like biochar from waste peanut shells (PSs) via hydrothermal and pyrolysis processes. An electrochemical sensor, PS@glassy carbon electrode (PS@GCE), was then developed by coating the prepared graphene-like biochar on the surface of a glass electrode to enhance its conductivity. The feasibility of using this sensor for the detection of TC in the aqueous system was investigated. The PS@GCE sensor exhibited excellent sensitivity with a low detection limit of 3.6 × 10 --9 nM and a linear range of 10 -10 -10 2 μM. These results were attributed to the large specific surface area and high conductivity, of the PS biochar. The stability of the PS@GCE sensor was also investigated in the presence of TC (10 -4  M) and interfering species (10 -2  M) and recovery rates in the range of 86.4%-116.0% were achieved, thus indicating the absence of an interference range of range of 84.3%-98.2% with relative standard deviation lower than 6% were achieved upon the detection of TC in natural water samples using the designed sensor, thus confirming the superior repeatability of the PS@GCE sensor. Consequently, the designed electrode has a high potential for application in the detection of TC in natural aqueous systems., 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 Inc. All rights reserved.)

Objective: Two-dimensional shear wave elastography (2-D SWE) has been proven to detect hyperlipidemia-induced elastic abnormality in the corpus cavernosum. This study investigated cytological factors affecting the elasticity of the corpus cavernosum in rabbits with hyperlipidemia using single-cell RNA sequencing (scRNA-seq)., Methods: Male New Zealand white rabbits were randomly divided into a hyperlipidemia group (high-cholesterol diet) and a control group (standard diet). Penile 2-D SWE was performed to detect the elastic abnormality in the corpus cavernosum. ScRNA-seq was performed to observe cellular changes in the corpus cavernosum of rabbits with hyperlipidemia. Immunohistochemistry, immunofluorescence and histological examinations were conducted to verify the results of scRNA-seq., Results: Two-dimensional SWE revealed that the Young's modulus of the corpus cavernosum was significantly greater in the hyperlipidemia group than that in the control group (p < 0.001). Histological findings revealed extracellular matrix accumulation within the corpus cavernosum, with stronger staining of collagen types I and Ⅲ. ScRNA-seq revealed that fibroblasts, smooth muscle cells, and endothelial cells were the major cell types in the corpus cavernosum. A novel subtype of fibroblasts (myofibroblast) was discovered in the hyperlipidemia group, which was verified by immunofluorescence staining and gene ontology analysis. Fibroblasts, smooth muscle cells and endothelial cells were three cellular sources for myofibroblasts., Conclusion: Myofibroblasts are activated and proliferate and secrete large amounts of collagen fibers in the corpus cavernosum during hyperlipidemia, leading to abnormal Young's modulus detected by 2-D SWE and their recognition as a new factor affecting the hyperlipidemia-induced elastic abnormality of the corpus cavernosum., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Walnut Oil (WO) is recognized for its potential to improve cognition, but the mechanisms of its action related to improving cognitive impairment are not yet clear. In this study, the components of walnut oil were measured, and it was found that WO supplementation for 8 weeks could significantly prevent cognitive behavioral deficits and synaptic dysfunction induced by intraperitoneal injection of scopolamine (SCOP) in mice. By comparing and analyzing the changes in the hippocampal synaptic structure, oxidative stress, neurotransmitter fluctuations, brain transcriptome, inflammatory factors and gut microbiota in mice from different treatment groups, we observed a significant correlation between synaptic transmission genes, gut microbiota and neurotransmission in the WO supplemented group. It was found that WO supplementation could influence the secretion of neurotransmitters Ach and 5-HT by modulating the gut microbiota in vivo , thereby improving cognitive impairment through the central nervous system and hypothalamic-pituitary-adrenal (HPA) axis regulation.

The biochars of WP300, WP500, and WP700 were prepared by pyrolyzing walnut green husk under 300℃, 500℃, and 700℃ with the oxygen-free condition for removing Pb 2+ , Cu 2+ , and Cd 2+ in an aqueous solution. The results revealed that WP500 prepared under the medium pyrolysis temperature achieved the best adsorption performance for heavy metals, and the highest removal efficiency was reached when the solution pH was 8, in which the removal efficiency of Pb 2+ , Cu 2+ , and Cd 2+ were 97.87%, 99.78%, and 71.15%, respectively. The required biochar dosage for heavy metal removal varied under different adsorption conditions. In the single-metal system, the optimal dosage for WP500 in the Pb 2+ , Cu 2+ , and Cd 2+ solutions was 1.3 g·L -1 , 2.1 g·L -1 , and 1.9 g·L -1 , respectively, whereas in the pollution metals system, the optimal biochar dosage was 5.1 g·L -1 . In addition, the adsorption capacity of WP500 for the three heavy metals followed the order of Pb 2+ >Cu 2+ >Cd 2+ under the single and combined-metals system, indicating that there were no synergistic or antagonistic effects among these three adsorbates. The fitting results of the adsorption isotherm model suggested that various immobilization methods existed in adsorption process between WP500 and Pb 2+ , Cu 2+ , and Cd 2+ . The kinetic fitting results suggested that the main reaction between WP500 and Pb 2+ , Cu 2+ , and Cd 2+ was chemical adsorption. The mechanisms of WP500 for heavy metals involved pore-filling, electrostatic attraction, ion-exchange, mineral precipitation, complexation, and π-π electron donor-accepter interaction. To conclude, this study offered a new insight for the resource utilization of the waste walnut green husk.

Background: Smooth muscle cell (SMC) phenotypic switching has been increasingly detected in aortic aneurysm and dissection (AAD) tissues. However, the diverse SMC phenotypes in AAD tissues and the mechanisms driving SMC phenotypic alterations remain to be identified., Methods: We examined the transcriptomic and epigenomic dynamics of aortic SMC phenotypic changes in mice with angiotensin II-induced AAD by using single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin. SMC phenotypic alteration in aortas from patients with ascending thoracic AAD was examined by using single-cell RNA sequencing analysis., Results: Single-cell RNA sequencing analysis revealed that aortic stress induced the transition of SMCs from a primary contractile phenotype to proliferative, extracellular matrix-producing, and inflammatory phenotypes. Lineage tracing showed the complete transformation of SMCs to fibroblasts and macrophages. Single-cell sequencing assay for transposase-accessible chromatin analysis indicated that these phenotypic alterations were controlled by chromatin remodeling marked by the reduced chromatin accessibility of contractile genes and the induced chromatin accessibility of genes involved in proliferation, extracellular matrix, and inflammation. IRF3 (interferon regulatory factor 3), a proinflammatory transcription factor activated by cytosolic DNA, was identified as a key driver of the transition of aortic SMCs from a contractile phenotype to an inflammatory phenotype. In cultured SMCs, cytosolic DNA signaled through its sensor STING (stimulator of interferon genes)-TBK1 (tank-binding kinase 1) to activate IRF3, which bound and recruited EZH2 (enhancer of zeste homolog 2) to contractile genes to induce repressive H3K27me3 modification and gene suppression. In contrast, double-stranded DNA-STING-IRF3 signaling induced inflammatory gene expression in SMCs. In Sting -/- mice, the aortic stress-induced transition of SMCs into an inflammatory phenotype was prevented, and SMC populations were preserved. Finally, profound SMC phenotypic alterations toward diverse directions were detected in human ascending thoracic AAD tissues., Conclusions: Our study reveals the dynamic epigenetic induction of SMC phenotypic alterations in AAD. DNA damage and cytosolic leakage drive SMCs from a contractile phenotype to an inflammatory phenotype., Competing Interests: Disclosures Dr LeMaire serves as a consultant for Terumo Aortic and Cerus and serves as a principal investigator for clinical studies sponsored by Terumo Aortic and CytoSorbents. The other authors report no conflicts.

Background: The combination of ropivacaine and dexmedetomidine has been used as an epidural analgesic for inducing labor. However, there is limited data regarding the administration of epidural analgesia for labor maintenance, hence, this study aimed to determine the optimum concentration through dose-response curves of ropivacaine plus dexmedetomidine, which could be used along with the Programmed Intermittent Epidural Bolus (PIEB) technique. Methods: One hundred parturients were randomized into 4 groups who were administered four different doses of ropivacaine (dexmedetomidine at 0.4 μg mL -1 ): 0.04%, 0.06%, 0.08%, and 0.1%. The primary outcome that was determined included the proportion of patients experiencing breakthrough pain during their 1st stage of labor. Breakthrough pain was described as a visual analog scale [VAS] score of >30 mm, requiring supplemental epidural analgesia after the administration of at least one patient-controlled bolus. The effective concentration of analgesia that was used for labor maintenance in 50% (EC50) and 90% (EC90) of patients were calculated with the help of probit regression. Secondary outcomes included epidural block characteristics, side effects, neonatal outcomes, and patient satisfaction. Results: The results indicated that the proportion of patients without breakthrough pain was 45% (10/22), 55% (12/22), 67% (16/24), and 87% (20/23) for 0.04%, 0.06%, 0.08%, and 0.10% doses of the analgesic that were administered, respectively. The EC50 value was 0.051% (95% confidence interval [CI], 0.011%-0.065%) while the EC90 value was recorded to be 0.117% (95% CI, 0.094%-0.212%). Side effects were similar among groups. Conclusion: A ropivacaine dose of 0.117% can be used as epidural analgesia for maintaining the 1st stage of labor when it was combined with dexmedetomidine (0.4 μg mL -1 ) and the PIEB technique. Clinical Trial Register: https://www.chictr.org.cn/index.aspx, identifier ChiCTR2200059557., 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 Shen, Drzymalski, Zhu, Lin, Tu, Shen and Xiao.)

Aims: Specific fibroblast markers and in-depth heterogeneity analysis are currently lacking, hindering functional studies in cardiovascular diseases (CVDs). Here, we established cell-type markers and heterogeneity in murine and human arteries and studied the adventitial fibroblast response to CVD and its risk factors hypercholesterolaemia and ageing., Methods and Results: Murine aorta single-cell RNA-sequencing analysis of adventitial mesenchymal cells identified fibroblast-specific markers. Immunohistochemistry and flow cytometry validated platelet-derived growth factor receptor alpha (PDGFRA) and dipeptidase 1 (DPEP1) across human and murine aorta, carotid, and femoral arteries, whereas traditional markers such as the cluster of differentiation (CD)90 and vimentin also marked transgelin+ vascular smooth muscle cells. Next, pseudotime analysis showed multiple fibroblast clusters differentiating along trajectories. Three trajectories, marked by CD55 (Cd55+), Cxcl chemokine 14 (Cxcl14+), and lysyl oxidase (Lox+), were reproduced in an independent RNA-seq dataset. Gene ontology (GO) analysis showed divergent functional profiles of the three trajectories, related to vascular development, antigen presentation, and/or collagen fibril organization, respectively. Trajectory-specific genes included significantly more genes with known genome-wide associations (GWAS) to CVD than expected by chance, implying a role in CVD. Indeed, differential regulation of fibroblast clusters by CVD risk factors was shown in the adventitia of aged C57BL/6J mice, and mildly hypercholesterolaemic LDLR KO mice on chow by flow cytometry. The expansion of collagen-related CXCL14+ and LOX+ fibroblasts in aged and hypercholesterolaemic aortic adventitia, respectively, coincided with increased adventitial collagen. Immunohistochemistry, bulk, and single-cell transcriptomics of human carotid and aorta specimens emphasized translational value as CD55+, CXCL14+ and LOX+ fibroblasts were observed in healthy and atherosclerotic specimens. Also, trajectory-specific gene sets are differentially correlated with human atherosclerotic plaque traits., Conclusion: We provide two adventitial fibroblast-specific markers, PDGFRA and DPEP1, and demonstrate fibroblast heterogeneity in health and CVD in humans and mice. Biological relevance is evident from the regulation of fibroblast clusters by age and hypercholesterolaemia in vivo, associations with human atherosclerotic plaque traits, and enrichment of genes with a GWAS for CVD., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis., Methods: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis., Results: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors., Conclusions: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation., Competing Interests: Disclosures S.H. Lin is an Advisory Board member of AstraZeneca, Beyond Spring Pharmaceuticals, and STCube Pharmaceuticals. The other authors report no conflicts.

Background: Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear., Methods: We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples., Results: We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy., Conclusions: In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR., (© 2023. The Author(s).)

Tryptophan is one of important amino acids in the human body, therefore its detection is particularly important. The 3,5-bis(4-pyridyl)-4-amino-1,2,4-triazole (BPAT) organic molecule was designed to be used as fluorescence detectors to detect tryptophan molecules for the interaction between the host and the guest. BPAT shows good sensitivity and selectivity towards tryptophan compared with other amino acid molecules. The limit of detection obtained from formula 3δ/K SV is considered to be 5.43 × 10 -7  mol/L. We speculated that this change is mainly caused by the hydrogen bond between tryptophan and the host molecule BPAT. This conjecture was verified by the controlled experiments with other host molecules., (© 2023 John Wiley & Sons Ltd.)