Search

Qi Huang,1– 3,* Xu-Yun Huang,1,2,* Yu-Ting Xue,1,2,* Xiao-Hui Wu,1,2,* Yu-Peng Wu,1,2,* Zhi-Bin Ke,1,2 Zhen Kang,1,2 Yi-Cheng Xu,1,2 Dong-Ning Chen,1,2 Yong Wei,1,2 Xue-Yi Xue,1,2 Zhi-Yang Huang,3 Ning Xu1,2,4 1Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, People’s Republic of China; 3Department of Urology, Quanzhou First Hospital, Fujian Medical University, Quanzhou, 362000, People’s Republic of China; 4Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning Xu, Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, People’s Republic of China, Tel +86-059187981687, Email drxun@fjmu.edu.cn Zhi-Yang Huang, Department of Urology, Quanzhou First Hospital, Fujian Medical University, No. 250, East Street, Licheng District, Quanzhou, Fujian, 362000, People’s Republic of China, Email hzy8902@126.comIntroduction: This study aims to explore the role of cuproptosis-related genes in ACC, utilizing data from TCGA and GEO repositories, and to develop a predictive model for patient stratification.Methods: A cohort of 123 ACC patients with survival data was analyzed. RNA-seq data of 17 CRGs were examined, and univariate Cox regression identified prognostic CRGs. A cuproptosis-related network was constructed to show interactions between CRGs. Consensus clustering classified ACC into three subtypes, with transcriptional and survival differences assessed by PCA and survival analysis. Gene set variation analysis (GSVA) and ssGSEA evaluated functional and immune infiltration characteristics across subtypes. Differentially expressed genes (DEGs) were identified, and gene clusters were established. A risk score (CRG_score) was generated using LASSO and multivariate Cox regression, validated across datasets. Tumor microenvironment, stem cell index, mutation status, drug sensitivity, and hormone synthesis were examined in relation to the CRG_score. Protein expression of key genes was validated, and functional studies on ASF1B and NDRG4 were performed.Results: Three ACC subtypes were identified with distinct survival outcomes. Subtype B showed the worst prognosis, while subtype C had the best. We identified 214 DEGs linked to cell proliferation and classified patients into three gene clusters, confirming their prognostic value. The CRG_score predicted patient outcomes, with high-risk patients demonstrating worse survival and possible resistance to immunotherapy. Drug sensitivity analysis suggested higher responsiveness to doxorubicin and etoposide in high-risk patients.Conclusion: This study suggests the potential prognostic value of CRGs in ACC. The CRG_score model provides a robust tool for risk stratification, with implications for treatment strategies.Keywords: cuproptosis, overall survival, immune microenvironment, molecular signature

Hai-bo Liu,1,* Min Yang,2,* Wan Li,2 Ting Luo,2 Yang Wu,2 Xiang-yu Huang,2 Yao-lei Zhang,3 Tao Liu,2 Yong Luo2,* 1Department of Biomedical Engineer, General Hospital of Western Theater Command, Chengdu, Sichuan, People’s Republic of China; 2Department of Traditional Chinese Medicine, General Hospital of Western Theater Command, Chengdu, Sichuan, People’s Republic of China; 3Basic Medical Laboratory, General Hospital of Western Theater Command, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong Luo, Department of Traditional Chinese Medicine, General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, People’s Republic of China, Tel +86 28-86571619, Email yongl019@sina.comPurpose: Dispelling dampness, relieving turbidity and dredging collaterals decoction (DED), is a traditional Chinese medicine used in the treatment of hyperuricemia. We aimed to explore the effect and mechanism of DED in the treatment of hyperuricemia.Methods: The effects of DED (9.48, 4.74, and 2.37 g/kg/d) on potassium oxonate (750 mg/kg/d)-induced hyperuricemia in rats were evaluated by serum uric acid (UA), creatinine (CRE), blood urea nitrogen (BUN), and renal pathological changes. Network pharmacology was used to identify the effective components and targets of DED, and the key targets and signaling pathways for its effects on hyperuricemia were screened. Molecular docking was used to predict the action of DED. H&E, immunohistochemistry, WB, and PCR were used to validate the network pharmacology results.Results: DED can effectively alleviate hyperuricemia, inhibit UA, CRE, BUN, and xanthine oxidase (XOD) activity, and reduce renal inflammatory cell infiltration and glomerular atrophy. The experiment identified 27 potential targets of DED for hyperuricemia, involving 9 components: wogonin, stigmasterol 3-O-beta-D-glucopyranoside, 3β-acetoxyatractylone, beta-sitosterol, stigmasterol, diosgenin, naringenin, astilbin, and quercetin. DED can relieve hyperuricemia mainly by inhibiting RAGE, HMGB1, IL17R, and phospho-TAK1, and by regulating the AGE-RAGE and IL-17 signaling pathways.Conclusion: DED can alleviate hyperuricemia by inhibiting XOD activity and suppressing renal cell apoptosis and inflammation via the AGE-RAGE signaling pathway and IL-17 signaling pathway. This study provides a theoretical basis for the clinical application of DED.Graphical Abstract: Keywords: dispelling dampness, relieving turbidity, dredging collaterals, hyperuricemia, network pharmacology

Zi-Li Huang,1,2,* Ping-Bao Zhang,1,3,* Jun-Tao Zhang,4 Feng Li,5 Ting-Ting Li,6 Xiu-Yan Huang1 1Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China; 2Department of Radiology, Xuhui District Central Hospital of Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 4Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China; 5School of Materials of Science and Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 6Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiu-Yan Huang, Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yi Shan Road, Shanghai, People’s Republic of China, Tel/Fax +86-21-64701361, Email xyhuang1119@163.comBackground: FAT atypical cadherin 1 (FAT1) acts as a tumor suppressor or oncogene, which regulates cell adherence, proliferation, motility, and actin kinetics. FAT1 gene expression is closely related to hepatocarcinogenesis; however, the function and mechanism of FAT1 in hepatocellular carcinoma (HCC) remain unclear.Methods: Here, we screened for the FAT1, which is intimately linked to the development and progression of HCC, both in circulating tumor cells (CTCs) and tumor tissues using next generation sequencing (NGS). Immunohistochemical staining was performed to detect FAT1 protein expression. To determine the impact of FAT1 on epithelial–mesenchymal transition (EMT), migration and invasion of HCC, an in vitro transwell assay and Western blot were performed. Moreover, Gene Set Enrichment Analysis was carried out to discover the underlying mechanism. Finally, animal experiments were conducted to confirm the effects of FAT1 on HCC metastasis and tumorigenicity.Results: Our results showed that FAT1 expression was decreased in HCC tissues, while in vitro and in vivo, the FAT1 knockdown facilitated invasion, cell motility, colony formation, and proliferation. FAT1 knockdown also resulted in decreased expression of E-cadherin and markedly elevated expression of N-cadherin, vimentin, and snail. We also confirmed our hypothesis from the analysis of group differences in the CTC phenotype and lung metastasis in nude mice.Conclusion: Our findings illustrated that FAT1 played a negative regulatory role in the HCC EMT and metastasis, providing further evidence for the role played by FAT1 in the formation and progression of HCC.Keywords: hepatocellular carcinoma, FAT1, epithelial-mesenchymal transition, circulating tumor cells, metastasis

The precise measurement of the spectrum of protons, the most abundant component of the cosmic radiation, is necessary to understand the source and acceleration of cosmic rays in the Milky Way. This work reports the measurement of the cosmic ray proton fluxes with kinetic energies from 40 GeV to 100 TeV, with 2 1/2 years of data recorded by the DArk Matter Particle Explorer (DAMPE). This is the first time that an experiment directly measures the cosmic ray protons up to ~100 TeV with high statistics. The measured spectrum confirms the spectral hardening at ~300 GeV found by previous experiments and reveals a softening at ~13.6 TeV, with the spectral index changing from ~2.60 to ~2.85. Our result suggests the existence of a new spectral feature of cosmic rays at energies lower than the so-called knee and sheds new light on the origin of Galactic cosmic rays.

The precise measurement of the spectrum of protons, the most abundant component of the cosmic radiation, is necessary to understand the source and acceleration of cosmic rays in the Milky Way. This work reports the measurement of the cosmic ray proton fluxes with kinetic energies from 40 GeV to 100 TeV, with 2 1/2 years of data recorded by the DArk Matter Particle Explorer (DAMPE). This is the first time that an experiment directly measures the cosmic ray protons up to ~100 TeV with high statistics. The measured spectrum confirms the spectral hardening at ~300 GeV found by previous experiments and reveals a softening at ~13.6 TeV, with the spectral index changing from ~2.60 to ~2.85. Our result suggests the existence of a new spectral feature of cosmic rays at energies lower than the so-called knee and sheds new light on the origin of Galactic cosmic rays.

Libo Liang,1,* Xinyan Huang,2,* He He,3 Ji-Yan Liu4 1Department of International Medical Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China; 2West China School of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China; 3Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China; 4Department of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ji-Yan Liu Email liujiyan1972@163.comBackground: The correlation between the radiosensitivity genes combined with CD19 status and clinical outcome was investigated to identify gastric cancer (GC) patients who would benefit from radiotherapy combined with CAR-T cell therapy.Methods: The gene expression and clinical features were downloaded from The Cancer Genome Atlas (TCGA) Stomach Cancer (STAD). To identify the hub radiosensitivity genes and CD19 status, 407 patients were categorized into two groups: radiosensitivity (RS) and radioresistance (RR) based on the prognosis. The chi-square test, Mann–Whitney test, and Kaplan–Meier survival analysis were applied to compare the differential expression in these groups and analyze the correlation between the gene expression and clinical outcome and features. Finally, the influencing factors for the prognosis of GC were investigated by multiple Cox regression, especially in RS patients.Results: A total of 15 differential expression genes, containing two communities with 8 hub radiosensitivity genes, were identified. We also identified a 2-gene signature model with a negative coefficient and calculated the risk score for the prognosis of GC. Also, Helicobacter pylori infection was validated, and the high-risk score of radiosensitivity genes was the risk factor, and high CD19 expression was the protective factor for the prognosis.Conclusion: The radiosensitivity gene signature and CD19 expression predicted the clinical outcome of GC patients.Keywords: gastric cancer, radiosensitivity genes, CAR-T cell therapy, TCGA database

Ping-Bao Zhang,1,2,* Zi-Li Huang,3,* Jia-Bei Li,1 Xiu-Yan Huang1 1Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, People’s Republic of China; 2Department of Urinary Surgery, Affiliated Hospital of Nantong University, Nantong 226021, People’s Republic of China; 3Department of Radiology, The Central Hospital of Shanghai Xuhui District, Shanghai 200031, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiu-Yan HuangDepartment of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yi Shan Road, Shanghai 200233, People’s Republic of ChinaTel/Fax +86-21-64701361Email xyhuang1119@163.comAbstract: Despite advancements in diagnosis and therapy, relapse of rectal cancer after clinical complete remission (cCR) remains a frequent event. The key factors influencing the treatment strategy for the management of patients achieving cCR following neoadjuvant chemoradiotherapy (Neo-CRT) remain to be identified. We present the case of a 64-year-old man with rectal cancer. The patient was initially admitted to the hospital in September 2011 with a 3-month history of change in his stools. Following his re-hospitalization in November 2011, a biopsy specimen of the neoplasm suggested the presence of rectal adenocarcinoma; laboratory investigations also revealed elevated levels of carcinoembryonic antigens (CEA; carbohydrate antigen 199) in the serum. Subsequently, the patient received Neo-CRT, as well as symptomatic and supportive treatment. The level of serum CEA returned to normal, without signs of swollen lymph nodes in the pelvic cavity. The patient was diagnosed with rectal cancer based on the elevated level of serum CEA, colonoscopy, and contrast-enhanced magnetic resonance imaging. He relapsed 4 months after cCR following Neo-CRT and underwent laparoscopic Miles’ surgery in April 2013. The relapse may have been mainly attributed to residual tumor cells. This case report and literature review may contribute to the clinical recognition of treatment for patients with rectal cancer achieving cCR following Neo-CRT.Keywords: rectal cancer, neoadjuvant chemoradiotherapy, Neo-CRT, clinical complete remission, cCR

Lehe Yang,1–3,* Jifa Li,1,* Lingyuan Xu,1–3,* Shichong Lin,1–3 Youqun Xiang,3 Xuanxuan Dai,3 Guang Liang,2 Xiaoying Huang,3 Jiandong Zhu,1 Chengguang Zhao1,2 1Department of Respiratory Medicine, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People’s Republic of China; 2Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People’s Republic of China; 3Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, People’s Republic of China *These authors contributed equally to this work Background: Non-small-cell lung cancer (NSCLC) comprises about 85% of all lung cancers and is usually diagnosed at an advanced stage with poor prognosis. The IL-6/STAT3 signaling pathway plays a pivotal role in NSCLC biology. Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that Rhein has significant antitumor effects, supporting the potential uses of Rhein as an antitumor agent.Methods: Cell viability and colony formation were performed to examine Rhein’s potent antiproliferative effect in human NSCLC cell lines PC-9, H460 and A549. Flow cytometry-based assay was employed to study whether Rhein could affect cell apoptosis and cycle. The expression level of P-STAT3, apoptosis and cycle-related proteins Bcl-2, Bax, MDM2, CDC2, P53 and CyclinB1 were detected by Western blotting. The xenograft models were used to evaluate the in vivo effect of Rhein.Results: We found that Rhein could significantly reduce the viability and stimulate apoptosis in human NSCLC cells in a dose-dependent manner. Western blot analysis results suggested that the antitumor effect of Rhein might be mediated via STAT3 inhibition. Rhein upregulated the expression of the proapoptotic protein Bax and downregulated the expression of the antiapoptotic protein Bcl-2. In addition, Rhein induced the arrest of NSCLC cells in the G2/M phase of the cell cycle and dose dependently inhibited the expression of cycle-related proteins. The Rhein also inhibited tumor growth in H460 xenograft models.Conclusion: Rhein shows potent efficacy against NSCLC through inhibiting the STAT3 pathway. Our results also suggest that Rhein has a promising potential to be used as a novel antitumor agent for the treatment of NSCLC. Keywords: Rhein, NSCLC, STAT3, EGFR, diacerein, apoptosis, inhibitor

Min-Wei Zhou,1,* Xiao-Yun Huang,2,* Zong-You Chen,1 Zhen-Yang Li,1 Yi-Ming Zhou,1 Yi Yang,1 Zi-Hao Wang,1 Jian-Bin Xiang,1 Xiao-Dong Gu1 1Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Electromyogram, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Some patients with low rectal cancer experience anorectal and urogenital dysfunctions after surgery, which can influence the long-term quality of life. In this study, we aimed to protect nerve function in such scenarios by performing intraoperative monitoring of pelvic autonomic nerves (IMPAN). Patients and methods: We retrospectively investigated a series of 87 patients undergoing laparoscopic low anterior resection of rectal cancer. Nerve-sparing was evaluated both visually and electrophysiologically. IMPAN was performed by stimulating the pelvic autonomic nerves under processed electromyography of the internal anal sphincter. Urination, defecation, sexual function, and the quality of life were evaluated using validated and standardized questionnaires preoperatively and at follow-up, 12 months after surgery. Results: Among a total of 87 patients (53 male and 34 female patients), IMPAN with simultaneous electromyography of the internal anal sphincter was performed in 58 (66.7%) patients. Bilateral positive IMPAN results for both measurements, indicating successfully confirmed pelvic autonomic nerve preservation, were obtained in 45 (51.7%) patients. No significant difference was found in terms of urogenital and anorectal functions between preoperative and postoperative patients with bilateral positive IMPAN (P>0.05). Compared to preoperative patients with IMPAN (unilateral) or without IMPAN, these patients exhibited higher International Prostate Symptom Score, a lower International Index of Erectile Function-5, and a lower Female Sexual Function Index score at 12 months postoperatively (P

Feng-jia Chen,* Xin-yan Huang,* Yang-li Liu, Geng-peng Lin, Can-mao Xie Department of Respiratory Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: Fractional exhaled nitric oxide (FeNO) is an easy, sensitive, reproducible, and noninvasive marker of eosinophilic airway inflammation. Accordingly, FeNO is extensively used to diagnose and manage asthma. Patients with COPD who share some of the features of asthma have a condition called asthma–COPD overlap syndrome (ACOS). The feasibility of using FeNO to differentiate ACOS patients from asthma and COPD patients remains unclear. Methods: From February 2013 to May 2016, patients suspected with asthma and COPD through physician’s opinion were subjected to FeNO measurement, pulmonary function test (PFT), and bronchial hyperresponsiveness or bronchodilator test. Patients were divided into asthma alone group, COPD alone group, and ACOS group according to a clinical history, PFT values, and bronchial hyperresponsiveness or bronchodilator test. Receiver operating characteristic (ROC) curves were obtained to elucidate the clinical functions of FeNO in diagnosing ACOS. The optimal operating point was also determined. Results: A total of 689 patients were enrolled in this study: 500 had asthma, 132 had COPD, and 57 had ACOS. The FeNO value in patients with ACOS was 27 (21.5) parts per billion (ppb; median [interquartile range]), which was significantly higher than that in the COPD group (18 [11] ppb). The area under the ROC curve was estimated to be 0.783 for FeNO. Results also revealed an optimal cutoff value of >22.5 ppb FeNO for differentiating ACOS from COPD patients (sensitivity 70%, specificity 75%).Conclusion: FeNO measurement is an easy, noninvasive, and sensitive method for differentiating ACOS from COPD. This technique is a new perspective for the management of COPD patients. Keywords: fractional exhaled nitric oxide, chronic obstructive pulmonary disease, asthma, ACOS, cutoff point

Ran Zhao,1,* Geng Li,1,* Xiu-juan Kong,1 Xiu-yan Huang,2 Wei Li,1 Yao-ying Zeng,2 Xiao-ping Lai31Traditional Chinese Medicinal College, Guangzhou University of Chinese Medicine, 2Life Science College, Jinan University, Guangzhou, 3Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, People’s Republic of China*These authors contributed equally to this workAbstract: Edible bird’s nest (EBN) is regarded as an immune-enhancing food in the People’s Republic of China. The aim of this study is to demonstrate the efficiency of EBN in improving the immunity of mouse both in vivo and in vitro. We observed the effects of EBN on spleen lymphocytes proliferation and activation, as well as immunoglobulin isotypes as indicators. In addition, we evaluated the content of total sIgA in the intestinal juice to assess mucosal immunity. The results showed that EBN could promote the proliferation and activation of B-cells and increase IgE, IgA, IgM, and IgG3 levels. We also found that EBN extract can promote the secretion of sIgA in the small intestine. Using cyclophosphamide (CY), we established an immunosuppressed mouse model in which we identified a reversal influence on the ratio of CD3+/CD19+ cells, which indicates that EBN also protects B-cells from the damage induced by CY. We also applied polymyxin B to exclude the interference of lipopolysaccharide throughout the experiment. In conclusion, we found that EBN can reduce the intestinal immune injury induced by CY by accelerating the proliferation and activation of B-cells and enhancing antibody secretion of B-cells.Keywords: chemotherapy, immunological enhancement, intestinal mucosal immune, EBN

PURPOSE: To explore the effects of ethanolic extract of Radix Scrophulariae (EERS) on ventricular remodeling in rats. METHODS: Rats with coronary artery ligation (CAL) were randomly assigned to 5 groups: CAL model; CAL plus 40mg/kg captopril; CAL plus 60mg/kg, 120mg/kg, 240mg/kg EERS. Sham operation rats were randomly assigned to 2 groups, sham-operated control and sham-operated plus 120mg/kg EERS. The rats were orally administered with the corresponding drugs or drinking water for 14weeks. The left ventricular weight index (LVWI) and heart weight index (HWI) were determined. Myocardium tissue was stained with hematoxylin and eosin or picric acid/Sirius red for cardiomyocyte cross-section area or collagen content measurements respectively. The concentrations of hydroxyproline (Hyp), matrix metalloproteinase 2 (MMP-2), angiotensin II (Ang II), aldosterone (ALD), endothelin 1 (ET-1), atrial natriuretic peptide (ANP), tumor necrosis factor [alpha] (TNF-[alpha]) and renin activity (RA) in myocardium or serum were determined. Real-time RT-PCR was used to detect the mRNA expressions of angiotensin converting enzyme (ACE), ET-1 and ANP. RESULTS: EERS could significantly reduce the LVWI and HWI, decrease heart tissue concentrations of Hyp and collagen deposition, diminish cardiomyocyte cross-section area, reduce the tissue level of Ang II, ET-1, ANP and TNF-[alpha]. EERS could also down regulate the mRNA expression of ACE, ET-1 and ANP in myocardium. CONCLUSION: EERS attenuates ventricular remodeling. The mechanisms may be related to restraining the excessive activation of RAAS, TNF-[alpha] and modulating some gene expressions associated with cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Rosacea is a chronic inflammatory skin disease, which is prone to flares and requires continuous management and treatment. However, long-term use of drugs can lead to additional adverse drug reactions. Based on the comorbid relationship between rosacea and Parkinson's disease, bioinformatics and network pharmacology analysis were used to identify a safer drug for rosacea. It has been demonstrated that ISA has an ameliorative impact on the symptoms of Parkinson's disease. The results demonstrated that ISA exhibited anti-inflammatory properties, including reducing erythema areas and inflammatory cell infiltration in rosacea-like mice models, and inhibiting the expression of inflammatory factors in cellular inflammation models. Furthermore, the anti-inflammatory effect of ISA was associated with inhibition of the Erk, p38 and NF-κB signaling pathways and inhibition of macrophage polarization to M1 type. In addition, molecular docking and drug affinity responsive target stability experiment results indicated that VEGFA and RELA were the direct targets of ISA in the treatment for rosacea. In conclusion, these results suggested that ISA may be a potential therapeutic agent for rosacea., 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 B.V. All rights reserved.)

Objective: Our research aims to evaluate the diagnostic accuracy of colposcopy-guided biopsy (CGB) in detecting high-grade cervical lesions and explore how human papilloma virus (HPV) integration status and other factors affect its performance., Methods: A retrospective cohort analysis involving 550 patients was conducted to evaluate whether the HPV integration plays a role in identifying high-grade cervical lesions and cervical cancer. Logistic regression models and area under the curve (AUC) calculations were employed., Results: Our findings revealed that 53.5% of CGB/surgery pairs demonstrated congruent diagnoses, whereas 17.1% showed underestimation and 29.5% overestimation. Furthermore, multivariate logistic regression analysis identified several key predictors for cervical intraepithelial neoplasia (CIN)2+ and CIN3+ according to surgical pathology. Notably, a CGB confirming CIN2+ [odds ratio (OR)=6.0, 95% confidence interval (CI): 3.9-9.1, P<0.001], high-grade cytology (OR=2.6, 95% CI: 1.4-1.9, P=0.003), and HPV integration positivity (OR=2.2, 95% CI: 1.3-3.5, P<0.001) emerged as significant factors for CIN2+. Similarly, for CIN3+ identification, CGB confirming CIN2+ (OR=5.3, 95% CI: 3.4-8.3, P<0.001), high-grade cytology (OR=2.6, 95% CI: 1.5-4.7, P=0.001), and HPV integration positivity (OR=2.0, 95% CI: 1.3-3.1, P=0.003) were independent predictors., Conclusion: Our study highlights the innovative role of HPV integration testing as a pivotal adjunct to CGB and cytology, offering a comprehensive approach that may enhance the diagnostic precision for high-grade cervical lesions, ultimately achieving more precise management strategies., Competing Interests: Conflict of Interest Statement. The authors declare that there is no conflict of interest with any financial organization or corporation or individual that can inappropriately influence this work., (© 2024. Huazhong University of Science and Technology.)

The strategy of organic ligand exchange is proposed to tune the optical properties of organic-inorganic hybrid cuprous halides. In this work, the chiral ligand (S)-(-)-2,2'-bis(di- p -tolylphosphino)-1,1'-binaphthyl ((S)-Tol-BINAP) and achiral triphenylphosphine (PPh 3 ) are introduced into cuprous halides CuX-PPh 3 -[(S)-Tol-BINAP] (X = Cl, Br, I) through organic ligand exchange. As a result, the mixed organic ligands can enhance second harmonic generation (SHG) and aggregation-induced emission (AIE) optical properties. Moreover, the title compounds exhibit progressively enlarged SHG effects along with heavier halogen substitution due to their stronger polarizability. In the meantime, the reduced π-π stacking interaction of the organic ligand will improve their photoluminescence quantum yield. The experimental results combined with the theoretical calculation clarify the structure-property relationship well. Furthermore, the title compounds have been developed for the application of latent fingerprint detection.

The recent worldwide outbreaks of mpox prioritize the development of a safe and effective mRNA vaccine. The contemporary mpox virus (MPXV) exhibits changing virological and epidemiological features, notably affecting populations already vulnerable to human immunodeficiency virus (HIV). Herein, we profile the immunogenicity of AR-MPXV5, a penta-component mRNA vaccine targeting five specific proteins (M1R, E8L, A29L, A35R, and B6R) from the representative contemporary MPXV clade II strain, in both naive and simian immunodeficiency virus (SIV)-infected nonhuman primates. Immunization with two doses of AR-MPXV5 to cynomolgus macaques effectively elicits antibody responses and cellular responses. Importantly, based on the challenge model with a contemporary MPXV clade II strain, AR-MPXV5 demonstrates effective efficacy in preventing skin lesions, eliminating viremia and reducing viral loads in multiple tissues after challenge in naive male animals. More importantly, AR-MPXV5 is well-tolerated in stable chronic SIV-infected rhesus monkeys, while eliciting comparable MPXV-specific humoral and cellular responses in both naive and SIV-infected monkeys. Together, these results support further clinical development of the AR-MPXV5 vaccine., Competing Interests: Competing interests: C.F.Q., Q.Y., R.R.Z., and Z.J.W. have filed a patent related to the vaccine reported in the study. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Natural products play a vital role in human health because people find that they can reduce the incidence of many diseases, such as cancer and cardiovascular diseases. Therefore, researchers have developed many effective techniques for screening and separating active compounds from natural products. High-speed countercurrent chromatography is a unique unsupported liquid-liquid chromatography technology that has been widely used in the separation of natural products. In this paper, the research progress of screening and separating active components from natural products by combining high-speed countercurrent chromatography technology with other technologies is reviewed from two aspects: pre-column activity assay and post-column activity assay. The purpose of this paper is to provide some theoretical support for the screening and separation of natural active compounds by high-speed countercurrent chromatography. I hope that the contents summarized in this paper can provide more basis for the development of screening and separation of natural active compounds to realize large-scale preparation., (© 2024 Wiley‐VCH GmbH.)

In this work, different injection modes (single injection, overlapping injection, and continuous injection) of countercurrent chromatography were used and compared for the isolation and purification of glabridin from the crude extract of Glycyrrhiza glabra. The two-phase solvent system consisting of n-hexane/ethyl acetate/methanol/water (5:4:5:4, v/v) was employed as stationary and mobile phases. Compared with single injection mode, both overlapping injection and continuous injection modes exhibited higher separation efficiency at the same sample loading capacity. Their total separation times were 89.68% and 53.97% of the single injection mode, and the total solvent consumption were 74.88% and 52.49% of the single injection mode, respectively. Meanwhile, the yield, purity, and recovery rate of these three injection modes were almost the same. It was demonstrated that high-speed countercurrent chromatography in continuous injection mode was the most effective way for separating glabridin in three methods and it can be further applied to the separation of other economically valuable natural products., (© 2024 Wiley‐VCH GmbH.)

Host hemolymph is an important place of growth and development for most endoparasitoids. Immunofluorescence assay showed that parasitism induced Chilo suppressalis larvae to produce large numbers of granulocytes, but high temperatures led to granulocytes apoptosis and loss of phagocytosis. In addition, high temperatures activated the endoplasmic reticulum apoptotic pathway, leading to apoptosis of prohemocytes. In the present study, the initiator Cscaspase-8 was obtained from the rice pest C. suppressalis. The results of real-time PCR showed that Cscaspase-8 expression was highest in hemocytes; furthermore, transcription was most highly in female adults. Cscaspase-8 was significantly induced when larvae were exposed to 39 °C for a 2-h period. Cscaspase-8 expression was significantly elevated after 2 d of parasitism. Results of the interference test showed that the survival rate of C. suppressalis larvae is not affected by Cscaspase-8 gene silencing under high temperature and parasitism stress. However, developmental delays were observed in Cotesia chilonis larvae when the host Cscaspase-8 gene was knocked down. These results contribute to the current knowledge on the regulatory mechanisms of apoptosis in insects subjected to high temperature and parasitism stress., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rice grains typically contain relatively high levels of toxic arsenic (As) but low levels of essential micronutrients. Biofortification of essential micronutrients while decreasing As accumulation in rice would benefit human nutrition and health. We generated transgenic rice expressing a gain-of-function mutant allele astol1 driven by the OsGPX1 promoter. astol1 encodes a plastid-localized O-acetylserine (thiol) lyase (OAS-TL) with Ser189Asn substitution (OsASTOL1 S189N ), which enhances cysteine biosynthesis by forming an indissociable cysteine synthase complex with its partner serine acetyltransferase (SAT). The effects on growth, As tolerance, and nutrient and As accumulation in rice grain were evaluated in hydroponic, pot and field experiments. The expression of OsASTOL1 S189N in pOsGPX1::astol1 transgenic lines enhanced SAT activity, sulphate uptake, biosynthesis of cysteine, glutathione, phytochelatins and nicotianamine, and enhanced tolerance to As. The expression of OsASTOL1 S189N decreased As accumulation while increased the accumulation of multiple macronutrients (especially sulphur, nitrogen and potassium) and micronutrients (especially zinc and selenium) in rice grain in a pot experiment and two field experiments, and had little effect on plant growth and grain yield. Our study provides a new strategy to genetically engineer rice to biofortify multiple essential nutrients, reducing As accumulation in rice grain and enhancing As tolerance simultaneously., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism., Competing Interests: Declarations. Ethics Approval and Consent to Participate: The study was approved by the Ethics committee of the First Affiliated Hospital of Wenzhou Medical University. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Rationale and Objectives: To evaluate glymphatic function changes and their relationships with clinical features in patients with metabolic dysfunction-associated fatty liver disease (MAFLD), thereby facilitating early intervention before this disease progresses to cirrhosis., Materials and Methods: A cross-sectional cohort of 46 pre-cirrhotic MAFLD patients and 30 age-, sex-, and education-matched controls was enrolled, with diffusion-tensor imaging (DTI) data, laboratory and neurocognitive scores collected. The DTI analysis along the perivascular space (DTI-ALPS) index was computed for qualifying glymphatic function. Generalized linear model and partial correlation analyses were applied to evaluate relationships between the ALPS index and clinical variables., Results: MAFLD group exhibited a decreased ALPS index and increased diffusivity along the y-axis in the projection fiber compared to the controls. The altered ALPS index was associated with clock drawing test (CDT) score (3.931 [0.914, 6.947], P = 0.011) and was correlated with diastolic pressure level (r = -0.315, P = 0.033) in MAFLD group. The relationships of ALPS index with CDT score (6.263 [2.069, 10.458], P = 0.003) and diastolic pressure level (r = -0.518, P = 0.014) remained in the MAFLD with metabolic syndrome (MetS) group. Furthermore, the ALPS index was even associated with Auditory Verbal Learning Test-Immediate recall score (-23.853 [-45.417, -2.289], P = 0.030) in MAFLD with MetS group., Conclusion: MAFLD patients may have a glymphatic dysfunction prior to cirrhosis, and this alteration may be related to cognition and diastolic pressure. Glymphatic dysfunction has a more severe impact on cognition when MAFLD patient is accompanied by MetS., 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 Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

We previously described that the KDM5B histone H3 lysine 4 demethylase is an oncogene in estrogen-receptor-positive breast cancer. Here, we report that KDM5A is amplified and overexpressed in basal breast tumors, and KDM5 inhibition (KDM5i) suppresses the growth of KDM5-amplified breast cancer cell lines. Using CRISPR knockout screens in a basal breast cancer cell line with or without KDM5i, we found that deletion of the ZBTB7A transcription factor and core SAGA complex sensitizes cells to KDM5i, whereas deletion of RHO-GTPases leads to resistance. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed co-localization of ZBTB7A and KDM5A/B at promoters with high histone H3K4me3 and dependence of KDM5A chromatin binding on ZBTB7A. ZBTB7A knockout altered the transcriptional response to KDM5i at NF-κB targets and mitochondrion-related pathways. High expression of ZBTB7A in triple-negative breast cancer is significantly associated with poor response to neoadjuvant chemotherapy. Our work furthers the understanding of KDM5-mediated gene regulation and identifies mediators of sensitivity to KDM5i., Competing Interests: Declaration of interests K.P. serves on the scientific advisory boards of Ideaya Biosciences and Scorpion Therapeutics, holds equity options in Scorpion Therapeutics and Ideaya Biosciences, and receives sponsored research funding from Novartis, where she also consults. H.W.L. receives research funding from Novartis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Exertional heatstroke (EHS) is a life-threatening condition with potential for tissues and organs injury, including heart. Effective drug strategies to treat patients with EHS are warranted to unlock the therapeutic potential. Considering the cardioprotective effects of L-carnitine (LC), this study aimed to investigate the effects of LC on EHS-induced myocardial injury in rats and to explore the underlying mechanisms. Here, we found that LC exerted a greater protective effect on EHS-induced cardiac dysfunction and mortality, which also significantly attenuated certain negative effects, including increased myocardial apoptosis, pathological changes, and ultrastructural impairment, enhanced activity levels of such serum enzymes as AST, LDH, CK, and CK-MB, reduced BCL-2 expression, increased the expression of cleaved caspase-3 and the critical endoplasmic reticulum stress (ERS) indices like CHOP and GRP78 in EHS rats. Besides, pretreatment of EHS rats with PBA (4-Phenyl butyric acid), a chemical chaperone that attenuates ERS, restored BCL-2 expression, reduced the protein levels of cleaved caspase-3, CHOP, and GRP78. Furthermore, thapsigargin (TG), which induces ERS, enhanced the expression of BAX, cleaved caspase-3, CHOP, and GRP78, attenuated BCL-2 expression, and enhanced mitochondrial impairment in EHS + LC rats. Mechanismly, the protective effects of LC were mediated, at least partly, by inhibiting the activation of PERK pathway against ERS-associated myocardial damage. These results indicate that supplementation of LC might be a potential strategy to reduce myocardial injury by affecting ERS via inhibiting the PERK pathway against EHS., Competing Interests: 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., (© 2024 The Authors.)

Seed dormancy, an essential trait for plant adaptation, is determined by the embryo itself and the surrounding tissues. Here, we found that rice (Oryza sativa) FERTILIZATION INDEPENDENT ENDOSPERM1 (OsFIE1) regulates endosperm-imposed dormancy and the dorsal aleurone thickness in a manner dependent on the parent of origin. Maternally expressed OsFIE1 suppresses gibberellin (GA) biosynthesis in the endosperm by depositing trimethylation of lysine 27 on histone H3 (H3K27me3) marks on GA biosynthesis-related genes, thus inhibiting germination and aleurone differentiation. Knockout of rice GA 20-oxidase1 (OsGA20ox1) alleviated the phenotypic defects in osfie1. The aleurone-positive determinant Crinkly 4 (OsCR4) is another target of the OsFIE1-containing Polycomb repressive complex 2 (PRC2). We found that OsFIE1 plays an important role in genomic imprinting in the endosperm of germinating seeds, particularly for paternally expressed genes associated with H3K27me3. The increased aleurone thickness of osfie1 substantially improved grain nutritional quality, indicating that the osfie1 gene may be utilized for breeding nutrient-enriched rice. The findings provide insights into the essential roles of PRC2-mediated H3K27me3 methylation in the acquisition of seed dormancy and endosperm cell differentiation in rice., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. 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.)

The heart, in addition to its primary role in blood circulation, functions as an endocrine organ by producing cardiac hormone natriuretic peptides. These hormones regulate blood pressure through the single-pass transmembrane receptor guanylyl cyclase A (GC-A), also known as natriuretic peptide receptor 1. The binding of the peptide hormones to the extracellular domain of the receptor activates the intracellular guanylyl cyclase domain of the receptor to produce the second messenger cyclic guanosine monophosphate. Despite their importance, the detailed architecture and domain interactions within full-length GC-A remain elusive. Here we present cryo-electron microscopy structures, functional analyses and molecular dynamics simulations of full-length human GC-A, in both the absence and the presence of atrial natriuretic peptide. The data reveal the architecture of full-length GC-A, highlighting the spatial arrangement of its various functional domains. This insight is crucial for understanding how different parts of the receptor interact and coordinate during activation. The study elucidates the molecular basis of how extracellular signals are transduced across the membrane to activate the intracellular guanylyl cyclase domain., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Both mistletoes and their hosts are challenged by increasing drought, highlighting the necessity of understanding their comparative hydraulic properties. The high transpiration of mistletoes requires efficient water transport, while high xylem tensions demand strong embolism resistance, representing a hydraulic paradox. This study, conducted across four environments with different aridity indices in Yunnan, China, examined the xylem traits of 119 mistletoe-host species pairs. Mistletoes showed lower water use efficiency, indicating a more aggressive water use. They also showed lower hydraulic efficiency (lower vessel diameter and theoretical hydraulic conductivity) but higher safety (lower vulnerability index and higher conduit wall reinforcement, vessel grouping index, and wood density) compared with their hosts, supporting the trade-off between efficiency and safety. Environmental variation across sites significantly affected xylem trait comparisons between mistletoes and hosts. Additionally, the xylem traits of mistletoes were strongly influenced by host water supply efficiency. The overall xylem trait relationships in mistletoes and hosts were different. These findings stress the impact of host and site on the hydraulic traits of mistletoes, and suggest that mistletoes may achieve high transpiration by maintaining high stomatal conductance under low water potentials. This study illuminates the distinctive adaptation strategies of mistletoes due to their parasitic lifestyle., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Calcium is a vital trace element for the human body, and its deficiency can result in a range of pathological conditions, including rickets and osteoporosis. Despite the numerous types of calcium supplements currently available on the market, these products are afflicted with a number of inherent deficiencies, such as low calcium content, poor aqueous solubility, and low human absorption rate. Many microorganisms, particularly beneficial microorganisms, including edible fungi, lactic acid bacteria, and yeast, are capable of absorbing and enriching calcium, a phenomenon that has been widely documented. This opens the door to the potential utilization of microorganisms as novel calcium enrichment carriers. However, the investigation of calcium-rich foods from microorganisms still faces many obstacles, including a poor understanding of calcium metabolic pathways in microorganisms, a relatively low calcium enrichment rate, and the slow growth of strains. Therefore, in order to promote the development of calcium-rich products from microorganisms, this paper provides an overview of the impacts of calcium addition on strain growth, calcium enrichment rate, antioxidant system, and secondary metabolite production. Additionally, it highlights calcium transport and enrichment mechanisms in microorganism cells and offers a detailed account of the progress made on calcium-binding proteins, calcium transport pathways, and calcium storage and release. This paper offers insights for further research on the relevant calcium enrichment in microorganism cells.

Objective: To analyze the genus, drug resistance/virulence and phylogenetic characteristics of Brucella strains isolated from brucellosis surveillance sentinels in Henan Province from 2013 to 2022, and provide baseline data for the surveillance, early warning and outbreak tracing of brucellosis. Methods: Blood samples were collected from patients with Brucella infection for strain isolation, culture and species identification, drug susceptibility test, whole genome sequencing, splicing and assembly, functional/virulence/resistance gene prediction analysis and phylogenetic tree drawing based on single nucleotide polymorphism (SNP). Results: In 36 brucellosis patients, the majority were men (86.11%, 31/36), young adults aged 18-50 (88.89%, 32/36) and farmers/herdsmen (72.22%, 26/36). A total of 36 strains of Brucella melitensis were isolated, and average 1 305 functional proteins of 21 categories were predicted by strain genome; all the strains carried four main virulence factors (pmm, VirB group, BtpA/BtpB, BvrS/BvrR). The drug sensitivity rate was 100.00% to six types of antibiotics including levofloxacin, rifampicin, doxycycline, streptomycin, tetracycline and gentamicin, they showed different resistances to three antibiotics including compound trimethoprim-sulfamethoxazole, ciprofloxacin and ampicillin. The strains carried four types of resistance genes and two clusters of resistance genes, with four combinations of genotypes, the resistance mechanisms included antibiotic degradation/modification enzymes, resistant nodular cell differentiation (RND) efflux pumps, 16S/23S ribosomal rRNA binding site mutations, etc . The number of SNP differed in the genomes of 36 Brucella melitensis strains ranged from 0 to 454 and phylogenetic tree was divided into three major branches, with relative branch distances between 0.000 0 and 0.498 6 for each strain. Conclusions: Human Brucella melitensis strains isolated from surveillance sentinels in Henan from 2013 to 2022 carried multiple virulence and antibiotic resistance genes and had different drug resistance phenotypes. Single nucleotide polymorphism analysis and phylogenetic tree analysis showed significant differences in phylogenetic relationships among different strains.

Multimorbidity is significantly associated with life quality decline, disability, and increased mortality risk. Additionally, it leads to greater consumption of healthcare resources, presenting substantial challenges to healthcare systems globally. To better assess the burden of multimorbidity, its impact on patient health outcomes and healthcare services, and to explore the underlying mechanisms in its development, this paper summarizes the existing methods used for measuring and analyzing multimorbidity in research and practice, including disease count, disease-weighted indices, multimorbidity pattern recognition (such as disease association analysis, clustering analysis, and network analysis) and longitudinal methods to provide references for the accurate assessment of the prevalence of multimorbidity and its changes and improve the validity and universality of research findings.

Surgical site infection (SSI) following lumbar disc herniation (LDH) surgery leads to prolonged hospital stays, increased costs and reoperations. Therefore, we aim to develop and validate a nomogram to predict the risk of SSI following LDH surgery, thereby helping spine surgeons design personalized prevention strategies and promote early recovery. Data from 647 patients with SSI who underwent LDH surgery at the First Affiliated Hospital of Air Force Medical University (AFMU) from 2020 to 2023 were collected. Ultimately, 241 patients with SSI were selected based on inclusion and exclusion criteria. Patients were randomly divided into training and validation sets with a ratio of 7:3. LASSO regression, univariate, and multivariate logistic regression were utilized to identify target variables and establish the prediction model, which was subsequently validated. Six factors-Age, Body Mass Index (BMI), Postoperative Suction Drainage (PSD), Gelatin Sponge (GS), None-Preoperative Antibiotic (NPTA), and Thrombin Time (TT)-were selected to construct the nomogram model. In the training set, the area under the curve (AUC) for the nomogram was 0.818 (95% CI 0.779-0.857). In the validation set, the AUC was 0.782 (95% CI 0.717-0.846). Calibration curves for both sets showed satisfactory agreement between predicted and actual SSI probabilities. Decision curve analysis indicated that the nomogram is clinically useful with a threshold range of 1-90%. The Clinical Impact Curve (CIC) demonstrated an acceptable cost-benefit ratio. The developed nomogram model effectively predicts the risk of SSI following LDH surgery, enabling spine surgeons to formulate more professional and rational clinical prevention strategies., (© 2024. The Author(s).)