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Nan Lin,1,&ast; Dang Li,1,2,&ast; Si Lin,1 Yilang Ke,1 Jianping Lu,3 Yinrong Wu,1 Tianwen Huang,1,3 Huashan Hong1 1Fujian Key Laboratory of Vascular Aging, Department of Geriatrics, Fujian Institute of Geriatrics, Fujian Clinical Research Center for Senile Vascular Aging and Brain Aging, Fujian Medical University Union Hospital, Fuzhou, Fujian, People’s Republic of China; 2Nursing Department, Fujian Medical University Union Hospital, Fuzhou, Fujian, People’s Republic of China; 3Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huashan Hong, Fujian Key Laboratory of Vascular Aging, Department of Geriatrics, Fujian Institute of Geriatrics, Fujian Clinical Research Center for Senile Vascular Aging and Brain Aging, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, People’s Republic of China, Tel +86 591 8621 8525, Fax +86 591 8621 8545, Email 15959159898@163.comPurpose: The prevalence of osteoporosis in elderly individuals is high, and osteoporosis is strongly associated with chronic inflammation. The monocyte-to-high-density lipoprotein ratio (MHR) is acknowledged as a marker for assessing systemic inflammation and oxidative stress, and changes in the MHR are associated with many chronic disease prevalent among the elderly population. This study investigated the relationships between the MHR and the incidence of osteoporosis in older adults, along with its predictive value.Patients and Methods: Data from 563 participants aged ≥ 70 years were retrospectively analysed. The haematological parameters were evaluated via established methodologies, utilizing fasting blood samples collected from the participants. The absolute monocyte count was used to calculate the MHR (MHR=monocyte/HDL-C). BMD was measured by dual-energy X-ray absorptiometry. The results were evaluated via comparative statistical analyses, Spearman correlation, logistic regression analyses, and receiver operating characteristic (ROC) curve analysis.Results: The differences in the MHR were statistically significant among the osteoporosis groups (p < 0.001). Spearman correlation analysis revealed a positive correlation between the MHR and BMD. Furthermore, stratifying the sample into four groups on the basis of quartiles of MHR (M1, M2, M3, and M4) revealed a decreased risk of osteoporosis in the highest quartile compared with the lowest quartile (p < 0.001). Multiple logistic regression analysis revealed that BMI and the MHR were independent risk factors for osteoporosis. The area under the ROC curve and the cut-off value of the MHR were 0.710 and 0.308(109/mmol), with specificity and sensitivity of 0.599 and 0.735, respectively (95% CI: 0.668~0.752, p < 0.0001).Conclusion: A low MHR was associated with a greater risk of senile osteoporosis. In clinical practice, the MHR has shown predictive value for senile osteoporosis, contributing to early intervention and treatment of this disease.Keywords: senile osteoporosis, monocyte-to-high-density lipoprotein ratio, bone mineral density, inflammation, senescence

Lining Zhou,1,&ast; Hong Hong,2,&ast; Fuying Chu,1 Xiang Chen,1 Chenlu Wang1 1Department of Clinical Laboratory, The Second Affiliated Hospital of Nantong University and Nantong City No.1 People’s Hospital, Nantong, People’s Republic of China; 2Department of Clinical Laboratory, Nantong Traditional Chinese Medicine Hospital, Nantong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chenlu Wang; Xiang Chen, Email wangchenlu0101@163.com; ntchenx0520@163.comBackground: Recurrence is the main factor for poor prognosis in ovarian cancer, but few prognostic biomarkers were reported. In this study, we used machine learning methods based on multiple biomarkers to develop a specific prediction model for the recurrence of ovarian cancer.Methods: A total of 277 ovarian cancer patients were enrolled in this study and randomly classified into training and testing cohorts. The prediction information was obtained through 47 clinical parameters using six supervised clustering machine learning algorithms, including K-Nearest Neighbor (K-NN), Decision Tree (DT), Random Forest (RF), Adaptive Boosting (AdaBoost), Gradient Boosting Machine (GBM), and Extreme Gradient Boosting (XGBoost).Results: In predicting the recurrence of ovarian cancer, machine learning algorithm was superior to conventional logistic regression analysis. In this study, XGBoost showed the best performance in predicting the recurrence of ovarian cancer, with an accuracy of 0.95. In addition, neoadjuvant chemotherapy, Monocyte ratio (MONO%), Hematocrit (HCT), Prealbumin (PAB), Aspartate aminotransferase (AST), and carbohydrate antigen 125 (CA125) are the most important biomarkers to predict the recurrence of ovarian cancer.Conclusion: The machine learning techniques can achieve a more accurate assessment of the recurrence of ovarian cancer, which can help clinicians make decisions, and develop personalized treatment strategies.Keywords: ovarian cancer, recurrence, machine learning, biomarkers, predictive modeling

Hao Hong,1,&ast; Suya Zhou,2,&ast; Junyao Zheng,3 Haimin Shi,3 Yue Chen,4 Ming Li3 1Department of Intensive Care Unit, The First Affiliated Hospital of Soochow University, Soochow, Suzhou, People’s Republic of China; 2Laboratory Nephrology, Jinshan hospital of Fudan University, Shanghai, People’s Republic of China; 3Laboratory Nephrology, The First Affiliated Hospital of Soochow University, Soochow, Suzhou, People’s Republic of China; 4Laboratory Nephrology, The First People’s Hospital of Kunshan, Soochow, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Li, Email 1925924373@qq.comPurpose: The aim of this study was to investigate the changes of different metabolites in the body fluids of non-dialysis patients with chronic kidney disease (CKD) using a metabolomics approach. The goal was to identify early biomarkers of CKD progression through metabolic pathway analysis.Patients and Methods: Plasma samples from 47 patients with stages 1– 4 CKD not requiring dialysis and 30 healthy controls were analyzed by liquid chromatography-mass spectrometry (LC-MS). Using multivariate data analysis, specifically a partially orthogonal least squares discriminant analysis model (OPLS-DA), we investigated metabolic differences between different stages of CKD. The sensitivity and specificity of the analysis were evaluated using the Area Under Curve (AUC) method. Furthermore, the metabolic pathways were analyzed using the Met PA database.Results: Plasma samples from CKD patients and controls were successfully differentiated using an OPLS-DA model. Initially, twenty-five compounds were identified as potential plasma metabolic markers for distinguishing CKD patients from healthy controls. Among these, six compounds (ADMA, D-Ornithine, Kynurenine, Kynurenic acid, 5-Hydroxyindoleacetic acid, and Gluconic acid) were found to be associated with CKD progression It has been found to be associated with the progression of CKD. Changes in metabolic pathways associated with CKD progression include arginine and ornithine metabolism, tryptophan metabolism, and the pentose phosphate pathway.Conclusion: By analyzing the metabolic pathways of different metabolites, we have identified the significant impact of CKD progression. The main metabolic pathways involved are Arginine and Ornithine metabolism, Tryptophan metabolism, and Pentose phosphate pathway. ADMA, D-Ornithine, L-Kynurenine, Kynurenic acid, 5-Hydroxyindoleacetic acid, and Gluconic acid could serve as potential early biomarkers for CKD progression. These findings have important implications for the early intervention and treatment of CKD, as well as for further research into the underlying mechanisms of its pathogenesis.Keywords: arginine and ornithine metabolism, tryptophan metabolism, pentose phosphate pathway, biomarkers

Hao Hong,1 Junyao Zheng,2 Haimin Shi,2 Suya Zhou,3 Yue Chen,4 Ming Li2 1Department of Intensive Care Unit, The First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 2Laboratory Nephrology, The First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 3Laboratory Nephrology, Jinshan Hospital of Fudan University, Shanghai, People’s Republic of China; 4Laboratory Nephrology, The First People’s Hospital of Kunshan, Soochow, People’s Republic of ChinaCorrespondence: Ming Li, Email 1925924373@qq.comPurpose: Changes in inflammation, immunity, and nutritional status can promote the development of chronic kidney disease (CKD), and the Naples prognostic score (NPS) reflects changes in these three general clinical parameters. Indoleamine 2.3-dioxygenase (IDO) can block the function of inflammatory cells and inhibit the production of inflammatory cytokines. We examined use of the NPS and IDO activity to predict early-stage CKD.Patients and Methods: Clinical and demographic parameters and the NPS were recorded for 47 CKD patients and 30 healthy controls. A one-way ANOVA or the rank sum test was used to compare variables in the different groups. Spearman or Pearson correlation coefficients were calculated, and logistic regression was used to identify significant factors. Receiver operating characteristic (ROC) analysis was also performed.Results: The NPS had a positive correlation with plasma IDO activity and IDO activity was lowest in controls, and increased with CKD stage. ROC analysis indicated that NPS had an area under the curve (AUC) of 0.779 when comparing controls with all CKD patients. A prediction model for CKD (− 4.847 + [1.234 × NPS] + [6.160 × plasma IDO activity]) demonstrated significant differences between controls and patients with early-stage CKD, and for patients with different stages of CKD. This model had AUC values of 0.885 (control vs CKD1– 4), 0.876 (control vs CKD2), 0.818 (CKD2 vs CKD3), and 0.758 (CKD3 vs CKD4).Conclusion: A prediction model based on the NPS and IDO provided good to excellent predictions of early-stage CKD.Keywords: inflammation, immune, nutrition, score, metabolomic, kynurenine pathway

Hao Hong,1,&ast; Junyao Zheng,2,&ast; Haimin Shi,2 Suya Zhou,3 Yue Chen,4 Ming Li2 1Intensive Care Unit, the First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 2Laboratory Nephrology, the First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 3Laboratory Nephrology, Jinshan Hospital of Fudan University, Shanghai, People’s Republic of China; 4Laboratory Nephrology, the First People’s Hospital of Kunshan, Soochow, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Li, Email 1925924373@qq.comPurpose: We aimed to explore changes in plasma and urine indole lactic acid (ILA) levels and the relationship between inflammation and ILA in chronic kidney disease (CKD) patients and healthy people.Patients and Methods: Forty-seven CKD patients and 30 healthy individuals were included in this study. One-way ANOVA was used for variables with normal distribution and homogeneous variance. A rank-sum test was performed for non-normally distributed variables. Correlation analyses were performed using Pearson’s or Spearman correlation analyses. Independent relationship between patients and CKD was analyzed using ordinal and binary logistic regressions. Receiver operating characteristic (ROC) curve was used.Results: Plasma and urine ILA levels were positively correlated (r = 0.51, P < 0.01). Plasma ILA was positively correlated with BMI, age, creatinine, BUN, triglycerides, and uric acid and negatively correlated with hemoglobin levels. Urine ILA levels were positively correlated with age, creatinine, BUN, and uric acid and negatively correlated with hemoglobin and albumin levels. Ordered logistic regression analysis showed that CKD was significantly correlated with plasma ILA (OR=4.49, P

Summary: There are anywhere from 5 to 8 priority antibiotics in typical wastewater treatment plants (WWTPs) whose concentrations exceed the maximum allowed, out of 12 priority antibiotics designated by the World Health Organization as the species to pose severe health hazard than others. If the priority antibiotics to deal with could be reduced to just one or two, such reduction would greatly simplify the construction and operation of the treatment plants. Introduced here is a concept of ‘primary’ antibiotic, the abatement of which ensures mitigation of all the other priority antibiotics in the wastewater. A criterion for determining primary antibiotic is developed. For a demonstration of the approach, the wastewater systems treated with solar-based photocatalysts are considered. The criterion reveals that the primary antibiotic in the typical European WWTP as well as in the typical municipal and hospital wastewater is ciprofloxacin, whereas the typical industrial wastewater contains ciprofloxacin and oxytetracycline.

Yong Li,1 Ju Gao,1 Lin Jiang,2 Canlin Sun,2 Hua Hong,2 Dapeng Yu2 1Department of Anesthesiology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu Province, People’s Republic of ChinaCorrespondence: Dapeng Yu, Department of Anesthesiology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China, Email xiaosiyu1@163.comAbstract: Dexmedetomidine is a selective and potent α2-adrenoceptor agonist used for sedation, analgesia, and anxiolysis, with minimal respiratory depression; therefore, it is widely used in clinical practice. Transient hypertension has been reported to be an indication for the use of dexmedetomidine. The authors report three female patients who experienced hypertensive crisis when used atropine to treat bradycardia caused by dexmedetomidine. The transient hypertension is a relatively common side effect of dexmedetomidine, hypertensive crisis seen with coadministration of atropine is much less frequently reported. This is the first report to describe the use of atropine to treat bradycardia induced by dexmedetomidine, which may cause severe hypertension in female patients. They discuss the reason for and treatment of hypertension caused by administration of atropine and dexmedetomidine together and review the relevant literature.Keywords: dexmedetomidine, atropine, bradycardia, hypertension

Xiaohang Zheng,1,2 Jianxin Qiu,1,2 Ning Gao,3 Ting Jiang,1,2 Ze Li,1,2 Weikang Zhang,1,2 Yuhang Gong,1,2 Zhenghua Hong,1,2 Huaxing Hong1,2 1Orthopedic Department, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, People’s Republic of China; 2Enze Medical Research Center, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, People’s Republic of China; 3Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Huaxing Hong; Zhenghua Hong, Taizhou Hospital Affiliated to Wenzhou Medical University, No. 150, Ximen Street, Taizhou City, Zhejiang Province, People’s Republic of China, Fax +86 0576-8512-0120, Email tzyyhhx@126.com; 0001hzh@163.comBackground: Osteoarthritis (OA), a common chronic joint disease, is characterized by cartilage degeneration and subchondral bone reconstruction. NF-κB signaling pathway-activated inflammation and NLRP3-induced pyroptosis play essential roles in the development of OA. In this study, we examine whether paroxetine can inhibit pyroptosis and reduce osteoclast formation, thereby delaying the destruction of knee joints.Methods: We employed high-density cultures, along with quantitative polymerase chain reactions and Western blotting techniques, to investigate the effects of paroxetine on extracellular matrix synthesis and degradation. The expression levels of NF-κB and pyroptosis-related signaling pathway proteins were examined by Western blotting and immunofluorescence. Furthermore, the impact of paroxetine on RANKL-induced osteoclast formation was evaluated through TRAP staining and F-actin ring fluorescence detection. To investigate the role of paroxetine in vivo, we constructed a mouse model with destabilization of the medial meniscus (DMM) surgery. Safranin O-Fast Green staining, Hematoxylin-Eosin staining, and immunohistochemistry were conducted to observe the extent of knee joint cartilage deformation. In addition, TRAP staining was used to observe the formation of osteoclasts in the subchondral bone.Results: In the in vitro experiments with ATDC5, paroxetine treatment attenuated IL-1β-induced activation of the pyroptosis-related pathway and suppressed extracellular matrix catabolism by inhibiting the NF-kB signaling pathway. In addition, paroxetine treatment decreased the expression of RANKL-induced osteoclast marker genes and reduced osteoclast formation. In animal experiments conducted in vivo, mice treated with paroxetine exhibited thicker knee cartilage with a smoother surface compared to the DMM group. Additionally, the formation of osteoclasts in the subchondral bone was reduced in the paroxetine-treated mice. Further analysis revealed that paroxetine treatment played a role in preserving the balance of the extracellular matrix and delaying knee joint degeneration.Conclusion: Paroxetine can inhibit pyroptosis and reduce osteoclast formation via inhibiting the NF-κB signaling pathway, suggesting that it may have therapeutic effects in patients with OA.Keywords: paroxetine, pyroptosis, inflammation, osteoclasts, osteoarthritis

Jae-Woo Ju,1 Jiwon You,1 Hyunsook Hong,2 Chang Kyung Kang,3 Won Ho Kim,1,4 Ho-Jin Lee1,4 1Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Republic of Korea; 3Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 4Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Republic of KoreaCorrespondence: Ho-Jin Lee, Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea, Tel +82-2-2072-0039, Fax +82-2-747-8363, Email zenerdiode03@gmail.comPurpose: We aimed to investigate the impact of enhanced in-hospital infection prevention during the coronavirus disease 2019 (COVID-19) pandemic on postoperative pneumonia in older surgical patients.Patients and Methods: We retrospectively reviewed the electronic medical records of consecutive patients ≥ 70 years who underwent elective surgery between 2017 and 2021 at our institution. All perioperative variables were retrieved from the electronic medical records. The primary outcome was new-onset postoperative pneumonia during the hospitalization period. Since February 2020, our institution implemented a series of policies to enhance infection prevention, hence patients were divided into groups according to whether they underwent surgery before or during the COVID-19 pandemic. An interrupted time series analysis was performed to evaluate the difference between pre- and post-intervention slopes of the primary outcome.Results: Among the 29,387 patients included in the study, 10,547 patients underwent surgery during the COVID-19 pandemic. Although there was a decreasing trend of the monthly incidence rate of postoperative pneumonia compared to before the COVID-19 pandemic, there was no statistical significance in the trend (slope before COVID-19 period: β-coefficient, − 0.007; 95% CI, − 0.022 to 0.007).Conclusion: Our study revealed that enhanced in-hospital infection prevention implemented to manage the COVID-19 pandemic did not significantly affect the decreasing trend of postoperative pneumonia at our institution.Keywords: coronavirus, COVID-19, healthcare-associated pneumonia, pandemic, pneumonia, severe acute respiratory syndrome coronavirus 2

Abstract Siderophores belonging to the ferrichrome family are essential for the viability of fungal species and play a key role for virulence of numerous pathogenic fungi. Despite their biological significance, our understanding of how these iron-chelating cyclic hexapeptides are assembled by non-ribosomal peptide synthetase (NRPS) enzymes remains poorly understood, primarily due to the nonlinearity exhibited by the domain architecture. Herein, we report the biochemical characterization of the SidC NRPS, responsible for construction of the intracellular siderophore ferricrocin. In vitro reconstitution of purified SidC reveals its ability to produce ferricrocin and its structural variant, ferrichrome. Application of intact protein mass spectrometry uncovers several non-canonical events during peptidyl siderophore biosynthesis, including inter-modular loading of amino acid substrates and an adenylation domain capable of poly-amide bond formation. This work expands the scope of NRPS programming, allows biosynthetic assignment of ferrichrome NRPSs, and sets the stage for reprogramming towards novel hydroxamate scaffolds.

Jiaoping Mi,1,2,&ast; Yijie Fang,3,&ast; Jianzhong Xian,4 Guojie Wang,3 Yuanqing Guo,5 Haiyu Hong,2 Mengshi Chi,2 Yong-Fang Li,2 Peng He,2 Jiebing Gao,3 Wei Liao2 1Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Otolaryngology Head and Neck Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 3Department of Radiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 4Department of Ultrasound, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 5Department of Spinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Liao, Department of Otolaryngology Head and Neck Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, 519020, People’s Republic of China, Email liaowei23@mail.sysu.edu.cn Jiebing Gao, Department of Radiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China, Email Gaojb@mail.sysu.edu.cnObjective: Accurate preoperative localization of abnormal parathyroid glands is crucial for successful surgical management of secondary hyperparathyroidism (SHPT). This study was conducted to compare the effectiveness of preoperative MRI, 4D-CT, and ultrasonography (US) in localizing parathyroid lesions in patients with SHPT.Methods: We performed a retrospective review of prospectively collected data from a tertiary-care hospital and identified 52 patients who received preoperative MRI and/or 4D-CT and/or US and/or 99mTc-MIBI and subsequently underwent surgery for SHPT between May 2013 and March 2020. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each imaging modality to accurately detect enlarged parathyroid glands were determined using histopathology as the criterion standard with confirmation using the postoperative biochemical response.Results: A total of 198 lesions were identified intraoperatively among the 52 patients included in this investigation. MRI outperformed 4D-CT and US in terms of sensitivity (P < 0.01), specificity (P = 0.455), PPV (P = 0.753), and NPV (P = 0.185). The sensitivity and specificity for MRI, 4D-CT, and US were 90.91%, 88.95%, and 66.23% and 58.33%, 63.64%, and 50.00%, respectively. The PPV of combined MRI and 4D-CT (96.52%) was the highest among the combined 2 modalities. The smallest diameter of the parathyroid gland precisely localized by MRI was 8× 3 mm, 5× 5 mm by 4D-CT, and 5× 3 mm by US.Conclusion: MRI has superior diagnostic performance compared with other modalities as a first-line imaging study for patients undergoing renal hyperparathyroidism, especially for ectopic or small parathyroid lesions. We suggest performing US first for diagnosis and then MRI to make a precise localization, and MRI proved to be very helpful in achieving a high success rate in the surgical treatment of renal hyperparathyroidism in our own experience.Keywords: MRI, 4D-CT, ultrasonography, SHPT, preoperative localization, parathyroidectomy

Anni Yang,1,&ast; Menglei Jv,2,&ast; Jun Zhang,1,&ast; Yuqi Hu,1 Jiaoping Mi,1 Haiyu Hong1 1Allergy Center, Department of Otolaryngology Head and Neck Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 2Department of Nephrology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyu Hong, Allergy Center, Department of Otorhinolaryngology Hospital, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China, Email honghy@sysu.edu.cnObjective: This study aimed to explore whether children with AH have a higher obesity prevalence and analyze the risk factors for otitis media with effusion(OME) in AH children.Methods: AH patients aged 3– 12 years old that were hospitalized in our hospital for adenoidectomy from June 2020 to September 2022 were included in this study. Height and weight were measured to calculate the body mass index, weight for height and weight z-score to evaluate the development of AH children. Propensity score matching was applied to minimize patient selection bias and adjust for confounding factors to analyze the risk factors for OME in children with AH.Results: A total of 887 children with AH were enrolled in this study. The prevalence of overweight or obesity was higher in children with AH than the control group. The size of adenoids is significantly different between AH children with and without OME. For children aged over 5, there are significantly higher counts of white blood cells, neutrophils, and monocytes in the AH children with OME than those without OME. More individuals represent to be atopic in children with OME than those without OME.Conclusion: The obstruction of the Eustachian tube is the most important factor of OME in AH children. It seems that there is no apparent correlation between OME and atopic conditions in AH children. In addition to surgical resection of adenoids, active control of infection and inflammation are also important to prevent OME for AH children aged over 5.Keywords: adenoid hypertrophy, otitis media with effusion, risk factors, atopic conditions

Heta Dinesh Bhatt,1 Lorne M Golub,1 Hsi-Ming Lee,1 Jihwan Kim,2 Thomas Zimmerman,3 Jie Deng,4 Houlin Hong,5 Francis Johnson,6 Ying Gu7 1Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA; 2Department of Pediatric Dentistry, University of Buffalo School of Dental Medicine, Buffalo, NY, USA; 3Division of Laboratory Animal Resources (DLAR) at Stony Brook, Stony Brook University, Stony Brook, NY, USA; 4Department of Orthodontics, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, People’s Republic of China; 5Department of Community Health & Social Sciences, Graduate School of Public Health & Health Policy, City University of New York, New York City, NY, USA; 6Department of Chemistry and Pharmacological Sciences, School of Medicine, Stony Brook University, Stony Brook, NY, USA; 7Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USACorrespondence: Heta Dinesh Bhatt, Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, 11794, USA, Tel +1631820-5311, Email drhetabhatt@gmail.comPurpose: CMC2.24, a novel 4-(phenylaminocarbonyl)-chemically-modified-curcumin, is a pleiotropic MMP-Inhibitor of various inflammatory/collagenolytic diseases including periodontitis. This compound has demonstrated efficacy in host modulation therapy along with improved resolution of inflammation in various study models. The objective of current study is to determine the efficacy of CMC2.24 in reducing the severity of diabetes, and its long-term role as an MMP-inhibitor, in a rat model.Methods: Twenty-one adult male Sprague-Dawley rats were randomly distributed into three groups: Normal (N), Diabetic (D) and Diabetic+CMC2.24 (D+2.24). All three groups were orally administered vehicle: carboxymethylcellulose alone (N, D), or CMC2.24 (D+2.24; 30mg/kg/day). Blood was collected at 2-months and 4-months’ time-point. At completion, gingival tissue and peritoneal washes were collected/analyzed, and jaws examined for alveolar bone loss by micro-CT. Additionally, sodium hypochlorite(NaClO)-activation of human-recombinant (rh) MMP-9 and its inhibition by treatment with 10μM CMC2.24, Doxycycline, and Curcumin were evaluated.Results: CMC2.24 significantly reduced the levels of lower-molecular-weight active-MMP-9 in plasma. Similar trend of reduced active-MMP-9 was also observed in cell-free peritoneal and pooled gingival extracts. Thus, treatment substantially decreased conversion of pro- to actively destructive proteinase. Normalization of the pro-inflammatory cytokine (IL-1ß, resolvin-RvD1), and diabetes-induced osteoporosis was observed in presence of CMCM2.24. CMC2.24 also exhibited significant anti-oxidant activity by inhibiting the activation of MMP-9 to a lower-molecular-weight (82kDa) pathologically active form. All these systemic and local effects were observed in the absence of reduction in severity of hyperglycemia.Conclusion: CMC2.24 reduced activation of pathologic active-MMP-9, normalized diabetic osteoporosis, and promoted resolution of inflammation but had no effect on the hyperglycemia in diabetic rats. This study also highlights the role of MMP-9 as an early/sensitive biomarker in the absence of change in any other biochemical parameter. CMC2.24 also inhibited significant activation of pro-MMP-9 by NaOCl (oxidant) adding to known mechanisms by which this compound treats collagenolytic/inflammatory diseases including periodontitis.Keywords: matrix metalloproteinases, diabetes mellitus, resolvin, anti-oxidant activity, host modulation therapy

Hao Hong,1 Suya Zhou,2 Haimin Shi,3 Ming Li3 1Intensive Care Unit, The First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 2Laboratory Nephrology, Department of Nephrology, Jinshan Hospital of Fudan University, Shanghai, People’s Republic of China; 3Laboratory Nephrology, The First Affiliated Hospital of Soochow University, Soochow, People’s Republic of ChinaCorrespondence: Ming Li, Tel +86 13656237709, Fax +0512-67972681, Email szdrli@163.comPurpose: Our aim was to determine the relationship between plasma and urine indoleamine 2.3-dioxygenase (IDO) activity and stage of chronic kidney disease (CKD).Patients and Methods: Demographic and clinical parameters, including plasma and urine IDO activity, were recorded in 47 CKD patients and 30 controls. One-way ANOVA with the least significant difference method was used to compare means of variables that had normal distributions and homogeneous variance. Variables with non-normal distributions were log-transformed and compared using the rank sum test Pearson or Spearman correlation coefficients were determined. Binary logistic regression and ordinal logistic regression were used to identify independently significant factors. Receiver operating characteristic (ROC) analysis was performed.Results: The control group had higher levels of hemoglobin and albumin and lower levels of creatinine and blood urea nitrogen (BUN; all P< 0.01). The level of highly sensitive C reactive protein (hs-CRP) increased as CKD stage increased (P

Sang-Jin Park,1,&ast; Seung Ro Han,2,3,&ast; Yun Hee Kang,2,3,&ast; Eun-Jin Lee,1 Eu-Gene Kim,1 Hyobong Hong,4 Jae-Chan Jeong,4 Myung-Shin Lee,2,3 Seung-Hoon Lee,2,5 Dae-Yong Song1 1Department of Anatomy and Neuroscience, Eulji University School of Medicine, Daejeon, Korea; 2Eulji Biomedical Science Research Institute, Eulji University School of Medicine, Daejeon, Korea; 3Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, Korea; 4Artifcial Intelligence Research Laboratory, Electronics and Telecommunications Research Institute (ETRI), Daejeon, Korea; 5Department of Neurosurgery, Eulji University School of Medicine, Daejeon, Korea&ast;These authors contributed equally to this workCorrespondence: Seung-Hoon Lee, Department of Neurosurgery, Eulji University School of Medicine, Daejeon, Korea, Tel +82-42-259-1612, Fax +82-42-259-1669, Email nslsh@eulji.ac.kr Dae-Yong Song, Department of Anatomy and Neuroscience, Eulji University School of Medicine, Daejeon, Korea, Tel +82-42-259-1622, Fax +82-42-259-1669, Email dysong@eulji.ac.krPurpose: Magnetic particle imaging (MPI) is an emerging radiation-free, non-invasive three-dimensional tomographic technology that can visualize the concentrations of superparamagnetic iron oxide nanoparticles (SPIONs). To verify the applicability of the previously proposed point-of-care testing MPI (PoCT-MPI) in medical diagnosis and therapeutics, we imaged SPIONs in animal tumor models.Methods: CT26 or MC38 mouse colon carcinoma cells (2 × 106 cells) were subcutaneously injected into the right flank of BALB/c mice. SPIONs were either injected directly into the tumor lesions in the intratumoral group or through tail veins in the intravenous group. CT26 and MC38 tumor models were examined both intratumorally and intravenously to confirm the biological availability of SPIONs using PoCT-MPI.Results: Signals were observed in the tumor lesions from day 1 to day 7. This is the first study to successfully image the pathological region and show the biodistribution of SPIONs in CT26 tumor models using the recently developed PoCT-MPI technology. Furthermore, MC38 tumor models were examined, resulting in similar images to those of the CT26 tumor model in both intratumoral and intravenous groups.Conclusion: The present study demonstrates the biological applicability of PoCT-MPI, which promises to be a powerful diagnostic and therapeutic technique in biomedical imaging.Keywords: colon cancer, syngeneic mouse tumor model, point-of-care testing MPI, diagnostics

Cervical cancer is the second most common gynecologic cancer in Vietnam but based on the literature, only ~25% of Vietnamese women reported ever being screened for cervical cancer. To inform strategies to reduce the cervical cancer burden in Southern Vietnam where disease incidence is higher than the national average, this study examined behaviors, awareness, barriers, and beliefs about cervical cancer screening among rural and urban women in this geographical region. In October-November 2021, we conducted a cross-sectional study among 196 rural and 202 urban women in Southern Vietnam; participants completed a cervical cancer screening questionnaire. Descriptive analyses and rural-urban differences in screening behavior, awareness, barriers, and beliefs are presented. About half of the rural and urban participants reported ever being screened for cervical cancer. Most participants showed high perceived severity of cervical cancer and benefits of screening. Further, they reported that they would screen if it was recommended by doctors and/or friends/family. However, most women showed low awareness and perceived susceptibility to cervical cancer. Logistical and psychosocial barriers to physician-based screening methods were reported. Based on our results, the World Health Organization 2030 goals for cervical cancer screening are not currently met in Southern Vietnam. Increasing health literacy and engaging doctors and family members/social networks emerged as important avenues to improve screening. HPV (Human papillomavirus) self-sampling is also a potential approach to increase uptake of cervical cancer screening given the identified psychosocial and logistical barriers.

Shinwon Park,1,&ast; Haejin Hong,1,2,&ast; Rye Young Kim,1,3,&ast; Jiyoung Ma,1 Suji Lee,1 Eunji Ha,1,2 Sujung Yoon,1,2 Jungyoon Kim1,2 1Ewha Brain Institute, Ewha Womans University, Seoul, South Korea; 2Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, South Korea; 3Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, South Korea&ast;These authors contributed equally to this workCorrespondence: Sujung Yoon Email sujungjyoon@ewha.ac.krJungyoon Kim Email jungyoon.kimm@ewha.ac.krPurpose: To investigate the cerebral blood flow (CBF) alterations associated with poor sleep quality and memory performance in firefighters.Participants and Methods: Thirty-seven firefighters (the FF group) and 37 non-firefighter controls (the control group) with sleep complaints were enrolled in this study. We performed brain arterial spin labeling perfusion magnetic resonance imaging (MRI) and compared the CBF between the two groups using whole-brain voxel-wise analyses. Self-reported sleep problems and actigraphy-measured sleep parameters, including the sleep efficiency, wake after sleep onset (WASO), total sleep time, and sleep latency, were assessed. Spatial working memory and learning performances were evaluated on the day of the MRI scan.Results: The FF group, relative to the control group, had lower CBF in the right hemispheric regions: Middle temporal/lateral occipital, orbitofrontal, and insular cortices. Lower CBF in the right orbitofrontal cortex was linearly associated with poor sleep quality, as indicated by lower sleep efficiency and longer WASO. The CBF of the right insular cortex was also associated with longer WASO. Despite comparable degrees of self-reported sleep problems between the two groups, the FF group had lower sleep efficiency and longer WASO in the actigraphy, and lower spatial working memory and learning performance, relative to the control group. Poor sleep efficiency was linearly associated with lower spatial working memory performance.Conclusion: These results demonstrated an association of poor sleep quality with decreased brain perfusion in the right orbitofrontal and insular cortices, as well as with reduced working memory performance.Keywords: firefighters, sleep efficiency, wake after sleep onset, cerebral blood flow, arterial spin labeling, perfusion magnetic resonance imaging

Heejeong Hong,1 Hyun-Kuk Song,1 Bohee Jang,1 Eunhye Park,1 Dong Soo Han,2 Seong-Eun Kim,3 Eok-Soo Oh1 1Department of Life Sciences, Ewha Womans University, Seoul, South Korea; 2Department of Internal Medicine, Hanyang University College of Medicine, Guri, South Korea; 3Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Institute, Seoul, South KoreaCorrespondence: Eok-Soo OhDepartment of Life Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemoon-Gu, Seoul, 03760, South KoreaTel +82-2-3277-3761Fax +82-2-3277-3760Email OhES@ewha.ac.krIntroduction: Syndecan-2 expression is elevated during chronic inflammation and cancer development, and its shedding is observed in cancer patients. However, it remained unknown whether inflammation triggers syndecan-2 shedding.Methods: The colitis model was produced in C57BL/6 mice by oral administration of 2– 3% dextran sulfate sodium (DSS) in the drinking water. Syndecan-2 and MMP-7 expression levels in tissues and cells were detected by real-time PCR, Western blotting, and immunohistochemistry. Shed syndecan-2 levels were detected by slot blotting. For tissue culture, colon tissues were divided into proximal, transverse, and distal parts, and incubated in culture media.Results: In C57BL/6 mice with DSS-induced colitis, syndecan-2 shedding began to increase after week 12 of chronic inflammation and continued to increase at week 15. The level of shed syndecan-2 correlated with the colocalization of syndecan-2 and MMP-7 in distal colon tissues. The mRNA expression of IL-6 was increased specifically in trans-distal colon tissues from weeks 9 to 15. IL-6 induced syndecan-2 expression and shedding and MMP-7 expression in ex vivo-cultured distal colon tissues and adenoma cell lines derived from the distal colon. IL-6 treatment induced STAT3 phosphorylation and MMP-7 expression in DLD-1 cells. The application of MMP-7 to ex vivo-cultured colon tissues increased the shedding of syndecan-2 to the culture medium.Conclusion: Our findings suggest that chronic inflammation induces syndecan-2 shedding via the site-specific colocalization of syndecan-2 with MMP-7 in the distal colon.Keywords: chronic inflammation, syndecan-2, MMP-7, shedding

Zhenpeng Liao,1,&ast; Jianling Guo,1,&ast; Jiaoping Mi,1,&ast; Wei Liao,1 Shulin Chen,1 Yili Huang,1 Yingxiang Xu,1 Jun Zhang,1 Qintai Yang,2 Haiyu Hong1 1Allergy Center, Department of Otolaryngology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 2Department of Otolaryngology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qintai YangDepartment of Otolaryngology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Guangzhou, 510630, People’s Republic of ChinaEmail yang.qt@163.comHaiyu HongAllergy Center, Department of Otolaryngology, The Fifth Affiliated Hospital of Sun Yat-sen University, No. 52, Meihua East Road, Zhuhai, 519020, People’s Republic of ChinaEmail honghy@sysu.edu.cnIntroduction: Intractable epistaxis refers to deep occult bleeding and uncontrolled persistent bleeding. Effective treatment can only be implemented if the bleeding site is quickly identified and the underlying disease controlled.Objective: The relationship between the bleeding site and the pathogenic factors of intractable epistaxis was analyzed to further strengthen the prevention and treatment of intractable epistaxis by outpatient doctors, family doctors and otolaryngologists. Through accurate search and minimally invasive hemostasis, it helped optimize the treatment plan for intractable epistaxis.Methods: This study retrospectively analyzed the clinical data of 90 patients with intractable epistaxis who were admitted to hospital from January 2016 to December 2017. Chi-square test was used to analyze the relationship between intractable epistaxis site with underlying disease, gender and age.Results: The distribution of intractable epistaxis was associated with hypertension (χ2=13.76, P=0.017). The incidence of hypertension was the highest in the olfactory sulcus of the middle turbinate region at about 60%. In addition, age was also identified as a factor that affects the distribution of intractable epistaxis (χ2=21.95, P=0.02). The incidence of intractable epistaxis on the vault of inferiornasal meatus region was highest (63%) in young patients. On the other hand, the olfactory sulcus of the middle turbinate region accounted for the highest incidence in the middle-aged and elderly group (66.7%). There was no obvious relation between the bleeding site of intractable epistaxis with diabetes, cardiovascular disease, chronic sinusitis and allergic rhinitis.Conclusion: The bleeding site of intractable epistaxis is related to hypertension and age. This may improve the identification of the site of intractable epistaxis for timely implementation of treatment and can further strengthen the prevention and treatment of intractable epistaxis in outpatients or family doctors.Keywords: intractable epistaxis, bleeding site, hypertension, age

Rongfei Su,1,* Yuqi Hu,1,* Zhenpeng Liao,1,* Kai Sen Tan,2 Haiyu Hong,1 Yunping Fan3 1Allergy Center, Department of Otolaryngology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 2Department of Otolaryngology, National University of Singapore, National University Health System, Singapore; 3Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haiyu Hong, Allergy Center, Department of Otolaryngology, The Fifth Affiliated Hospital of Sun Yat-sen University, No. 52, Meihua East Road, Zhuhai, 519020, People’s Republic of China, Email honghy@sysu.edu.cn; Yunping Fan, Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, People’s Republic of China, Email zhfanyp@163.comAbstract: The number of confirmed COVID-19 cases continues to rise around the world, which is a huge threat to the safety of people and the social economy. Despite the introduction of vaccines, effectively preventing and controlling the epidemic, especially in protecting vulnerable populations, remains a big challenge for countries worldwide. By summarizing the trajectory of several officially reported COVID-19 cases, we found that because the COVID-19 primary routes of transmission consist of respiratory droplets, aerosols and close contacts it remains containable with public health measures. Public health measures to contain the outbreak do not rely on the healthcare institution and government agencies alone but require the concerted efforts of the public with sustained vigilance and social responsibility. People who are showing symptoms or have had suspected contact need to keep wearing masks and be quarantined in time to prevent further chains of transmission.Keywords: COVID-19, public health measures, masks wearing, social distancing, disease prevention, social responsibility

Xin-ping Yu,1 Lei Wang,1 Hai-yang Yu,2 Yu-wei Zou,3 Chang Wang,1 Jin-wen Jiao,1 Hao Hong,4 Shuai Zhang2 1Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 2Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 3Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 4Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of ChinaCorrespondence: Shuai ZhangDepartment of Radiology, The Affiliated Hospital of Qingdao University, NO. 1677 Wutaishan Road, Huangdao District, Shandong Province 266000, People’s Republic of ChinaTel +86 18661804638Email zhangshuai19860302@163.comObjective: To investigate whether multidetector computed tomography (MDCT)-based radiomics features can discriminate between serous borderline ovarian tumors (SBOTs) and serous malignant ovarian tumors (SMOTs).Patients and Methods: Eighty patients with SBOTs and 102 patients with SMOTs, confirmed by pathology (training set: n = 127; validation set: n = 55) from December 2017 to June 2020, were enrolled in this study. The interclass correlation coefficient (ICC) and least absolute shrinkage and selection operator (LASSO) regression were applied to select radiomics parameters derived from MDCT images on the arterial phase (AP), venous phase (VP), and equilibrium phase (EP). Receiver operating characteristic (ROC) analysis of each selected parameter was carried out. Heat maps were created to illustrate the distribution of the radiomics parameters. Three models incorporating selected radiomics parameters generated by support vector machine (SVM) classifiers in each phase were analyzed by ROC and compared using the DeLong test.Results: The most predictive features selected by ICC and LASSO regression between SBOTs and SMOTs included 9 radiomics parameters on AP, VP, and EP each. Three models on AP, VP, and EP incorporating the selected features generated by SVM classifiers produced AUCs of 0.80 (accuracy, 0.75; sensitivity, 0.74; specificity, 0.75), 0.86 (accuracy, 0.78; sensitivity, 0.80; specificity, 0.75), and 0.73 (accuracy, 0.69; sensitivity, 0.71; specificity, 0.67), respectively. There were no significant differences in the AUCs among the three models (AP vs. VP, P = 0.199; AP vs. EP, P = 0.260; VP vs. EP, P = 0.793).Conclusion: MDCT-based radiomics features could be used as biomarkers for the differentiation of SBOTs and SMOTs.Keywords: ovarian tumors, multidetector computed tomography; MDCT, radiomics

Ning Xie,1,* Tao Qin,1,* Wei Ren,1 Herui Yao,1,2 Yunfang Yu,1 Huangming Hong1 1Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People’s Republic of China; 2Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunfang Yu; Huangming Hong Tel +86-20-34071337Fax +86-20-81332833Email yunfangyu@foxmail.com; honghm3@mail.sysu.edu.cnPurpose: To assess the efficacy and safety of cyclin-dependent kinases 4 and 6 inhibitors (CDKi) combined with endocrine therapy (ET) in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and compare the efficacy of different CDKi (palbociclib, ribociclib, or abemaciclib).Materials and Methods: This study based on randomized Phase 2 or 3 trials of CDKi plus ET compared with placebo plus ET for women with HR+/HER2−ABC and identify relevant randomized clinical trials (RCTs) published prior to February 2020. The primary endpoint was progression-free survival (PFS), the secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit response (CBR) and safety. The PROSPERO registry number is 42018081105.Results: The results from eight trials including 4580 participants were pooled. Evidence indicated that the PFS of CDKi group was significantly prolonged (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.50– 0.60, P < 0.01) compared with placebo group. The ORR and CBR were better (risk ratio [RR] 1.47, 95% CI 1.30– 1.67, P < 0.01; 1.24, 95% CI 1.15– 1.35, P < 0.01) in the CDKi group. The OS of CDKi group (HR 0.75, 95% CI 0.67– 0.85, P < 0.01) was significantly longer than ET alone. Subgroup analyses confirmed that the benefit was consistent across most subgroups. Subgroup analyses showed no statistically significant difference of PFS among three CDKi: palbociclib vs ribociclib (HR 0.55, 95% CI 0.49– 0.60, P = 0.34), palbociclib vs abemaciclib (HR 0.53, 95% CI, 0.47– 0.59, P = 0.61), and ribociclib vs abemaciclib (HR 0.56, 95% CI, 0.51– 0.62, P = 0.72). Treatment-related grade 3 or 4 hematologic adverse events (AEs) were more frequently in CDKi group.Conclusion: CDKi combined with ET can significantly prolong PFS and improve the ORR, CBR and OS in patients with HR+/HER2− ABC. However, the advantage of different CDKi has not been established.Keywords: CDK4/6 inhibitor, HR-positive, HER2-negative, advanced breast cancer

Sio Teng Lam,1,2,* He Huang,1,* Xiaojie Fang,1 Zhao Wang,1 Huangming Hong,3 Quanguang Ren,1 Ying Tian,1 Suxia Lin,4 Tongyu Lin1 1Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China; 2Department of Medical Oncology, Centro Hospitalar Conde De Sao Januario, Macau, People’s Republic of China; 3Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 4Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tongyu LinDepartment of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, People’s Republic of ChinaTel +86-20-87343363Fax +86-20-87343294Email tongyulin@hotmail.comPurpose: Programmed death ligand 1 (PD-L1) has been proposed as an important prognostic factor in many types of cancer. However, the role of predicting the prognosis of PD-L1 in extranodal natural killer/T-cell lymphoma (ENKTL) was controversial. Combining other biomarkers might enhance its predictive power. This study aims to evaluate the prognostic value of PD-L1 in conjunction with tumor-infiltrating FoxP3+Tregs for ENKTL after non-anthracycline-based chemotherapy.Patients and Methods: A total of 81 patients with ENKTL were included in this study. Clinicopathological characteristics were collected, and prognostic significance of PD-L1 in neoplastic cells (nPD-L1) and tumor-infiltrating FoxP3+Tregs were evaluated.Results: Patients with nPD-L1-positive had significantly inferior overall survival (OS) and progression-free survival (PFS) compared with nPD-L1-negative (3-year OS, 37.2% vs 67.3%, p = 0.014; 3-year PFS, 31.0% vs 61.8%, p =0.010, respectively). Patients who had low FoxP3+Tregs had significantly inferior OS and PFS compared with high FoxP3+Tregs (3-year OS, 36.4% vs 63.0%, p = 0.004; 3-year PFS, 31.7% vs 56.3%, p = 0.020, respectively). The results of multivariate analysis showed that nPD-L1 positivity (HR 6.629, 95% CI 1.966– 22.350, p=0.002) and low FoxP3+Tregs (HR 7.317, 95% CI 2.154– 24.855, p=0.001) were independent predictors of inferior OS. Using these 2 variables, we constructed a new prognostic model that singled out 3 groups with different risk profiles: group 1, no adverse factors; group 2, 1 adverse factor; and group 3, 2 adverse factors. The 3-year OS rates of group 1, group 2, and group 3 were 93.3%, 46.6% and 20.8%, respectively (p< 0.001), and the 3-year PFS rates were 86.7%, 40.8% and 15.0%, respectively (p=0.001).Conclusion: This study is the first to validate the prognostic value of nPD-L1 and tumor-infiltrating FoxP3+Tregs in ENKTL; the new immunological prognostic model might be used to stratify ENKTL patients in clinical trials for new therapeutic strategies.Keywords: extranodal natural killer/T-cell lymphoma, PD-L1, FoxP3+Tregs, prognosis

Although low-frequency quasiperiodic oscillations (LFQPOs) are commonly detected in the X-ray light curves of accreting black hole X-ray binaries, their origin still remains elusive. In this study, we conduct phase-resolved spectroscopy in a broad energy band for LFQPOs in MAXI J1820+070 during its 2018 outburst, utilizing Insight-HXMT observations. By employing the Hilbert–Huang transform method, we extract the intrinsic quasiperiodic oscillation (QPO) variability, and obtain the corresponding instantaneous amplitude, phase, and frequency functions for each data point. With well-defined phases, we construct QPO waveforms and phase-resolved spectra. By comparing the phase-folded waveform with that obtained from the Fourier method, we find that phase folding on the phase of the QPO fundamental frequency leads to a slight reduction in the contribution of the harmonic component. This suggests that the phase difference between QPO harmonics exhibits time variability. Phase-resolved spectral analysis reveals strong concurrent modulations of the spectral index and flux across the bright hard state. The modulation of the spectral index could potentially be explained by both the corona and jet precession models, with the latter requiring efficient acceleration within the jet. Furthermore, significant modulations in the reflection fraction are detected exclusively during the later stages of the bright hard state. These findings provide support for the geometric origin of LFQPOs and offer valuable insights into the evolution of the accretion geometry during the outburst in MAXI J1820+070.

This multi-case study investigated self-regulation of preservice science teachers' (PSTs), focusing on their ability to learn from their own teaching experiences and to regulate teaching practices to pose higher-level cognitive questions. The participants were three PSTs enrolled in a certification program for teaching secondary science, representing low, intermediate, and high self-regulated learning (SRL). Data were collected from classroom materials, semi-structured interviews on planning classroom questions, classroom observations, classroom audio recordings, and semi-structured interviews on enacting questions. The findings revealed that while each case exhibited unique characteristics, all PSTs demonstrated improvements in their SRL practices and questioning. The analysis highlighted PSTs' SRL practices in planning and enacting classroom questions, suggesting ways to enhance PSTs' questioning skills through the integration of SRL into teacher preparation. Furthermore, the findings underscored the importance of university supervisors and cooperating teachers tailoring their coaching to PSTs based on their initial SRL skills and utilizing well-defined models of SRL development for guidance.

Hailun Zheng,1,2,* Huang Hong,1,* Lulu Zhang,1,2,* Xiong Cai,1,2 Meng Hu,1,2 Yuepiao Cai,2 Bin Zhou,1 Jiayuh Lin,3 Chengguang Zhao,2 Wanle Hu1 1Department of Coloproctology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 2Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MA, USA *These authors contributed equally to this work Abstract: Activation of the signal transducer and activator of transcription 3 (STAT3) is observed in multiple cancer types, including gastric cancer, and represents a potential drug target for chemotherapy. Currently, clinically available small-molecule inhibitors targeting STAT3 are lacking. Here, we report that nifuratel, an antiprotozoal and antifungal drug, is a potent inhibitor of STAT3. We found that nifuratel significantly suppressed proliferation and induced apoptosis of gastric cancer cells. Studies of the mechanism of action of nifuratel indicated that it acts by inhibiting the constitutive and interleukin-6-induced STAT3 activation. Taken together, our findings demonstrate that nifuratel may be a novel, clinically accessible STAT3 inhibitor in gastric cancer cells. Keywords: nifuratel, STAT3, gastric cancer, inhibitor, drug

Haiyu Hong,1,* Fenghong Chen,2,* Xiaobin Zheng,3 Wei Liao,1 Zhenpeng Liao,1 Yujie Cao,2 Haixin He,1 Zhe Zhu,4,5 Yunping Fan1 1Department of Otolaryngology and Head Neck Surgery of 5th Hospital, Affiliated with Sun Yat-sen University, Zhuhai, 2Department of Otolaryngology and Head Neck Surgery of 1st Hospital, Affiliated with Sun Yat-sen University, Guangzhou, 3Department of Respiration of 5th Hospital, Affiliated with Sun Yat-sen University, Zhuhai, China; 4Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 5Sanford Consortium, Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA *These authors contributed equally to this work Objective: There is little evidence on the role of topical budesonide in reducing the frequency of adenoidectomy, although it was reported that topical budesonide can effectively ameliorate the symptoms of adenoid hypertrophy (AH). This study was aimed to investigate the possibility and safety of alternatives to adenoidectomy with a 12-week treatment with nasal budesonide. Materials and methods: One hundred patients with AH were randomized to receive either a double-blind budesonide (1 mg once daily) or placebo treatment for 2 weeks by transnasal nebulization. A further 12-week open study, budesonide spray (64 µg per nostril at bedtime) was administered to the treatment group. During the final 12 weeks of follow-up, the frequency of adenotonsillectomy, side effects, the degree of nasal obstruction, nasal discharge, and snoring were assessed. Results: Out of the 100 total enrolled patients, 92 children with AH completed the study. After the 2-week treatment with transnasal budesonide nebulization, the symptoms of AH significantly decreased compared to the control group. Responders (n=26) who had initially improved showed significantly decreased symptoms of AH, and the frequency of adenotonsillectomy during the follow-up (14 and 26 weeks) was compared with that of the control group and non-responders (n=21) who did not respond to the initial 2-week budesonide therapy. The 12-week nasal budesonide treatment did not suppress the growth rate of children’s height or cause other side effects. Conclusion: AH children who had improved after an initial 2-week budesonide therapy can achieve clinical improvements and decreased frequency of adenoidectomy following the therapy with a 12-week treatment with nasal budesonide. Keywords: adenoid hypertrophy, adenoidectomy, budesonide, frequency, treatment

BackgroundPrognostic stratification is the cornerstone of management in nonmetastatic prostate cancer (PCa). However, existing prognostic models are inadequate-often using treatment outcomes rather than survival, stratifying by broad heterogeneous groups and using heavily treated cohorts. To address this unmet need, we developed an individualised prognostic model that contextualises PCa-specific mortality (PCSM) against other cause mortality, and estimates the impact of treatment on survival.Methods and findingsUsing records from the United Kingdom National Cancer Registration and Analysis Service (NCRAS), data were collated for 10,089 men diagnosed with nonmetastatic PCa between 2000 and 2010 in Eastern England. Median follow-up was 9.8 years with 3,829 deaths (1,202 PCa specific). Totals of 19.8%, 14.1%, 34.6%, and 31.5% of men underwent conservative management, prostatectomy, radiotherapy (RT), and androgen deprivation monotherapy, respectively. A total of 2,546 men diagnosed in Singapore over a similar time period represented an external validation cohort. Data were randomly split 70:30 into model development and validation cohorts. Fifteen-year PCSM and non-PCa mortality (NPCM) were explored using separate multivariable Cox models within a competing risks framework. Fractional polynomials (FPs) were utilised to fit continuous variables and baseline hazards. Model accuracy was assessed by discrimination and calibration using the Harrell C-index and chi-squared goodness of fit, respectively, within both validation cohorts. A multivariable model estimating individualised 10- and 15-year survival outcomes was constructed combining age, prostate-specific antigen (PSA), histological grade, biopsy core involvement, stage, and primary treatment, which were each independent prognostic factors for PCSM, and age and comorbidity, which were prognostic for NPCM. The model demonstrated good discrimination, with a C-index of 0.84 (95% CI: 0.82-0.86) and 0.84 (95% CI: 0.80-0.87) for 15-year PCSM in the UK and Singapore validation cohorts, respectively, comparing favourably to international risk-stratification criteria. Discrimination was maintained for overall mortality, with C-index 0.77 (95% CI: 0.75-0.78) and 0.76 (95% CI: 0.73-0.78). The model was well calibrated with no significant difference between predicted and observed PCa-specific (p = 0.19) or overall deaths (p = 0.43) in the UK cohort. Key study limitations were a relatively small external validation cohort, an inability to account for delayed changes to treatment beyond 12 months, and an absence of tumour-stage subclassifications.Conclusions'PREDICT Prostate' is an individualised multivariable PCa prognostic model built from baseline diagnostic information and the first to our knowledge that models potential treatment benefits on overall survival. Prognostic power is high despite using only routinely collected clinicopathological information.

Conversion of low-grade waste heat into electricity is an important energy harvesting strategy. Here, the authors fabricate carbon nanotube aerogel-based thermo-electrochemical cells, which are potentially low-cost and relatively high-efficiency materials for this application.

The use of data to explain natural phenomena has been a core feature of science education, and science educators continue to call for an increased emphasis on teaching data practices. This mixed methods design-based research study adds to the growing body of research on data practices in science by explaining the learning trends of science teachers involved in a three-year collaborative professional development (PD) using computational thinking (CT) and self-regulated learning (SRL) as a means to support teachers in implementing data practices. The PD resulted in long-term high-quality teacher learning outcomes for all three elements of the PD (data practices, CT, and SRL) despite the upheaval of teaching platforms due to the COVID-19 pandemic. Since the teachers were involved in design-based research, their professional learning focused on collaboratively creating an electronic, interactive notebook with lessons for use in science classrooms across the United States. Creating a common product as an outcome of the PD may have served as motivation for teachers to learn about and implement more data practices, CT, and SRL, which suggests that design-based research is another valuable design for teacher PD.

The cellular oncogene c-Fos (c-Fos) is a component of activator protein 1 (AP1), a master transcriptional regulator of cells. The suppression of c-Fos signaling by siRNA treatment resulted in significant induction of TLR4, which subsequently activates p38 and ERK1/2 mitogen-activated protein kinases (MAPKs) and enhances F-actin polymerization, leading to an increase in B. abortus phagocytosis. During B. abortus infection, c-Fos signaling is induced, which activates the downstream innate-immunity signaling cascade for bacterial clearance. The inhibition of c-Fos signaling led to increased production of interleukin 10 (IL-10), which partially suppressed lysosome-mediated killing, resulting in increased survival of B. abortus inside macrophages. We present evidence of the regulatory role played by the c-Fos pathway in proliferation during B. abortus infection; however, this was independent of the anti-Brucella effect of this pathway. Another finding is the essential contribution of c-Fos/TRAIL to infected-cell necrosis, which is a key event in bacterial dissemination. These data provide the mechanism via which c-Fos participates in host defense mechanisms against Brucella infection and in bacterial dissemination by macrophages.

Fengqian Li,1,* Wen Wu,2,* Li Xiang,1 Gan Weng,1 Hua Hong,3 Hong Jiang,4 Jun Qian31Department of Pharmacy, Shanghai Xuhui Dahua Hospital, 2Department of Orthopaedics, Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, 3Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, 4School of Materials Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China*Co-first authors contributed equally to this workAbstract: Nanoporous magnesium–zinc–silicon (n-MZS) xerogels with a pore size of ~4 nm, a surface area of 718 cm2/g, and a pore volume of 1.24 cm3/g were synthesized by a sol–gel method. The n-MZS xerogels had high capacity to load vancomycin hydrochloride (VH) and human bone morphogenetic protein-2 (rhBMP-2), after soaking in phosphate buffered saline (PBS) for 24 hours (1.5 and 0.8 mg/g, respectively). Moreover, the n-MZS xerogels exhibited the sustained release of VH and rhBMP-2 as compared with magnesium–zinc–silicon (MZS) xerogels without nanopores (showing a burst release). The VH/rhBMP-2/n-MZS system not only exhibited a good antibacterial property but also promoted the MG63 cell proliferation and differentiation demonstrating good bactericidal activity and cytocompatibility. The results suggested that n-MZS with larger surface area and high pore volume might be a promising carrier for loading and sustained release of VH and rhBMP-2. Hence, the VH/rhBMP-2/n-MZS system might be one of the promising biomaterials for osteomyelitis treatment and bone repair.Keywords: nanoporous xerogels, sustained release, drugs, osteomyelitis, bone regeneration, bactericidal activity, cytocompatibility

In this study, we explore the regulatory roles of pro-inflammatory cytokine tumor necrosis factor alpha (TNF) in the innate immunity of macrophages against B. abortus infection. We show that infection of macrophage with B. abortus induces marked expression and secretion of TNF which subsequently binds to TNF receptor 1 (TNFR-1) and activates a downstream signaling cascade of the innate immunity. Blocking of TNF signaling resulted in a notable increase of B. abortus survival which was associated with an increase of anti-inflammatory cytokine interleukin 10 (IL-10), a beneficial effector of Brucella survival, as well as remarkable decrease of reactive oxygen species (ROS) and nitric oxide (NO), antibrucella molecules. However, surprisingly, the interference of TNF did not show any influence on phagolysosome and cell death events. Furthermore, the transcriptional factor NF-kB was found to be a main mediator of TNF signaling when blocking of NF-kB pathway drastically suppressed the TNF-induced brucellacidal effect. Taken together, these findings clearly indicate that the immune cascade activated by TNF/TNFR-1 is required for the sufficient resistance to B. abortus survival in macrophages.

ABSTRACT Syntrophus aciditrophicus is a model syntrophic bacterium that degrades key intermediates in anaerobic decomposition, such as benzoate, cyclohexane-1-carboxylate, and certain fatty acids, to acetate when grown with hydrogen-/formate-consuming microorganisms. ATP formation coupled to acetate production is the main source for energy conservation by S. aciditrophicus. However, the absence of homologs for phosphate acetyltransferase and acetate kinase in the genome of S. aciditrophicus leaves it unclear as to how ATP is formed, as most fermentative bacteria rely on these two enzymes to synthesize ATP from acetyl coenzyme A (CoA) and phosphate. Here, we combine transcriptomic, proteomic, metabolite, and enzymatic approaches to show that S. aciditrophicus uses AMP-forming, acetyl-CoA synthetase (Acs1) for ATP synthesis from acetyl-CoA. acs1 mRNA and Acs1 were abundant in transcriptomes and proteomes, respectively, of S. aciditrophicus grown in pure culture and coculture. Cell extracts of S. aciditrophicus had low or undetectable acetate kinase and phosphate acetyltransferase activities but had high acetyl-CoA synthetase activity under all growth conditions tested. Both Acs1 purified from S. aciditrophicus and recombinantly produced Acs1 catalyzed ATP and acetate formation from acetyl-CoA, AMP, and pyrophosphate. High pyrophosphate levels and a high AMP-to-ATP ratio (5.9 ± 1.4) in S. aciditrophicus cells support the operation of Acs1 in the acetate-forming direction. Thus, S. aciditrophicus has a unique approach to conserve energy involving pyrophosphate, AMP, acetyl-CoA, and an AMP-forming, acetyl-CoA synthetase. IMPORTANCE Bacteria use two enzymes, phosphate acetyltransferase and acetate kinase, to make ATP from acetyl-CoA, while acetate-forming archaea use a single enzyme, an ADP-forming, acetyl-CoA synthetase, to synthesize ATP and acetate from acetyl-CoA. Syntrophus aciditrophicus apparently relies on a different approach to conserve energy during acetyl-CoA metabolism, as its genome does not have homologs to the genes for phosphate acetyltransferase and acetate kinase. Here, we show that S. aciditrophicus uses an alternative approach, an AMP-forming, acetyl-CoA synthetase, to make ATP from acetyl-CoA. AMP-forming, acetyl-CoA synthetases were previously thought to function only in the activation of acetate to acetyl-CoA.

Weizhong Zhao1, Xun Lu3, Yuan Yuan1, Changsheng Liu1, Baican Yang3, Hua Hong1, Guoying Wang3, Fanyan Zeng21The State Key Laboratory of Bioreactor Engineering, 2Key Laboratory for Ultrafine Materials of Ministry of Education and Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, 3Pharmacy Department of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaAbstract: In this study, the effects of the size and Chinese traditional processing (including elutriation, water cleaning, acid cleaning, alkali cleaning) on realgar nanoparticles (RN)-induced antitumor activity in human osteosarcoma cell lines (MG-63) and hepatoma carcinoma cell lines (HepG-2) were investigated. The human normal liver cell line (L-02) was used as control. RN was prepared by high-energy ball milling technology. The results showed that with the assistance of sodium dodecyl sulfate, the size of realgar could be reduced to 127 nm after 12 hours’ ball milling. The surface charge was decreased from 0.83 eV to −17.85 eV and the content of As2O3 clearly increased. Except for elutriation, the processing methods did not clearly change the size of the RN, but the content of As2O3 was reduced dramatically. In vitro MTT tests indicated that in the two cancer cell lines, RN cytotoxicity was more intense than that of the coarse realgar nanoparticles, and cytotoxicity was typically time- and concentration-dependent. Also, RN cytotoxicities in the HepG-2 and L-02 cells all increased with increasing milling time. Due to the reduction of the As2O3 content, water cleaning, acid cleaning, and alkali cleaning decreased RN cytotoxicity in HepG-2, but RN after elutriation, with the lowest As2O3 (3.5 mg/g) and the smallest size (109.3 nm), showed comparable cytotoxicity in HepG-2 to RN without treatment. Meanwhile, RN-induced cytotoxicity in L-02 cells was clearly reduced. Therefore, it can be concluded that RN may provide a strong antiproliferation effect in the MG-63 and HepG-2 cells. Elutriation processing is a suitable approach to limit the dangerous side-effects of As2O3, while maintaining the effectiveness of RN.Keywords: realgar nanoparticles, cytotoxicity, size, processing, apoptosis

The objective of this paper is to examinereasons for pressure rise in the Zama X2X pool in northwestern Alberta, Canada, that was used foracid gas disposal, and whether subsequent pressure decay was a result of pressure dissipation into a larger aquifer. The Zama X2X pool, approximately 1 km2 in size, is connected to four other nearby poolsthrough a common underlying aquifer. Pressure analysis for all the pools indicates that they are in goodhydraulic communication. Initial pressure in the Zama X2X pool was approximately 15 MPa. Pressuredeclined first during oil production, stabilizing at around 10 MPa in the early 1970s, after which started toincrease such that it reached 26 MPa in 1986. Subsequently, pressure declined reaching 22 MPa by 1995just prior to starting injection of acid gas (80% CO2 and 20% H2S). The operator injected acid gas at lowerrates and wellhead pressures than those licensed by the regulatory agency. Despite significant production ofwater and hydrocarbons, the pressure in the Zama X2X pool continued to be higher than the initial reservoirpressure by more than 5 MPa, such that disposal operations were suspended in late 1998. Oil productioncontinued all this time until 2002. Numerical simulations using CMG-IMEXTM and corresponding sensitivity studies reported in this papershow that disposal of more than 1 million m3 of water between 1970 and 1988 and again in 1992-1993 inthe adjacent Zama YY pool, which is in good hydrodynamic communication with the Zama X2X poolthrough the aquifer below the oil column, is the main reason for the high pressures observed in the ZamaX2X pool. Sensitivity studies indicate that pressure decay in the X2X pool was due to fluid production.The study indicates that while pressure rise has been caused by hydraulic communication between theX2X and YY pools through the common aquifer, the aquifer was not of large volume to allow dissipationof the pressure. In addition to the case study, the implications of pressure communication to geological storage of CO2 in aquifers are briefly discussed. Le but de l’article est de comprendre l’accroissement de pression dans le gisement de Zama X2X, utilisé pour le stockage degaz acide (NO de l’Alberta, Canada), et aussi d’examiner si la baisse de pression, observée ultérieurement,est la conséquence d’une dissipation par un aquifère de grande taille. Le gisement de Zama X2X, d’uneextension de 1 km2 environ, est connecté à quatre autres gisements voisins par l’intermédiaire d’un aquifère commun sous-jacent. L’analyse de la pression à travers tous ces gisements indique un bon niveau decommunication hydraulique. La pression initiale de l’accumulation de Zama X2X était d’environ 15 MPa.Pendant la production d’huile, la pression a commencé par décroître, pour se stabiliser vers 10 MPa audébut de la décennie 1970. Mais ensuite la pression a repris son ascension, jusqu’à atteindre 26 MPa en1986. Un nouvel épisode de baisse est alors intervenu et la pression s’est établie vers 22 MPa en 1995,au moment où l’on a commencé à injecter du gaz acide (80 % CO2 et 20 % H2S) – l’opérateur, toutefois,injectait ce gaz à des débits et à des pressions en tête de puits qui se situaient en deçà des seuils autoriséspar l’Administration. En dépit d’une production significative d’eau et d’hydrocarbures, la pression à ZamaX2X est ensuite restée plus élevée que la pression vierge, d’au moins 5 MPa, au point qu’en 1998 les opérations d’injection de gaz furent suspendues. La production d’huile a cependant été maintenue jusqu’en 2002. Des simulations numériques effectuées avec CMG-IMEXTM, assorties d’une analyse de sensibilité,montrent ici que la ré-injection de plus de 1 million de m3 d’eau dans le gisement voisin de Zama YY,entre 1970 et 1988 puis en 1992-93, est la principale cause du comportement de la pression à Zama X2X.Les deux champs sont en effet connectés hydrauliquement via l’aquifère situé au-dessous de la colonned’huile. L’analyse de sensibilité indique que la baisse de pression un moment enregistrée à Zama X2Xétait due à la production de fluides, mais aussi que l’aquifère commun n’est pas d’une dimension suffisante pour permettre une dissipation rapide et complète des effets de pression. Ce cas d’étude illustretoute l’importance, pour la transmission des pressions lors du stockage géologique de CO2, de la connectivité entre les réservoirs concernés.

Siderophores belonging to the ferrichrome family are essential for the viability of fungal species and play a key role for virulence of numerous pathogenic fungi. Despite their biological significance, our understanding of how these iron-chelating cyclic hexapeptides are assembled by non-ribosomal peptide synthetase (NRPS) enzymes remains poorly understood, primarily due to the nonlinearity exhibited by the domain architecture. Herein, we report the biochemical characterization of the SidC NRPS, responsible for construction of the intracellular siderophore ferricrocin. In vitro reconstitution of purified SidC reveals its ability to produce ferricrocin and its structural variant, ferrichrome. Application of intact protein mass spectrometry uncovers several non-canonical events during peptidyl siderophore biosynthesis, including inter-modular loading of amino acid substrates and an adenylation domain capable of poly-amide bond formation. This work expands the scope of NRPS programming, allows biosynthetic assignment of ferrichrome NRPSs, and sets the stage for reprogramming towards novel hydroxamate scaffolds.