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Hongmei Xu,1 Ningning Wu,2 Hui Yu,3 Chuanqing Wang,4 Jikui Deng,5 Hongmei Wang,5 Chunzhen Hua,6 Yinghu Chen,6 Xuejun Chen,7 Ting Zhang,8 Hong Zhang,9 Yiping Chen,10 Shifu Wang,11 Qing Cao,12 Huiling Deng,13 Sancheng Cao,14 Jianhua Hao,15 Wei Gao,16 Chunmei Jing2 1Infectious Disease Department, Children’s Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, People’s Republic of China; 2Department of Clinical Laboratory, Children’s Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, People’s Republic of China; 3Infectious Disease Department, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China; 4Department of Clinical Microbiology Laboratory, Nosocomial Infection Control Department, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China; 5Infectious Disease Department, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 6Infectious Disease Department, Children’s Hospital of Zhejiang University, Zhejiang, People’s Republic of China; 7Department of Medical Laboratory, Children’s Hospital of Zhejiang University, Zhenjiang, People’s Republic of China; 8Digestive and Infectious Disease Department, Children’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China; 9Department of Medical Laboratory, Children’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China; 10Pediatric Infectious Disease Department, Second Affiliated Hospital, and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 11Department of Medical Laboratory, Qilu Children’s Hospital, Shandong University, Shandong, People’s Republic of China; 12Infectious Disease Department, Shanghai Children’s Medical Center, Shanghai, People’s Republic of China; 13Infectious Disease Department, Xi’an Children’s Hospital, Xi’an, People’s Republic of China; 14Department of Medical Laboratory, Xi’an Children’s Hospital, Xi’an, People’s Republic of China; 15Infectious Disease Department, Children’s Hospital of Kaifeng City, Kaifeng, People’s Republic of China; 16Department of Medical Laboratory, Children’s Hospital of Kaifeng City, Kaifeng, People’s Republic of ChinaCorrespondence: Chunmei Jing, Department of Clinical Laboratory, Children’s Hospital of Chongqing Medical University, Chongqing Medical University, No. 136 Zhongshan Er Road, Yu Zhong District, Chongqing, 400014, People’s Republic of China, Email jcm791203@163.comObjective: Aim to investigate the pathogens distribution and drug resistance of gram-negative bacteria causing bloodstream infection (BSIs) in Infectious Disease Surveillance of Pediatric from 2016 to 2022. The prevalence of four important drug resistance phenotypes was studied: difficult-to-treat resistance, fluoroquinolone resistance, carbapenem resistance, and extended-spectrum cephalosporin resistance, and to provide reference basis for preventing and treating BSIs diseases in children.Methods: Strain identification and antimicrobial susceptibility tests were independently performed at each hospital. Data were analyzed using Whonet 5.6 and GraphPad Prism 8 software. The Mann–Whitney U-test was used to examine and compare temporal changes.Results: A total of 39977 BSIs strains were isolated, with 27.1% of the negative bacteria causing BSIs (10824 strains). The highest bacteria detected were E. coli and S. maltophilia in the neonatal and pediatric groups. The detection rate of carbapenem-resistant-K. pneumoniae (CRKPN) in neonate group was 31.4%, significantly increased compared with pediatric group, whose detection rate was 24.7%. The rates of resistance to levofloxacin and trimethoprim/sulfamethoxazole were significantly lower in neonatal groups than pediatric groups in BSIs caused by K. pneumoniae. To imipenem and meropenem were 3.6% and 3.9% among neonatal isolates, which was lower than 4.7% and 5.8 among pediatric BSIs caused by E. coli. Isolated from neonatal BSIs caused by A. baumannii showed lower resistance ratios to all the agents tested than those from pediatric. However, only the prevalence of piperacillin/tazobactam resistance was statistically lower than that in pediatric BSIs caused by P. aeruginosa. The average detection rates of carbapenem resistance, extended-spectrum cephalosporin resistance, and fluoroquinolone resistance for K. pneumoniae and E. coli were 28.1%,41.4%,11.6% and 4.0%,24.3%,31.1%, respectively.Conclusion: The detection rate of gram-negative pathogens showed an increasing trend among the bloodstream infection. The detection rate of CRKPN assumed a downward trend in 2018. There are differences types of pathogens between the neonatal group and the pediatric group, The detection rate of CRKPN in the neonate group was significantly higher than pediatric group. The first average detection rates for carbapenem resistance, extended-spectrum cephalosporin resistance, and fluoroquinolone resistance were obtained for A. baumannii, K. pneumoniae, and Escherichia coli, respectively. Those data showed a high level of antimicrobial resistance, which has posed an urgent threat to Children’s health, suggested that effective monitoring of antimicrobial resistance and antimicrobial stewardship among children in China are required.Keywords: bloodstream infection, pathogenic bacterium, difficult-to-treat resistance, carbapenem resistance, extended-spectrum cephalosporin resistance, fluoroquinolone resistance

Zesi Liu,1 Chunli Jing2 1Department of Gynecology and Obstetrics, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 2Department of Ultrasound of Gynecology and Obstetrics, The Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of ChinaCorrespondence: Chunli Jing, Department of Ultrasound of Gynecology and Obstetrics, The Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China, Tel +86-133-522-31070, Fax +86-82866055, Email tg980927@126.comBackground: Retroperitoneal ectopic pregnancy (REP) is an extremely rare type of ectopic pregnancy that can be life threatening. The pathogenesis of REP remains inconclusive and the diagnosis and treatment modalities are unclear.Case Presentation and Review of the Literature: A 27-year-old woman (gravida: 3; parturition: 0) underwent transvaginal ultrasound (TVS) 40 days after in vitro fertilization-embryo transfer (IVF-ET); no intrauterine gestational sac was detected. The patient was asymptomatic and had no abnormalities on physical examination. β-HCG and progesterone were 18.210 mIU/mL and 10.891 ng/mL, respectively. Transabdominal ultrasound (TAS) showed that the gestational sac had implanted adjacent to the abdominal aorta and near a branch of the iliac artery. Laparoscopic exploration was performed under general anesthesia; intraoperative findings showed that the gestational sac was approximately 2.5 cm in diameter and in the same location as suggested by preoperative ultrasound. Histopathological examination confirmed the diagnosis of EP. On day three post-surgery, the levels of β-HCG had fallen to 911 mIU/mL. We further systematically reviewed the REP cases reported in the English literature and performed a review on the diagnosis and treatment of REP.Conclusion: Clinicians should be alert to the occurrence of REP. Combined radiological examinations including ultrasonography (TAS and TVS), CT, and MRI are essential for the early diagnosis of REP. Once a definitive diagnosis is made, appropriate treatment should be administered immediately. Although there are cases of successful drug treatment described in the literature, surgery remains as the primary treatment option for REP.Keywords: retroperitoneal ectopic pregnancy, ultrasound, surgery, diagnosis, review

The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.

Lei Yang,1,2,* Xiafei Li,3,* Yiting Wu,4 Pengchong Du,1,5 Lulu Sun,1 Zhenyang Yu,2 Shuang Song,1 Jianshen Yin,1 Xianfen Ma,1 Changqin Jing,1 Junqiang Zhao,3 Hongli Chen,1 Yuzhen Dong,2 Qiqing Zhang,1 Liang Zhao1,6,7 1College of Life Science and Technology, Xinxiang Medical University, Xinxiang, People’s Republic of China; 2Department of Orthopedics, First Affiliated Hospital, Xinxiang Medical University, Xinxiang, People’s Republic of China; 3College of Medical Engineering, Xinxiang Medical University, Xinxiang, People’s Republic of China; 4Xiacun Community Health Service Center, Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, People’s Republic of China; 5Department of Cardio-Thoracic Surgery, Third Affiliated Hospital, Xinxiang Medical University, Xinxiang, People’s Republic of China; 6Key Laboratory of Cardiac Structure Research, Zhengzhou Seventh People’s Hospital, Zhengzhou, People’s Republic of China; 7The Central Lab, The Third People’s Hospital of Datong, Datong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liang Zhao; Yuzhen Dong Email zhaoliang4321@163.com; dongyuzhen1998@163.comPurpose: The development of tissue-engineered blood vessels provides a new source of donors for coronary artery bypass grafting and peripheral blood vessel transplantation. Fibrin fiber has good biocompatibility and is an ideal tissue engineering vascular scaffold, but its mechanical property needs improvement.Methods: We mixed polyurethane (PU) and fibrin to prepare the PU/fibrin vascular scaffolds by using electrospinning technology in order to enhance the mechanical properties of fibrin scaffold. We investigated the morphological, mechanical strength, hydrophilicity, degradation, blood and cell compatibility of PU/fibrin (0:100), PU/fibrin (5:95), PU/fibrin (15:85) and PU/fibrin (25:75) vascular scaffolds. Based on the results in vitro, PU/fibrin (15:85) was selected for transplantation in vivo to repair vascular defects, and the extracellular matrix formation, vascular remodeling, and immune response were evaluated.Results: The results indicated that the fiber diameter of the PU/fibrin (15:85) scaffold was about 712nm. With the increase of PU content, the mechanical strength of the composite scaffolds increased, however, the degradation rate decreased gradually. The PU/fibrin scaffold showed good hydrophilicity and hemocompatibility. PU/fibrin (15:85) vascular scaffold could promote the adhesion and proliferation of mesenchymal stromal cells (MSCs). Quantitative RT-PCR experimental results showed that the expression of collagen, survivin and vimentin genes in PU/fibrin (15:85) was higher than that in PU/fibrin (25:75). The results in vivo indicated the mechanical properties and compliance of PU/fibrin grafts could meet clinical requirements and the proportion of thrombosis or occlusion was significantly lower. The graft showed strong vasomotor response, and the smooth muscle cells, endothelial cells, and ECM deposition of the neoartery were comparable to that of native artery after 3 months. At 3 months, the amount of macrophages in PU/fibrin grafts was significantly lower, and the secretion of pro-inflammatory and anti-inflammatory cytokines decreased.Conclusion: PU/fibrin (15:85) vascular scaffolds had great potential to be used as small-diameter tissue engineering blood vessels.Keywords: PU/fibrin scaffold, small diameter, in vitro biocompatibility, biomechanical properties, vascular remodeling

Context Patients treated with maintenance hemodialysis experience significant symptom burden resulting in impaired quality of life. However, the association of patient reported symptom burden and the risk of healthcare use for patients with end stage kidney disease on hemodialysis has not been fully explored. Objectives To investigate if higher symptom burden, assessed by the Edmonton Symptom Assessment System-revised (ESASr), is associated with increased healthcare use in patients with end stage kidney disease on hemodialysis. Methods Prospective, single-center, study of adult patients on HD. Participants completed the ESASr questionnaire at enrollment. Baseline demographic, clinical information as well as healthcare use events during the 12-month following enrollment were extracted from medical records. The association between symptom burden and healthcare use was examined with a multivariable adjusted negative binomial model. Results Mean (SD) age of the 80 participants was 71 (13) years, 56% diabetic, and 70% male. The median (IQR) dialysis vintage was 2 (1–4) years. In multivariable adjusted models, higher global [incident rate ratio (IRR) 1.02, 95% confidence interval (CI) 1.00–1.04, p = .025] and physical symptom burden score [IRR 1.03, CI 1.00–1.05, p = .034], but not emotional symptom burden score [IRR 1.05, CI 1.00–1.10, p = .052] predicted higher subsequent healthcare use. Conclusions Our preliminary evidence suggests that higher symptom burden, assessed by ESASr may predict higher risk of healthcare use amongst patients with end stage kidney disease on hemodialysis. Future studies need to confirm the findings of this preliminary study and to assess the utility of ESASr for systematic symptom screening.

Jiajia Lin,1,* Tingting Fang,1,* Mengxuan Zhu,1,* Xin Xu,1 Juan Zhang,1 Susu Zheng,1 Chuyu Jing,1 Meixia Zhang,1 Binbin Liu,1 Boheng Zhang1,2 1The Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China; 2Center for Evidence-Based Medicine, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Boheng Zhang; Binbin LiuThe Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, People’s Republic of ChinaTel +86 216 403 8038Fax +86 216 403 8038Email zhang.boheng@zs-hospital.sh.cn; liu.binbin@zs-hospital.sh.cnObjective: Prognostic performance of inflammation-based prognostic scores, including the Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), Prognostic Index (PI) and Prognostic Nutritional Index (PNI) has been explored in patients with varied types of cancer, though little data is available in intrahepatic cholangiocarcinoma (ICC). This study sought to evaluate the impact of systemic inflammation on the overall survival (OS) of ICC patients, and to identify more optimal prognostic indices.Patients and methods: The prognostic power of all the scores mentioned above was compared in 123 patients underwent curative surgery for ICC using Kaplan–Meier curves, COX regression models and the receiver operating characteristics (ROC) curves. The results were validated in a cohort of 95 ICC patients.Results: Multivariate analysis identified LMR as the only independent inflammation-based predictor for OS in the training cohort (P=0.007, HR 2.082, 95% CI 1.218–3.558). More importantly, the combined score of LMR and pTNM designated the inflammation-based pathological stage (IPS) outperformed other established scores in terms of discriminatory ability, monotonicity and homogeneity in the training and validation cohorts.Conclusion: This study reveals that preoperative LMR is an independent predictor of OS in ICC patients after hepatectomy, and the IPS can be applied as a novel prognostic indicator in these patients.Keywords: inflammation-based prognostic score, the lymphocyte to monocyte ratio, intrahepatic cholangiocarcinoma, prognostic marker, staging system

Zeqiang Zhan,1 Xuebin Xu,2 Zhen Gu,3 Jianghong Meng,4 Xiayidan Wufuer,5 Mingliu Wang,6 Meilian Huang,7 Jianhui Chen,8 Chunmei Jing,9 Zhiying Xiong,1 Mei Zeng,10 Ming Liao,1 Jianmin Zhang1 1National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Key Laboratory of Zoonoses, Ministry of Agriculture, Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Animal Infectious Diseases Laboratory, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; 2Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China; 3Emerging Infections Program China Office, Beijing, 102206, China; 4Department of Food Science and Nutrition, University of Maryland, College Park, Maryland 20742, USA; 5Xinjiang Uygur Autonomous Region Center for Disease Control and Prevention, Urumchi 830001, China; 6Guangxi Zhuang Autonomous Region Disease Prevention and Control Center, Nanning 530028, China; 7Xiamen City Children’s Hospital, Xiamen 361006, China; 8Fujian Provincial Center for Disease Control and Prevention, Fuzhou 350001, China; 9Chongqing City Children’s Hospital, Chongqing 400014, China; 10Department of Infectious Diseases, Children’s Hospital of Fudan University, Shanghai 200336, ChinaCorrespondence: Mei ZengDepartment of Infectious Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, ChinaEmail zengmeigao@aliyun.comJianmin ZhangCollege of Veterinary Medicine, South China Agricultural University, No. 483 Wushan Road, Tianhe District, Guangzhou 510642, ChinaTel +86 20 8528 0240Fax +86 20 8528 5282Email junfeng-v@163.comPurpose: Human infections caused by invasive non-typhoidal Salmonella (iNTS) are highly prevalent worldwide. However, data for such infections in China are scarce. This study reports the epidemiology of iNTS in China.Methods: INTS isolates were recovered from blood and other clinical specimens collected during 2007–2016 across five provinces (Shanghai, Xinjiang, Fujian, Guangxi, and Chongqing) in China. Antimicrobial susceptibility was performed using the agar dilution method and molecular epidemiology was performed using standard microbiological techniques.Results: A total of 178 iNTS isolates were recovered from approximately 9700 patient specimens during 2007–2016. The predominant serovars were Salmonella Enteritidis (57/178, 32%), Salmonella Choleraesuis (47/178, 26.4%), and Salmonella Typhimurium (24/178, 13.5%). Up to 50 isolates (28.1%) were from patients who were ≤1 year of age, while 28 (15.7%) were from patients who were ≥60 years. Among these isolates, high rates of resistance to nalidixic acid (114/178, 64%), sulfisoxazole (59%), ciprofloxacin (15.2%), and cefotaxime (8.4%) were found. Moreover, 53.4% (95/178) exhibited multidrug resistance, and 3.9% (7/178) showed co-resistance to third-generation cephalosporins and ciprofloxacin. Steadily increasing numbers of nalidixic acid, cefotaxime, and ciprofloxacin-resistant isolates, but decreasing numbers of multidrug resistance isolates were detected during the study period. Detection of quinolone genes in 114 nalidixic acid-resistant isolates showed that 58.3% (67/114) harbored plasmid-mediated quinolone resistance (PMQR) genes [aac(6´)-Ib-cr, qnrA, qnrB, oqxAB, qepA, qnrS, and qnrD] and 98.2% (112/114) exhibited mutations in quinolone resistance determining regions [gyrA, parC, and parE]. Furthermore, we detected beta-lactamases genes in the ceftriaxone-resistant isolates. The most common were blaTEM-1 (93.3%), followed by blaCTX-M-55 (40%), blaCMY-2 (33.3%), and blaOXA-1 (33.3%). Finally, a range of pulsed-field gel electrophoresis patterns were detected among the Salmonella Enteritidis and Salmonella Typhimurium isolates.Conclusion: High rates of multidrug resistance and steadily increasing cefotaxime and ciprofloxacin-resistant iNTS could pose a significant challenge for the effective treatment of salmonellosis in China.Keywords: invasive non-typhoidal Salmonella, fluoroquinolones, multidrug resistant, beta-lactamases, pulsed field gel electrophoresis, China

We report an index case of histiocytic sarcoma arising in a 70-year-old patient with long-standing chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The patient presented in 2017 with painful, enlarging swelling of the left neck. He had remote history of cutaneous squamous cell carcinoma with no sign of recurrence, and his CLL/SLL was thought to be in remission. Computed tomography showed mild splenomegaly and multifocal lymphadenopathy including a 3-cm left neck mass. Biopsy of the left neck mass showed CLL/SLL with associated histiocytic sarcoma. Flow cytometry demonstrated a B cell neoplasm with CLL/SLL phenotype. Despite radiation therapy, he expired 3 months after presentation. Two similar cases (CLL/SLL and histiocytic sarcoma, follicular lymphoma and Langerhans cell sarcoma) from another institution are also illustrated. The pathological features of combined tumors in lymphoid neoplasms, a general framework to the work-up to determine interrelatedness of tumor components, and the clinical relevance are discussed.

Sol–gel encapsulation has been used as the basis for detecting cortisol by an immunoassay approach. Previous research showed that antibodies immobilized in the pores of a sol–gel derived silica were able to bind cortisol and be used as an immunosensor. However, this approach was not effective when measuring cortisol levels in human serum because of interference from other fluorescence sources. The present paper describes a protocol which overcomes these limitations and enables sol–gel immunoassays to effectively measure cortisol in human serum over the physiological range of cortisol blood concentrations in an adult (2–28 μg/dL). The method involves a standard additions approach in which various amounts of cortisol are added to the serum. The cortisol concentration values obtained with our sol–gel immunoassay were typically within 10% of the values obtained by traditional analytical methods. The protocol presented here represents a significant contribution to sol–gel sensing and immunoassays in particular, because of the ability to detect an analyte in human serum. In addition, this work reports the first comparison between results from a sol–gel immunosensor and an alternative immuno-binding method for analyte detection.

Our earth is immersed in the near-earth space plasma environment, which plays a vital role in protecting our planet against the solar-wind impact and influencing space activities. It is significant to investigate the physical processes dominating the environment, for deepening our scientific understanding of it and improving the ability to forecast the space weather. As a crucial part of the National Major Scientific and Technological Infrastructure–Space Environment Simulation Research Infrastructure (SESRI) in Harbin, the Space Plasma Environment Research Facility (SPERF) builds a system to replicate the near-earth space plasma environment in the laboratory. The system aims to simulate the three-dimensional (3-D) structure and processes of the terrestrial magnetosphere for the first time in the world, providing a unique platform to reveal the physics of the 3-D asymmetric magnetic reconnection relevant to the earth's magnetopause, wave–particle interaction in the earth's radiation belt, particles' dynamics during the geomagnetic storm, etc. The paper will present the engineering design and construction of the near-earth space plasma simulation system of the SPERF, with a focus on the critical technologies that have been resolved to achieve the scientific goals. Meanwhile, the possible physical issues that can be studied based on the apparatus are sketched briefly. The earth-based system is of great value in understanding the space plasma environment and supporting space exploration. [ABSTRACT FROM AUTHOR]

The fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

Abstract Background Vascular calcification is a crucial pathophysiological process associated with age-related cardiovascular diseases. Elabela, a recently identified peptide, has emerged as a significant player in the regulation of cardiovascular function and homeostasis. However, the effects and underlying mechanisms of Elabela on age-related vascular calcification remain largely unexplored. Methods In-vivo vascular calcifications of C57BL/6J mice (8-week-old) and young (8-week-old) or aged (72-week-old) SD rats were injected with vitamin D3 (VitD3) or saline, respectively. Furthermore, the VitD3-overloaded mice received Elabela (1 mg/kg/d), peroxisome proliferators-activated receptor-γ (PPAR-γ) activator Rosiglitazone (5 mg/kg/d) or copper-ionophore Elesclomol (20 mg/kg/d), respectively. As for in-vitro studies, primary rat vascular smooth muscle cells (VSMCs) were isolated from aortas and cultured for explore the role and underlying mechanism of Elabela in vascular calcification. Results There were marked increases in FDX1 and Slc31a1 levels in both aortas and VSMCs during vascular calcification, coinciding with a rise in copper levels and a decrease in Elabela levels. Alizarin red and von-Kossa staining indicated that the administration of Elabela effectively hindered the progression of vascular cuproptosis and arterial calcification in VitD3-overloaded mice and rat arterial rings models. Moreover, Elabela significantly suppressed osteogenic differentiation and calcium deposition in VSMCs and strikingly reversed high phosphate-induced augmentation of FDX1 expression, DLAT aggregation as well as intracellular copper ion levels. More importantly, Elabela exhibited remarkable abilities to prevent mitochondrial dysfunctions in primary rat VSMCs by maintaining mitochondrial membrane potential, inhibiting mitochondrial division, reducing mitochondrial ROS production and increasing ATP levels. Interestingly, Elabela mitigated cellular senescence and production of pro-inflammatory cytokines including IL-1α, IL-1β, IL-6, IL-18 and TNF-α, respectively. Furthermore, Elabela upregulated the protein levels of PPAR-γ in VitD3-overloaded mice. Administrating PPAR-γ inhibitor GW9662 or blocking the efflux of intracellular copper abolished the protective effect of Elabela on vascular calcification by enhancing levels of FDX1, Slc31a1, Runx2, and BMP2. Conclusion Elabela plays a crucial role in protecting against vascular cuproptosis and arterial calcification by activating the PPAR-γ /FDX1 signaling. Elabela supplementation and cuproptosis suppression serve as effective therapeutic approaches for managing vascular calcification and related cardiovascular disorders.

Abstract Embryonic axis formation is essential for patterning and morphogenesis in vertebrates and is tightly regulated by the dorsal organizer. Previously, we demonstrated that maternally derived Huluwa (Hwa) acts as a dorsal determinant, dictating axis formation by activating β-catenin signaling in zebrafish and Xenopus. However, the mechanism of activation and fine regulation of the Hwa protein remains unclear. Through candidate screening we identified a mutation at Ser168 in the PPNSP motif of Hwa that dramatically abolishes its axis-inducing activity. Mechanistically, mutating the Ser168 residue reduced its binding affinity to Tankyrase 1/2 and the degradation of the Axin protein, weakening β-catenin signaling activation. We confirmed that Ser168 is phosphorylated and that phosphorylation increases Hwa activity in β-catenin signaling and axis induction. Several kinases including Cdk16, Cdk2, and GSK3β, were found to enhance Ser168 phosphorylation in vitro and in vivo. Both dominant-negative Cdk16 expression and pHwa (Ser168) antibody treatment reduce Hwa function. Lastly, a knock-in allele mutating Ser168 to alanine resulted in embryos lacking body axes, demonstrating that Ser168 is essential to axis formation. In summary, Ser168 acts as a phosphorylation switch in Hwa/β-catenin signaling for embryonic axis induction, regulated by multiple kinases.

Abstract Alzheimer’s disease (AD), an age-related neurodegenerative disorder, is characterized by irreversible brain tissue degeneration. The amyloid-β (Aβ) cascade hypothesis stands as the predominant paradigm explaining AD pathogenesis. This study aimed to elucidate the mechanisms underlying Aβ-induced pyroptosis in AD. AD models were established using amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and Aβ-treated BV-2 cells (5 µM, 24 h). NEK7 expression was evaluated in vitro and in vivo. Cell pyroptosis was assessed before and after NEK7 expression was inhibited in BV-2 cells. Adeno-associated virus (AAV) vectors carrying short hairpin RNA (shRNA) against NEK7 (AAV-sh-NEK7) were administered to mice to knockdown NEK7 in vivo. Spatial learning and memory abilities were evaluated using the Morris water maze test. The interaction between NEK7 and histone H4 lysine 12 lactylation (H4K12la) were then investigated. The results suggested that NEK7 expression was markedly elevated in both in vitro and in vivo AD models. Treatment with Aβ significantly reduced cell viability and enhanced pyroptosis in BV-2 cells; these effects were reversed by inhibiting NEK7. Furthermore, AD mice with NEK7 knockdown exhibited shorter escape latencies and increased time spent in the target quadrant, suggesting that NEK7 inhibition improved cognitive function and memory retention. Mechanistically, Aβ treatment induced histone lactylation in BV-2 cells, and suppression of lactylation attenuated NEK7 transcriptional activity and mRNA levels. In summary, elevated NEK7 expression promoted histone lactylation in BV-2 cells, thereby facilitating pyroptosis. Inhibition of NEK7 conferred protection against Aβ-induced cellular damage and enhanced cognitive performance and memory retention in AD model mice. Collectively, targeting NEK7 represents a potential therapeutic strategy for alleviating AD symptoms. Graphical abstract

Abstract During the coronavirus disease 2019 (COVID-19) pandemic, the exploration of microecology has been essential for elucidating the intricacies of infection mechanisms and the recovery of afflicted individuals. To decipher the interplay of microorganisms between the intestinal and respiratory tracts, we collected sputum and throat swabs and feces from COVID-19 patients and explored the mutual migration among intestinal and respiratory microorganisms. Using next-generation sequencing (NGS) technology, we investigated intestinal and respiratory microorganism intermigration in two patients with severe COVID-19 during their hospitalization. Notably, we observed an expedited recovery of microecological equilibrium in one patient harboring Mycobacterium avium. Comparative analyses between 32 healthy controls and 110 COVID-19 patients with different disease severities revealed alterations in predominant microorganisms inhabiting the respiratory and intestinal tracts of COVID-19 patients. Among the alterations, intestinal Bacteroides vulgatus (BV) was identified as a noteworthy microorganism that exhibited marked enrichment in patients with severe COVID-19. BV, when highly abundant, may inhibit the transitional growth of Escherichia coli/Enterococcus, indirectly prevent the overgrowth of salivary streptococci, and maintain lung/intestinal microecology stability. In summary, this study elucidates the bidirectional microbial intermigration between the intestinal and respiratory tracts in COVID-19 patients. These findings are expected to provide new ideas for the treatment and management of COVID-19, underscoring the essential role of microecology in infectious diseases. Nevertheless, a systematic study of the roles of BV in recovery from infection is required to gain a deeper understanding of the mechanisms of microbial migration.

Abstract Background To analyze the clinical manifestations, endoscopic features, pathological features, endoscopic resection, and prognosis of esophageal granular cell tumors (GCTs). Methods The present study retrospectively analyzed and followed up the clinical data of 62 patients diagnosed with esophageal GCTs who underwent endoscopic resection at Zhongshan Hospital of Fudan University between July 2007 and March 2022. The clinicopathological features, endoscopic diagnosis, and treatment experience of esophageal GCT patients were summarized. Results Among the 62 patients with esophageal GCT, there were 34 males and 28 females, with an average age of 49.3 ± 11.7 years. Only 11 patients had symptoms, such as epigastric discomfort, regurgitation or dysphagia. One patient had multiple lesions, and the rest had single lesions, totaling 63 lesions. Most lesions (53/63) were located in the median and lower esophagus, the diameters ranged from 3 to 22 mm. The endoscopic morphology of the GCTs was molar, flat, hemispherical, or irregular submucosal protuberance. Endoscopic ultrasound (EUS) was performed in 38 cases, most cases (31/38) were hypoechoic, and 32 cases were appeared as homogeneous lesions. There were no complications during or after the endoscopic operations, and the en bloc resection rate was 100%. The negative rate of microscopic incisional margin was 63.5% (40/63). No patients developed recurrence during the follow-up period. The follow-up duration was 21–197 months (100.5 months for average). Conclusion Esophageal GCT is a rare disease with no obvious symptoms and a good prognosis. Endoscopic resection is a safe and effective method of diagnosis and treatment for esophageal GCTs. A microscopic positive tumor margin may not increase the rate of recurrence.

Abstract Background Mindfulness training is increasingly popular in China. The challenge of evaluating mindfulness practice objectively and accurately has attracted research attention. However, previous studies in China focused primarily on the quantity rather than the quality of mindfulness training. The Practice Quality - Mindfulness (PQ-M) can provide a solution. Consequently, the present study aimed to validate and assess the internal consistency and construct validity of the Chinese version of the Practice Quality - Mindfulness (Ch-PQ-M) in a non-clinical sample. Methods One hundred and sixty participants (female:81) were recruited to practice 20 min of mindfulness training daily for four consecutive days and to complete the Ch-PQ-M, the State Anxiety Inventory, and the Peace of Mind Scale immediately after each mindfulness practice. The Five Facet Mindfulness Questionnaire, the Trait Anxiety Inventory, and the Positive and Negative Affect Scale were administered pre- and post- 4-day treatment. Construct validity (confirmatory factor analysis), internal consistency, test–retest reliability, predictive validity and construct validity were examined. Results Ch-PQ-M demonstrated acceptable internal consistency and test–retest reliability. Confirmatory factor analysis supported the established two-factor model (perseverance and receptivity). The Ch-PQ-M attention score was significantly associated with changes of trait anxiety. It improved with short-term mindfulness practice. The perseverance score consistently correlates with scores on peace of mind, state anxiety, trait anxiety, and observe and nonreactivity. The receptivity score remains consistently correlated with the nonjudging. These findings suggest that Ch-PQ-M is a valid instrument for evaluating individual mindfulness quality for a single-session practice. Conclusions Our findings suggest that Ch-PQ-M (especially for the Ch-PQ-M perseverance score) has acceptable psychometric properties and is a reliable and valid instrument for assessing mindfulness practice quality in the Chinese cultural context.

Abstract Background Sepsis-induced organ failure and high mortality are largely ascribed to the failure of bacterial clearance from the infected tissues. Recently, probiotic bacteria-released extracellular vesicles (BEVs) have been implicated as critical mediators of intercellular communication which are widely involved in the regulation of the inflammatory response. However, their functional role in macrophage phagocytosis during sepsis has never been explored. Methods BEVs were collected from three different strains of probiotics including Lactiplantibacillus plantarum WCFS1 (LP WCFS1), Lactobacillus rhamnosus Gorbach-Goldin (LGG), and Escherichia coli Nissle 1917 (EcN), or from LGG cultured under three pH conditions (pH5-acid, pH6.5-standard, pH8-akaline) through differential centrifugation, filtration, and ultracentrifugation of their culture supernatants. In vitro phagocytosis was measured in Raw264.7 cells and bone marrow-derived macrophages using pHrodo red E. coli BioParticles. The in vivo therapeutic effects of BEVs were tested using a feces-injection-in-peritoneum (FIP) model of polymicrobial sepsis. Results LGG-derived EVs (BEVLGG) were the best among these three probiotics BEVs in stimulating macrophages to take up bacteria. Furthermore, BEVLGG collected from pH8 culture condition (BEVpH8) exhibited the strongest capacity of phagocytosis, compared with BEVpH5 and BEVpH6.5. Treatment of septic mice with BEVpH8 significantly prolonged animal survival; increased bacterial clearance from the blood, peritoneal lavage fluid, and multiple organs; and decreased serum levels of pro-inflammatory cytokines/chemokines, as well as reduced multiple organ injuries, in comparison with control-treated septic mice. Mechanistically, RNA-seq and bioinformatic analysis identified that the FPR1/2 signaling was remarkably activated, along with its downstream pathways (PI3K-Akt-MARCO and NADPH-ROS) in BEVpH8-treated macrophages, compared with control cells. Accordingly, pre-addition of Boc2, a specific antagonist of FPR1/FPR2, to macrophages significantly attenuated BEVpH8-mediated phagocytosis, compared to controls. Conclusions This study demonstrates that LGG-derived BEVs may have therapeutic effects against sepsis-induced organ injury and mortality through enhancing FPR1/2-mediated macrophage phagocytosis.

Abstract Oncostatin M (OSM) is a unique Interleukin 6 (IL-6) family cytokine that plays pivotal roles in numerous biological events by signaling via two types of receptor complexes. While type I OSM receptor complex is formed by glycoprotein 130 (gp130) heterodimerization with Leukemia Inhibitory Factor receptor (LIFR), type II OSM receptor complex is composed of gp130 and OSM receptor (OSMR). OSM is an important contributor to multiple inflammatory diseases and cancers while OSM inhibition has been shown to be effective at reducing symptoms, making OSM an attractive therapeutic target. Using cryogenic electron microscopy (cryo-EM), we characterize full extracellular assemblies of human type I OSM receptor complex and mouse type II OSM receptor complex. The juxtamembrane domains of both complexes are situated in close proximity due to acute bends of the receptors. The rigid N-terminal extension of OSM contributes to gp130 binding and OSM signaling. Neither glycosylation nor pro-domain cleavage of OSM affects its activity. Mutagenesis identifies multiple OSM and OSMR residues crucial for complex formation and signaling. Our data reveal the structural basis for the assemblies of both type I and type II OSM receptor complexes and provide insights for modulation of OSM signaling in therapeutics.

Abstract Background Lipid-lowering therapy (LLT) plays a central role in managing atherosclerotic cardiovascular disease (ASCVD) risk, but its underuse is reported in over 40% of the qualified population in the United States. Studies on factors, particularly actionable factors associated with guideline-directed LLT are limited. Methods This study evaluated participants from the Multi-Ethnic Study of Atherosclerosis (MESA) on their qualification for LLT at exam 5 (2010–2012) according to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on cholesterol management. Participants were categorized as on-LLT or off-LLT at the following exam (2016–2018). Multi-variable relative risk (RR) models were used to analyze between LLT usage and factors prior to 2013, including age, gender, race/ethnicity, education level and medical insurance, income, smoking, body mass index (BMI), diabetes, hypertension, and presence of coronary artery calcium (CAC). Results Among the 2114 participants qualified for LLT at exam 5 with an average age of 70.7, 1,129 (53.4%) were on LLT while 985 (46.6%) were off LLT at exam 6. Black participants were less likely to be on LLT compared to the reference white participants (RR 0.80, 95% confidence interval CI 0.71–0.90). Higher BMI showed borderline significant association with LLT. Comorbidities of diabetes and hypertension were positively associated with LLT use (RR 1.39 and 1.23, 95% CI 1.27–1.52 and 1.10–1.36, respectively). CAC score > 0 as an indicator of subclinical ASCVD was strongly associated with LLT too, independent of other demographic or comorbidity factors (RR 1.38, 95% CI 1.21–1.56). Conclusions This study identifies key factors influencing LLT use among MESA participants. Black participants were less likely to be on LLT, highlighting healthcare disparities. CAC presence was strongly associated with LLT use, suggesting that CAC measurement could be an actionable factor to improve adherence to LLT guidelines.

Abstract Background The effectiveness of adipose-derived stem cells (ADSCs) in therapy diminishes with age. It has been reported that transcription factors (TFs) play a crucial role in the aging and functionality of stem cells. Nevertheless, there is limited understanding regarding the involvement of TFs in the aging mechanism of ADSCs. Methods RNA sequencing (RNA-seq) was utilized to discern the differentially expressed genes in ADSCs obtained from donors of varying ages. TFs exhibiting significant variations across age groups were identified and subsequently validated. ADSCs were manipulated to exhibit either enhanced expression or reduced levels of HES1 and STAT1 via lentivirus transfection and small interfering RNA (siRNA) techniques. The impact of these genetic alterations on ADSCs’ proliferation, migration, and cellular senescence was assessed using EdU, transwell, and senescence-activated β-galactosidase (SA-β-gal) staining assays. The DNA sequences bound by HES1 were investigated through the CUT & Tag assay. Lastly, the therapeutic efficacy of aged ADSCs with HES1 overexpression was evaluated in skin injury model of male Sprague-Dawley rats. Results 678 genes showed differential expression between ADSCs obtained from young and old donors (Y-ADSCs and O-ADSCs), with 47 of these genes being TFs. Notably, the expression of the TF hairy and enhancer of split 1 (HES1) was notably reduced in ADSCs from old donors. Introducing HES1 overexpression in aged ADSCs resulted in improved cellular function and the suppression of cellular senescence, while reducing HES1 levels in young ADSCs had the opposite effect. Mechanistically, HES1 was found to interact with the promoter region of another TF, signal transducer and activator of transcription 1 (STAT1), to inhibit its transcription. Knocking down STAT1 could fully reverse the negative effects caused by decreased HES1 in ADSCs, leading to a reduction in the secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-8. Ultimately, restoring HES1 expression in aged ADSCs demonstrated enhanced therapeutic potential in promoting skin wound healing. Conclusion HES1 acts as an inhibitor of cellular senescence in the aging progression of ADSCs through the modulation of STAT1 expression, suggesting a promising avenue for rejuvenating senescent ADSCs and improving wound healing.

Abstract All-polymer aqueous batteries, featuring electrodes and electrolytes made entirely from polymers, advance wearable electronics through their processing ease, inherent safety, and sustainability. Challenges persist with the instability of polymer electrode redox products in aqueous environments, which fail to achieve high performance in all-polymer aqueous batteries. Here, we report a polymer-aqueous electrolyte designed to stabilize polymer electrode redox products by modulating the solvation layers and forming a solid-electrolyte interphase. Polyaniline is selected as an example for its dual functionality as a cathode or anode working by p/n doping mechanisms. This approach pioneers the application of polyaniline as an anode and enhances the high-voltage stability of polyaniline cathode in an aqueous electrolyte. The resulting all-polymer aqueous sodium-ion battery with polyaniline as symmetric electrodes exhibits a high capacity of 139 mAh/g, energy density of 153 Wh/kg, and a retention of over 92% after 4800 cycles. Spectroscopic characterizations have elucidated the hydration structure, solid-electrolyte interphase, and dual-ion doping mechanism. Large-scale all-polymer flexible batteries are fabricated with excellent flexibility and recyclability, heralding a paradigmatic approach to sustainable, wearable energy storage.

Abstract Phosphatidylinositol signaling system plays a crucial role in plant physiology and development, phosphatidylinositol phosphate kinases (PIPKs) are one of the essential enzymes responsible for catalyzing the synthesis of phosphatidylinositol bisphosphate (PIP2) within this signaling pathway. However, its mechanism of signal transduction remains poorly exploited in plants. OsMBL1, a jacalin-related mannose-binding lectin in rice, plays a crucial role in plant defense mechanisms, acting as a key component of the pattern-triggered immunity (PTI) pathway. Here, a rice phosphatidylinositol-phosphate kinase FAB (OsPIPK-FAB), a member of the rice PIPKs family, as an interacting protein of OsMBL1 through yeast-two-hybrid (Y2H) screening assay. And this interaction was confirmed by using co-immunoprecipitation (Co-IP) and pull-down assay techniques. Furthermore, we demonstrated that the deletion of OsPIPK-FAB gene in plant enhanced resistance against rice blast while overexpression of OsPIPK-FAB increases sensitivity to the fungal infection. Additionally, through determination and measurement of the plant inositol 1,4,5-trisphosphate (IP3) contents and the plant phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity, we revealed that OsMBL1 inhibits the PIP5K kinase activity of OsPIPK-FAB as well as the plant IP3 contents in rice. Conclusively, these findings indicated that OsPIPK-FAB serves as a novel and critical component that is negatively involved in PTI activation and was inhibited by OsMBL1.

We sequenced the complete mitochondrial genome of the aphid Periphyllus koelreuteriae. It is 16,828 bp long and includes 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosome RNA genes (rRNAs), a control region, and a repeat region. The control region contains a 273-bp repeat motif repeated 2.3 times. The species-specific repeat region between trnE and trnF comprises two 340-bp repeat units. The maximum-likelihood tree based on all 37 mitochondrial genes indicated a close relationship between P. koelreuteriae and Periphyllus diacerivorus. This study provides a valuable mitogenomic resource for future research on Chaitophorinae phylogeny and P. koelreuteriae diversification.

Central Asia, a crucible of prehistoric and historical Trans-Eurasian interactions, has been pivotal in shaping cultural exchanges, population dynamics, and genetic admixture. Recent insights from ancient DNA studies have shed light on the extensive population turnover within this region, encompassing a spectrum of groups from Paleolithic hunter-gatherers to Holocene herders and the nomadic pastoralist empires of historical times. The genomic analysis of ancient pathogens across the Eurasian steppe has further deepened our understanding of pathogen origins, clonal expansions, and the intricate processes of host-pathogen coevolution in relation to varying pathogen exposures and their spread. We consolidate the latest findings pertaining to the ancient human and pathogen genomes of Central Asia, elucidating their profound influence on the genomic tapestry of contemporary Central Asians. A notable gap in the current genomic databases for Central Asia is underscored, particularly within the scope of genomics-driven precision medicine. We stress the urgent need for the development of extensive, region-specific genomic resources that hold promise for revealing the genetic blueprints underlying human traits and diseases, refining polygenic scoring models for predictive medicine, and bolstering genomic research endeavors across Central Asia.

Abstract Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomic resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomic resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, anti-predator strategies, and resilience and adaptive responses. They also serve as essential models for studying broad genomic traits, such as evolutionary genome expansions and contractions, as they exhibit the widest range of genome sizes among all animal taxa and possess multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The emergence of long-read sequencing technologies, combined with advanced molecular and computational techniques that improve scaffolding and reduce computational workloads, is now making it possible to address some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC, https://mvs.unimelb.edu.au/amphibian-genomics-consortium ) in early 2023. This burgeoning community already has more than 282 members from 41 countries. The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and call on the research and conservation communities to unite as part of the AGC to enable amphibian genomics research to “leap” to the next level.

Fasting is typically used before feeding metabolizable energy assessment in broilers. Previous studies have shown that fasting cause atrophy of the intestinal villus. Whether fasting affects intestinal permeability during refeeding by altering barrier function and nutrient absorption is of concern. Here, 23-d-old broilers were randomly assigned to 5 treatments, fasted for 0, 12, 24, 36, and 48 h, respectively, and then refed for 2 d, to study the impact of different duration of fasting on the intestinal regeneration and barrier function during refeeding. Results showed that the intestinal morphology in fasted birds was recovered in 2 d of refeeding at most. As fasting durations increased, enterocytes per intestinal villus were linearly and quadratically increased (both P

Non-small cell lung cancer (NSCLC) is a major disease with high incidence, low survival rate and prone to develop drug resistance to chemotherapy. The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex, and studies have shown that the abnormal activation of STAT3 (Signal Transducer and Activator of Transcription 3) plays an important role in it. In this study, the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target. By modifying hydrophilic and hydrophobic blocks onto chitosan, a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine (VES-CTS-mPEG-His) micelles were synthesized. The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly, and load the recombinant pGPU6/GFP/Neo STAT3-shRNA (pDNA) through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA. The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN (Phosphatase and Tensin Homolog), down-regulate the expression of CD31, and induce apoptosis of tumor cells. The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein, further enhancing the efficacy of chemotherapy. Through this study, precision personalized treatment of NSCLC could be effectively achieved, reversing its resistance to chemotherapy drugs, and providing new strategies for the treatment of drug-resistant NSCLC.

The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delays stent reendothelialization, increasing the risk of stent thrombosis (ST) and sudden cardiac death. Here we present a new strategy for promoting stent reendothelialization and preventing ST by exploring the application of precise molecular targets with EC specificity. Proteomics was used to investigate the molecular mechanism of EC injury caused by rapamycin. Endothelial protein C receptor (EPCR) was screened out as a crucial EC-specific effector. Limus and paclitaxel repressed the EPCR expression, while overexpression of EPCR protected EC from coating (eluting) drug-induced injury. Furthermore, the ligand activated protein C (APC), polypeptide TR47, and compound parmodulin 2, which activated the target EPCR, promoted EC functions and inhibited platelet or neutrophil adhesion, and enhanced rapamycin stent reendothelialization in the simulated stent environment and in vitro. In vivo, the APC/rapamycin-coating promoted reendothelialization rapidly and prevented ST more effectively than rapamycin-coating alone, in both traditional metal stents and biodegradable stents. Additionally, overexpression or activation of the target EPCR did not affect the cellular behavior of SMC or the inhibitory effect of rapamycin on SMC. In conclusion, EPCR is a promising therapeutical agonistic target for pro-reendothelialization and anti-thrombosis of eluting stent. Activation of EPCR protects against coating drugs-induced EC injury, inflammatory cell, or platelet adhesion onto the stent. The novel application formula for APC/rapamycin-combined eluting promotes stent reendothelialization and prevents ST.

Circadian rhythm disruption is a universal phenomenon that is associated with a combination of internal and external factors, with internal factors referring to disturbances in the intrinsic regulatory mechanisms of sleep-wake behavior, and external factors including changes in sleep habits, severe sleep deprivation, shift work, social jet lag, prolonged exposure to nighttime light, and late nighttime eating. Shift work, as a common occupational factor, can lead to disruption of the central/ peripheral biological clock which regulates the expression of almost the entire genome, and the disruption of the biological clock can lead to genetic variants, hormonal secretion abnormalities, insulin resistance, oxidative stress, and systemic inflammation, which are risk factors for obesity. In the context of rapid advancement of global economy and industrialization, the prevalence of simple obesity in the traditional cognitive category is increasing in a linear trend, while the incidence of abdominal obesity, which is closely related to metabolic disorders, is also showing an increasing trend. In recent years, the mechanism of circadian rhythm disorder and obesity associated with shift work has attracted much attention, and this article summarized the latest research progress, aiming to provide a basis for the prevention and treatment of obesity caused by circadian rhythm disruption due to shift work.

This study aimed to construct a risk prediction model for male patients diagnosed with type 2 diabetes mellitus and sarcopenia, and subsequently assess its effectiveness in predicting efficacy. The study subjects consisted of male patients diagnosed with type 2 diabetes who were admitted to the hospital between August 2023 and February 2024. The participants were categorized into two groups: the sarcopenic group (n = 92) and the non-sarcopenic group (n = 196). Patients’ clinical data, lifestyle habits, comorbidities, medical history, and laboratory test markers were collected and subjected to statistical analysis. The findings from both univariate and multivariate logistic regression analyses indicate that age and uric acid (UA) are associated with an increased risk of developing sarcopenia in male patients with type 2 diabetes mellitus. Conversely, Body Mass Index (BMI) and vitamin D are associated with a decreased risk of sarcopenia in men with type 2 diabetes. The probability model for predicting the risk of Sarcopenia in male patients with type 2 diabetes: P = 1/[1 + exp(4.227 − 2.029X1 − 1.165X2 + 0.752X3 + 0.216X4)]. Hosmer and Lemeshow’s goodness-of-fit test showed that χ2 = 7.993, p = 0.434. Receiver Operator Characteristic Curve (ROC) curve analysis showed that Area Under the curve (AUC) was 0.911, 95% Confidence Interval (CI) was 0.879–0.944 respectively. The probability model value was 0.88, which is greater than 0.5, as indicated by the analysis of the overall model quality result. A high clinical predictive value was demonstrated by the risk prediction model of type 2 diabetes mellitus with sarcopenia, which can be used to facilitate early intervention and prevention of the disease.

Abstract Background Pulmonary embolism (PE) is life-threatening and requires timely and accurate diagnosis, yet current imaging methods, like computed tomography pulmonary angiography, present limitations, particularly for patients with contraindications to iodinated contrast agents. We aimed to develop a quantitative texture analysis pipeline using machine learning (ML) based on non-contrast thoracic computed tomography (CT) scans to discover intensity and textural features correlated with regional lung perfusion (Q) physiology and pathology and synthesize voxel-wise Q surrogates to assist in PE diagnosis. Methods We retrospectively collected 99mTc-labeled macroaggregated albumin Q-SPECT/CT scans from patients suspected of PE, including an internal dataset of 76 patients (64 for training, 12 for testing) and an external testing dataset of 49 patients. Quantitative CT features were extracted from segmented lung subregions and underwent a two-stage feature selection pipeline. The prior-knowledge-driven preselection stage screened for robust and non-redundant perfusion-correlated features, while the data-driven selection stage further filtered features by fitting ML models for classification. The final classification model, trained with the highest-performing PE-associated feature combination, was evaluated in the testing cohorts based on the Area Under the Curve (AUC) for subregion-level predictability. The voxel-wise Q surrogate was then synthesized using the final selected feature maps (FMs) and model score maps (MSMs) to investigate spatial distributions. The Spearman correlation coefficient (SCC) and Dice similarity coefficient (DSC) were used to assess the spatial consistency between FMs or MSMs and Q-SPECT scans. Results The optimal model performance achieved an AUC of 0.863 during internal testing and 0.828 on the external testing cohort. The model identified a combination containing 14 intensity and textural features that were non-redundant, robust, and capable of distinguishing between high- and low-functional lung regions. Spatial consistency assessment in the internal testing cohort showed moderate-to-high agreement between MSMs and reference Q-SPECT scans, with median SCC of 0.66, median DSCs of 0.86 and 0.64 for high- and low-functional regions, respectively. Conclusions This study validated the feasibility of using quantitative texture analysis and a data-driven ML pipeline to generate voxel-wise lung perfusion surrogates, providing a radiation-free, widely accessible alternative to functional lung imaging in managing pulmonary vascular diseases. Clinical trial number Not applicable.

Abstract Associations between the gut microbiota and Parkinson’s disease (PD) have been widely investigated. However, the replicable biomarkers for PD diagnosis across multiple populations remain elusive. Herein, we performed a meta-analysis to investigate the pivotal role of the gut microbiome in PD and its potential diagnostic implications. Six 16S rRNA gene amplicon sequence datasets from five independent studies were integrated, encompassing 550 PD and 456 healthy control samples. The analysis revealed significant alterations in microbial composition and alpha and beta diversity, emphasizing altered gut microbiota in PD. Specific microbial taxa, including Faecalibacterium, Roseburia, and Coprococcus_2, known as butyrate producers, were notably diminished in PD, potentially contributing to intestinal inflammation. Conversely, genera such as Akkermansia and Bilophila exhibited increased relative abundances. A network-based algorithm called NetMoss was utilized to identify potential biomarkers of PD. Afterwards, a classification model incorporating 11 optimized genera demonstrated high performance. Further functional analyses indicated enrichment in pathways related to neurodegeneration and metabolic pathways. These findings illuminate the intricate relationship between the gut microbiota and PD, offering insights into potential therapeutic interventions and personalized diagnostic strategies.