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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

Abstract Glaucoma poses a significant threat to vision, capable of causing irreversible damage and, in severe instances, leading to permanent blindness. Accurate optic cup (OC) and optic disc (OD) segmentation are essential in glaucoma screening. In this study, a novel OC and OD segmentation approach is proposed. Based on U‐Net, it is optimized by introducing cardinality dimensions. Moreover, attention gates are implemented to reinforce salient features while suppressing irrelevant information. Additionally, a convolutional block attention module (CBAM) is integrated into the decoder segment. This fusion hones in on effective information in both channel and spatial dimensions. Meanwhile, an image processing procedure is proposed for image normalization and enhancement. All of these increase the accuracy of the model. This model is evaluated on the ORIGA and REFUGE datasets, demonstrating the model's superiority in OC and OD segmentation compared to the state‐of‐the‐art methods. Additionally, after the proposed image processing, cup‐to‐disc ratio (CDR) prediction on a batch of 155 in‐house fundus images yields an absolute CDR error of 0.099, which is reduced by 0.04 compared to the case where only conventional processing was performed.

Jingyu Zhang,1,&ast; Shenhua Qu,2,&ast; Yuting Huang,1,&ast; Xia Zhang,1 Xiubing Tong,1 Yanping Fang,1 Tianyu Rao,1 Kezhi Liu,1 Jia Lin,1 Yuye Lin,1 Chufan Zeng,1 Guojun Zhang,1 Xianghong Jing,3 Jun Liao,1 Yu Kan1 1College of Acupuncture and Tuina, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, People’s Republic of China; 2Guangzhou Traditional Chinese Medicine Hospital, Guangzhou, 510000, People’s Republic of China; 3Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Liao; Yu Kan, Email 2007065@fjtcm.edu.cn; 2019035@fjtcm.edu.cnPurpose: Chronic cervical muscle injury is the first common cause of the development of cervical spondylosis, and Tuina can effectively promote the repair of chronic cervical muscle injury and alleviate neck pain, but the mechanism behind its efficacy is still unknown. The proliferation and differentiation of muscle satellite cells and the apoptosis of cervical myocytes play important roles in the repair of chronic cervical muscle injuries; therefore, this study aimed to explore the potential mechanisms of Tuina to promote the repair of cervical muscle injuries in terms of the proliferation and differentiation of satellite cells and the apoptosis of myocytes.Patients and Methods: Twenty-eight Wistar rats were randomly divided into control group, model group, Tuina group, and meloxicam group, with 7 rats in each group. Except for the control group, each group were establish a chronic cervical muscle injury model (CCMI). Meloxicam (0.79 mg/kg) was administered by gavage, and in the Tuina group, pressure was applied to the Fengchi acupoint on the affected side once a day. Morphological changes of cervical muscle tissues were detected by ultrasonic diagnostic instrument and HE staining, electrophysiological recordings of electromyographic changes, apoptosis rate was detected by TUNEL staining, and positive expression of Bax, Bcl-2, IGF-1, MyoD, and Pax-7 were detected by Immunohistochemistry and Western blot.Results: In CCMI model rats, we observed that the cervical muscle fibers were disorganized, with irregular morphology, and the amplitude of electromyography was significantly weakened, while Tuina could significantly improve these symptoms and effectively promote the repair of chronic cervical muscle injury. Meanwhile, compared with the model group, Tuina could significantly increase the expression levels of IGF-1 (P< 0.01) and MyoD (P< 0.05) and decrease the expression level of Pax7 (P< 0.05). In addition, we found that the number of apoptotic cells in cervical myocytes was reduced after Tuina intervention (P< 0.05), and Tuina inhibited the expression of pro-apoptotic factor Bax (P< 0.01) and promoted the expression of anti-apoptotic factor Bcl-2 (P< 0.05).Conclusion: Tuina can promote the proliferation and differentiation of satellite cells to repair chronic cervical muscle injury by regulating the expression of Pax7, MyoD, and IGF-1, as well as inhibiting the expression of Bax and promoting the expression of Bcl-2 to ameliorate the apoptosis of cervical myocytes in CCMI model rats.Keywords: Tuina, cervical spondylosis, neck pain, satellite cell

Abstract The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17α-MHCKO) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17fl/fl and A17α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.

Lingyu Lin,1,&ast; Zhuling Gao,2,&ast; Yanchun Peng,2 Sailan Li,1 Liangwan Chen,1,3 Yanjuan Lin1,2 1Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of China; 2Department of Nursing, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of China; 3Key Laboratory of Cardio-Thoracic Surgery(Fujian Medical University), Fujian Province University, Fuzhou, Fujian Province, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanjuan Lin, Department of Nursing, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, Fujian Province, People’s Republic of China, Tel +86059186218581, Fax +8683344034, Email fjxhyjl@163.com Liangwan Chen, Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, Fujian Province, People’s Republic of China, Fax +86059183301393, Email fjxhlwc@163.comPurpose: Many shift nurses experience poor sleep quality, and the effect on nurses’ cognitive function remains unclear. The study aims to investigate sleep status and explore its association with cognitive function.Methods: This descriptive cross-sectional study was conducted in a tertiary care hospital in Fujian, China between March and September 2022. By convenience sampling method, 588 shift nurses participated in this study. The Pittsburgh Sleep Quality Index (PSQI) and Bergen Shift Work Sleep Questionnaire (BSWSQ) were used to assess sleep quality, while the Chinese version of Ascertain Dementia-8 (AD-8) was used to evaluate cognitive function. A PSQI score ≤ 7 is classified as good sleep quality, and a score > 7 indicates poor sleep quality. An AD-8 score≥ 2 is considered indicative of memory impairment. Multivariate logistic regression analysis was conducted to explore the association between sleep status and memory impairment.Results: A total of 310 (52.6%) participants presented poor sleep quality. Among them, 52.2% of participants had day shift-related sleep problems, 45.9% had evening shift-related sleep problems, 61.9% had night shift-related sleep problems, and 15.0% reported rest-day/vacation-related sleep problems. The prevalence of poor sleep quality and each shift-related sleep problem in the memory impairment group were higher than in the normal memory group (P< 0.05). Multivariate logistic regression analysis indicated that poor sleep quality (OR=2.073, 95% CI: 1.398~3.072), evening shift-related sleep problems (OR=1.707, 95% CI: 1.028~2.835), night shift-related sleep problems (OR=1.859, 95% CI:1.104~3.129), and rest-day/vacation-related sleep problems (OR=2.069, 95% CI:1.170~3.659) was significantly associated with memory impairment.Conclusion: This study highlights the prevalence of poor sleep quality among clinical nurses and identifies poor sleep quality and shift-related sleep problems (excluding day shift) as risk factors for memory impairment. Nurse managers should prioritize sleep quality and focus on cognitive function to enhance nurses’ occupational health.Keywords: nurse, sleep disturbance, memory, cognitive function

Liparis gigantea is a Chinese traditional medicinal herb in the Orchidaceae family. It is a rare and special Liparis species that exhibits relatively large flowers. To illuminate its phylogenetic status and augment genomic resources, the complete chloroplast (cp) genome of L. gigantea was first sequenced and assembled using whole genome next-generation sequencing in this study. The cp genome size is 158,462 bp with a total GC content of 36.9%. Characterized by a quadripartite structure, the genome consists of a large single-copy (LSC) region of 86,032 bp, a small single-copy (SSC) region of 18,322 bp, which is separated by a pair of 27,054 bp inverted repeat regions (IRs). A total of 133 genes were annotated, including 87 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. Phylogenetic analysis strongly supported L. gigantea as the sister to two closely related terrestrial species, Liparis nervosa and L. vivipara. The results of this study provide genomic information for future research and application of this medicinal herb.

Jing He,1,&ast; Nan Lin,2,&ast; Ting Jin,2 Ming Lin,1 Zuowei Huang,1 Shuxian Li,1 Jinling Liu,1 Lin Su,1 Xian Ye,2 Lei Wu,1 Zhenghong Song,2 Hongzhen Xu,2 Zhimin Chen1 1Department of Pulmonology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China; 2Nursing Department, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhimin Chen, Department of Pulmonology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, People’s Republic of China, Email zmchen@zju.edu.cn Hongzhen Xu, Master of nursing, Nursing Department, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, People’s Republic of China, Email 6184020@zju.edu.cnBackground: Allergic conditions, identified as a significant global health challenge, are profoundly influenced by indoor allergens, especially house dust mites (HDM). Yet the relationship between mite sensitized components and respiratory allergies and asthma control remains poorly understood.Methods: A cohort of 96 children, either with allergic rhinitis (AR) or rhinitis with asthma syndrome (ARAS), was assessed. Protein microarray technology was deployed to quantify sIgE responses to the allergenic components of Der p and Der f.Results: The study cohort comprised 18 AR and 78 ARAS patients; with 43 mild and 53 moderate-to-severe AR; with 28 uncontrolled, 21 partially controlled, and 29 well-controlled asthma. Sensitization prevalence for HDM components was highest with Der p (97.9%), Der f 2 (97.9%), Der p 2 (94.8%), Der f 1(94.8%), Der p 1 (93.8%), Der p 23 (57.3%). Notably, sIgE concentrations for Der f and Der f 2 were significantly greater in the ARAS compared to AR (P < 0.05). While sIgE levels varied between mild and moderate-to-severe AR, the differences were not statistically significant (P > 0.05). However, Der p 23 sIgE levels demonstrated a significant fluctuation across the asthma control strata (P < 0.05), with the well-controlled group exhibiting the lowest readings.Conclusion: The sIgE levels to HDM allergens were higher in ARAS group compared to AR group, especially Der f and Der f 2, indicating an association between sIgE reactivity and the diagnosis of asthma. Reduced Der p 23 sIgE levels were indicative of enhanced asthma control.Keywords: house dust mite, allergic rhinitis, asthma, molecular sensitization, children

Abstract Small-cell lung cancer (SCLC) transformation accounts for 3–14% of resistance in EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT. We identified several pathways that shifted during transformation, and the transformation might be promoted by epigenetic alterations (such as HDAC10, HDAC1, DNMT3A) within the tumor cells instead of within the tumor microenvironment. For druggable pathways, transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling, while VEGF-VEGFR pathway remained active, indicating potential treatments after transformation. We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation, which obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future.

Chi-Han Lin,1,2,&ast; Yung-Chia Kuo,1– 3,&ast; Hsuan-Chih Kuo,1– 3,&ast; Ching-Ting Wang,4 Shi-Ming Lin,1,5 Alan Chao-Wei Lee,1,6 Ming-Chin Yu,1,6,7 Wei-Chen Lee,1,6 Cherry Chiao-Erh Chen,2,3 Jason Chia-Hsun Hsieh1– 3 1College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 2Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 3Division of Hematology-Oncology, Department of Internal Medicine, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan; 4Registered Nurse, Case Manager of Nursing Department, Chang Gung Memorial Hospital, Linkou, Taoyuan, 333, Taiwan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 6Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 7Department of Surgery, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan&ast;These authors contributed equally to this workCorrespondence: Jason Chia-Hsun Hsieh, Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, No. 5, Fu-Hsin Street, Gueishan District, Taoyuan City, 333, Taiwan, Tel +886-3-3281200 Ext 8825, Email wisdom5000@gmail.comBackground: Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear.Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns.Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses.Conclusion: Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.Keywords: hepatitis, immune checkpoint inhibitor, advanced hepatocellular carcinoma, liver enzymes, overall survival

Abstract Background To investigate the prognosis of longitudinal health-related quality of life (HRQOL) during concurrent chemoradiotherapy (CCRT) on survival outcomes in patients with advanced nasopharyngeal carcinoma (NPC). Methods During 2012–2014, 145 adult NPC patients with stage II-IVb NPC were investigated weekly using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORCT QLQ-C30) during their CCRT period. The effects of longitudinal trends of HRQOL on survival outcomes were estimated using joint modeling, and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were reported as a 10-point increase in HRQOL scores. Results After a median follow-up of 83.4 months, the multivariable models showed significant associations of longitudinal increasing scores in fatigue and appetite loss during the CCRT period with distant metastasis-free survival: 10-point increases in scores of fatigue and appetite loss domains during CCRT period were significantly associated with 75% (HR: 1.75, 95% CI: 1.01, 3.02; p = 0.047) and 59% (HR: 1.59, 95% CI: 1.09, 2.59; p = 0.018) increase in the risk of distant metastasis, respectively. The prognostic effects of the longitudinal HRQOL trend on overall survival and progress-free survival were statistically non-significant. Conclusion Increases in fatigue and appetite loss of HRQOL during the CCRT period are significantly associated with high risks of distant metastasis in advanced NPC patients. Nutritional support and psychological intervention are warranted for NPC patients during the treatment period.

Abstract Background Fusobacterium nucleatum (F. nucleatum) is one of the key tumorigenic bacteria in colorectal cancer (CRC), yet how F. nucleatum is involved in colorectal cancer carcinogenesis remains unknown. Results In the present study, we carried out PathSeq analysis on RNA sequencing data from the 430 primary colon adenocarcinomas in TCGA database to assess the relationship between patients’ survival and F. nucleatum abundance. Among patients with cecum and ascending colon tumors, we found that F. nucleatum transcriptome abundance is positively correlated with mutation load. We further demonstrated that patients with both high tumoral abundance of F. nucleatum and high mutation load exhibited poorer survival and DNA damage. We furthermore determined that F. nucleatum-conditioned medium (Fn. CM) induces DNA damage in both in vitro and in vivo studies. In addition, two F. nucleatum-secreted mutagens, namely DL-homocystine and allantoic acid, were identified to lead to DNA damage. Conclusions Our finding delineates the genotoxicity of F.nucleatum-secreted mutagens, which provides a basis for further work to investigate the role of F. nucleatum in the pathogenicity of CRC.

Xiaoyan Hong,1 Yangrong Huang,1 Wei Lin,1 Yi Zhang,1 Jianyun Lin,1 Shengguo Zhang,2 Fengquan Cai,1 Jie Chen1 1Department of Emergency, Third Affiliated Hospital of Wenzhou Medical University (Rui’an People’s Hospital), Wenzhou, Zhejiang, People’s Republic of China; 2Department of Infection, Third Affiliated Hospital of Wenzhou Medical University (Rui’an People’s Hospital), Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Fengquan Cai; Jie Chen, Department of Emergency, Third Affiliated Hospital of Wenzhou Medical University (Rui’an People’s Hospital), 108 Wansong Road, Wenzhou, 325200, Zhejiang, People’s Republic of China, Tel +86-13967723666 ; +86-13587409966, Email cfqruiyi@163.com; woshichenjie@wmu.edu.cnAbstract: Staphylococcus aureus (S. aureus) infection is readily disseminated, yet the multiple septic arthritis and extensive migratory skin and soft tissue infections it causes are uncommon and challenging to treat. The infection can be life-threatening, with a mortality rate of 15– 31%. Early, targeted antibiotic therapy is critical to improve prognosis. However, routine cultures are time-consuming and have low positivity rates, which may lead to errors in antibiotic regimen selection, depriving patients of optimal treatment. Genetic testing technologies, such as macrogenomic next-generation sequencing (mNGS) and digital polymerase chain reaction (dPCR), are now emerging as powerful tools for early pathogen diagnosis as well as pathogen diagnosis of target detectors with low microbial loads. In this study, we report a 53-year-old man who was admitted to the ICU for treatment of septic shock. The causative agent was targeted earlier as S. aureus by mNGS, and the shock was corrected more quickly with targeted antibiotic medication. However, he later developed multiple septic arthritis and an extensive migratory skin soft tissue infection with persistent fever, and at one point a gram-negative bacterial infection was suspected, and the antibiotic regimen was incorrectly changed. Blood dPCR suggested that the causative organism was still methicillin-sensitive S. aureus (MSSA), with no drug resistance gene detected, and the anti-infective regimen was readjusted, and the patient eventually recovered and was discharged from the hospital. We present this rare case and review related studies to validate the superiority of genetic testing technology in pathogen diagnosis, which deserves further application.Keywords: disseminated Staphylococcus aureus disease, multiple suppurative arthritis, extensive migratory skin and soft tissue infections, digital polymerase chain reaction, next-generation sequencing

Longfei Lin,1,&ast; Yuling Liu,1,&ast; Ruying Tang,1 Shilan Ding,1 Hongmei Lin,2,3 Hui Li1,4 1Institute Chinese Materia Medica China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3National Medical Products Administration Key Laboratory for Research Evaluation of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Institute of Traditional Chinese Medicine Health Industry, China Academy of Chinese Medical Sciences, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Li, Institute Chinese Materia Medica China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China, Email lihuizys@126.com Hongmei Lin, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China, Email lhmtcm@126.comAbstract: Evodiamine (EVO) is a tryptamine indole alkaloid and the main active ingredient in Evodia rutaecarpa. In recent years, the antitumor, cardioprotective, anti-inflammatory, and anti-Alzheimer’s disease effects of EVO have been reported. EVO exerts antitumor effects by inhibiting tumor cell activity and proliferation, blocking the cell cycle, promoting apoptosis and autophagy, and inhibiting the formation of the tumor microvasculature. However, EVO has poor solubility and low bioavailability. Several derivatives with high antitumor activity have been discovered through the structural optimization of EVO, and new drug delivery systems have been developed to improve the solubility and bioavailability of EVO. Current research found that EVO could have toxic effects, such as hepatotoxicity, nephrotoxicity, and cardiac toxicity. This article reviews the pharmacological activity, derivatives, drug delivery systems, toxicity, and pharmacokinetics of EVO and provides research ideas and references for its further in-depth development and clinical applications.Keywords: evodiamine, pharmacology, derivatives, drug delivery systems

Abstract Background In 2022, our team launched the pioneering national proficiency testing (PT) scheme for the pathological diagnosis of breast cancer, rapidly establishing its credibility throughout China. Aiming to continuously monitor and improve the proficiency of Chinese pathologists in breast pathology, the second round of the PT scheme was initiated in 2023, which will expand the number of participating institutions, and will conduct a nationwide investigation into the interpretation of HER2 0, 1+, and 2+/FISH- categories in China. Methods The methodology employed in the current round of PT scheme closely mirrors that of the preceding cycle in 2022, which is designed and implemented according to the “Conformity assessment—General requirements for proficiency testing”(GB/T27043—2012/ISO/IEC 17043:2010). More importantly, we utilized a statistics-based method to generate assigned values to enhance their robustness and credibility. Results The final PT results, published on the website of the National Quality Control Center for Cancer ( http://117.133.40.88:3927 ), showed that all participants passed the testing. However, a few institutions demonstrated systemic biases in scoring HER2 0, 1+, and 2+/FISH- with accuracy levels below 59%, considered unsatisfactory. Especially, the concordance rate for HER2 0 cases was only 78.1%, indicating challenges in distinguishing HER2 0 from low HER2 expression. Meanwhile, areas for histologic type and grade interpretation improvement were also noted. Conclusions Our PT scheme demonstrated high proficiency in diagnosing breast cancer in China. But it also identified systemic biases in scoring HER2 0, 1+, and 2+/FISH- at some institutions. More importantly, our study highlighted challenges in the evaluation at the extreme lower end of the HER2 staining spectrum, a crucial area for further research. Meanwhile, it also revealed the need for improvements in interpreting histologic types and grades. These findings strengthened the importance of robust quality assurance mechanisms, like the nationwide PT scheme conducted in this study, to maintain high diagnostic standards and identify areas requiring further training and enhancement.

Abstract The accurate prenatal diagnosis of skeletal anomaly (SKA) using prenatal imaging alone remains challenging. We aimed to investigate the efficacy of whole-exome sequencing (WES) in the prenatal molecular genetic diagnosis of skeletal system abnormalities, with or without additional ultrasound anomalies. All fetuses with SKA were subjected to sequential genetic tests, and after excluding fetal chromosomal abnormalities and clinically significant copy number variations (CNVs) consistent with the observed phenotype, the affected fetuses were further subjected to WES. The clinical features of fetal SKA were collected, and the results of molecular genetic testing and perinatal outcomes were analyzed. Following negative routine genetic test results of the 78 fetuses, trio-WES was conducted for 73 fetuses, and fetus-only WES (single WES) was performed for five fetuses due to parental refusal. Fetal skeletal system abnormalities in our cohort were subdivided into seven groups: 39 (50%) had short long bones, 14 (17.9%) had abnormal limb morphology, 4 (5.1%) had polydactyly, 4 (5.1%) had the absence of the radius tibia or tibiofibula, 5 (6.4%) had spine anomalies, 6 (7.7%) had strephenopodia, and 6 (7.7%) had multiple deformities. In total, we identified the molecular diagnoses for 32/78 fetuses with SKAs, and confirmed 41 pathogenic/likely pathogenic variants in 28 genes, including nine novel variants in our cohort. The overall diagnostic rate was 41% (32/78). Our findings demonstrate that WES can greatly improve the genetic diagnostic rate of fetal SKAs following routine genetic testing, which can comprehensively guide perinatal management and help assess the risk of recurrence in future pregnancies. Our data also provide a basis for the association between the SKA phenotype and related genotypes and expand the spectrum of fetal SKA phenotypes and related genes.

Abstract The relationship between serum uric acid (SUA) and mortality in patients with cardiovascular disease (CVD) remains controversial. We aimed to explore the relationship between SUA and all-cause mortality (ACM) and cardiovascular mortality (CVM) in adult patients with CVD. This cohort study included 3977 patients with CVD from the National Health and Nutrition Examination Survey (2005–2018). Death outcomes were determined by linking National Death Index (NDI) records through December 31, 2019. We explored the association of SUA with mortality using weighted Cox proportional hazards regression models, subgroup analysis, Kaplan-Meier survival curves, weighted restricted cubic spline (RCS) models, and weighted threshold effect analysis among patients with CVD. During a median follow-up of 68 months (interquartile range, 34–110 months), 1,360 (34.2%) of the 3,977 patients with cardiovascular disease died, of which 536 (13.5%) died of cardiovascular deaths and 824 (20.7%) died of non-cardiovascular deaths. In a multivariable-adjusted model (Model 3), the risk of ACM (HR 1.38, 95% CI 1.16–1.64) and the risk of CVM (HR 1.39, 95% CI 1.04–1.86) for participants in the SUA Q4 group were significantly higher. In patients with CVD, RCS regression analysis revealed a nonlinear association (p

Abstract The interest in the rare-earth monopnictides was boosted after the discovery of unconventional surface-state pairs in antiferromagnetically ordered NdBi. In contrast to other materials in which such states were reported, CeBi is known to have multiple antiferromagnetic phases. In this study, we perform angle-resolved photoemission spectroscopy (ARPES) measurements in conjunction with density functional theory (DFT) calculations to investigate the evolution of the electronic structure of CeBi upon a series of antiferromagnetic (AFM) transitions. We find evidence for a new AFM transition in addition to two previously known from transport studies. We demonstrate the development of an additional Dirac state in the ( + − + − ) ordered phase and a transformation of unconventional surface-state pairs in the ( + + − − ) ordered phase. This revises the phase diagram of this intriguing material, where there are now three distinct AFM states below T N in zero magnetic field instead of two as it was previously thought.

Abstract Baicalin is a natural flavonoid shown to attenuate inflammation, tumor, and cardiovascular diseases. However, its effect on endothelial function in diabetes remains unclear and was investigated in current study. A high‐fat diet (60% kcal fat diet) was used to feed male C57BL/6 mice for 14 weeks to build a diet‐induced obese (DIO) diabetic mouse model. Baicalin (50 and 100 mg/kg/day) or vehicle was applied to DIO mice by oral gavage in the last 4 weeks. Separated mouse aortic rings were induced by high glucose and primary rat aortic endothelial cells (RAECs) were stimulated by advanced glycation end products (AGEs), and cotreated with or without varying doses of baicalin and 5′AMP‐activated protein kinase (AMPK) inhibitor Compound C. Forty‐eight‐hour exposure to high glucose impaired acetylcholine‐induced endothelium‐dependent relaxations in mouse aortas and produced excessive levels of reactive oxygen species (ROS). Similar phenomenon was observed in aortas from DIO mice. Baicalin treatment could alleviate these damage through preventing expression and translocation of nuclear factor (NF)‐κB p65 pathway, accomplished with decreased expressions of vascular cell adhesion molecule 1 (VCAM‐1) and intracellular adhesion molecule 1 (ICAM‐1) as well as proinflammatory cytokines including tumor necrosis factor alpha (TNF‐α) and interleukin 6 (IL‐6). These improvements were AMPK‐dependent as Compound C abolished the effects. Similar beneficial effects of baicalin and inhibitory effects of Compound C were observed in AGEs (200 µg/mL, 24 h)‐induced RAECs. To conclude, baicalin protects against vascular inflammation and endothelial dysfunction associated with diabetes through suppression on inflammation and oxidative stress via activating AMPK.

Purpose: This study aimed to determine the therapeutic effectiveness of different machines in intense pulsed light (IPL) treatment of meibomian gland dysfunction (MGD). Methods: 213 subjects diagnosed with MGD underwent three sessions of IPL treatment in a control (M22) treatment group or experimental (OPL-I) treatment group and were followed up three to four weeks after each session. Tear breakup time (TBUT), meibomian gland secretion scores (MGSS), meibomian gland meibum scores (MGMS), corneal fluorescein staining (CFS) scores, and the Standard Patient Evaluation of Eye Dryness (SPEED) was used to assess eye dryness signs and symptoms at baseline and follow-up visits. Results: Two machines had the same working principles except that experimental (OPL-I) group consist of a dual filter system. Both groups showed significant improvements (P ​

Abstract Severe psoriasis has a long course and poor outcome, and it has long been a problem for patients. Understanding the independent risk factors that contribute to patients with severe psoriasis is critical for the development of effective treatment strategies. This large, multicenter study recruited 2,109 plaque psoriasis patients from 12 hospitals across China (October 31, 2019 – May 31, 2022). The logistic regression model underwent internal validation and external validation using two independent cohorts over future time periods (June 1, 2022 – January 31, 2023). The discriminative power of our model was substantiated by a C-index of 0.863 (95% CI: 0.848–0.879) in internal validation, further affirmed through 1,000 bootstrap validation (C-index: 0.860, 95% CI: 0.836–0.885) and external validation cohorts, where the C-index reached up to 0.910 (95% CI: 0.868–0.953) and 0.951 (95% CI: 0.924–0.977) in 2 external validation cohorts. To enhance accessibility for clinicians, the model has been made available as a dynamic nomogram and QR code. Our study identified 10 risk factors (the “DELPHI” consensus dichotomy, the DLQI index, the extent of skin involvement as measured by body surface area, the age of the patient at the time of clinical visit, sex, body weight in kilograms, career, the presence of scalp involvement, facial involvement, and arthropathy) for the overall severity of psoriasis (PASI ≥ 10). “Nomogram-10” provides clinicians with a practical tool to develop personalized intervention strategies based on an individual’s risk profile. Trial registration: Chinese Clinical Trial Registry: ChiCTR1900024852.

Abstract Purpose To develop and validate a preoperative prediction model based on multimodal ultrasound and biochemical indicator for identifying microvascular invasion (MVI) in patients with a single hepatocellular carcinoma (HCC) ≤ 5 cm. Methods From May 2022 to November 2023, a total of 318 patients with pathologically confirmed single HCC ≤ 5 cm from three institutions were enrolled. All of them underwent preoperative biochemical, conventional ultrasound (US), and contrast-enhanced ultrasound (CEUS) (Sonazoid, 0.6 mL, bolus injection) examinations. Univariate and multivariate logistic regression analyses on clinical information, biochemical indicator, and US imaging features were performed in the training set to seek independent predictors for MVI-positive. The models were constructed and evaluated using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis in both validation and test sets. Subgroup analyses in patients with different liver background and tumor sizes were conducted to further investigate the model’s performance. Results Logistic regression analyses showed that obscure tumor boundary in B-mode US, intra-tumoral artery in pulsed-wave Doppler US, complete Kupffer-phase agent clearance in Sonazoid-CEUS, and biomedical indicator PIVKA-II were independently correlated with MVI-positive. The combined model comprising all predictors showed the highest AUC, which were 0.937 and 0.893 in the validation and test sets. Good calibration and prominent net benefit were achieved in both sets. No significant difference was found in subgroup analyses. Conclusions The combination of biochemical indicator, conventional US, and Sonazoid-CEUS features could help preoperative MVI prediction in patients with a single HCC ≤ 5 cm. Critical relevance statement Investigation of imaging features in conventional US, Sonazoid-CEUS, and biochemical indicators showed a significant relation with MVI-positivity in patients with a single HCC ≤ 5 cm, allowing the construction of a model for preoperative prediction of MVI status to help treatment decision making. Key Points MVI status is important for patients with a single HCC ≤ 5 cm. The model based on conventional US, Sonazoid-CEUS and PIVKA-II performs best for MVI prediction. The combined model has potential for preoperative prediction of MVI status. Graphical Abstract

Abstract Aurora-B is a kinase that regulates spindle assembly and kinetochore-microtubule (KT-MT) attachment during mitosis and meiosis. SUMOylation is involved in the oocyte meiosis regulation through promoting spindle assembly and chromosome segregation, but its substrates to support this function is still unknown. It is reported that Aurora-B is SUMOylated in somatic cells, and SUMOylated Aurora-B contributes the process of mitosis. However, whether Aurora-B is SUMOylated in oocytes and how SUMOylation of Aurora-B impacts its function in oocyte meiosis remain poorly understood. In this study, we report that Aurora-B is modified by SUMOylation in mouse oocytes. The results show that Aurora-B colocalized and interacted with SUMO-2/3 in mouse oocytes, confirming that Aurora-B is modified by SUMO-2/3 in this system. Compared with that in young mice, the protein expression of SUMO-2/3 decreased in the oocytes of aged mice, indicating that SUMOylation might be related to mouse aging. Overexpression of Aurora-B SUMOylation site mutants, Aurora-BK207R and Aurora-BK292R, inhibited Aurora-B recruitment and first polar body extrusion, disrupting localization of gamma tubulin, spindle formation and chromosome alignment in oocytes. The results show that it was related to decreased recruitment of p-HDAC6 which induces the high stability of whole spindle microtubules including the microtubules of both correct and wrong KT-MT attachments though increased acetylation of microtubules. Therefore, our results corroborate the notion that Aurora-B activity is regulated by SUMO-2/3 in oocytes, and that SUMOylated Aurora B plays an important role in spindle formation and chromosome alignment.

Abstract Introduction Arterial calcification, an independent predictor of cardiovascular events, increases morbidity and mortality in patients with diabetes mellitus (DM), but its mechanisms remain unclear. Extracellular vesicles (EVs) play an important role in intercellular communication. The study investigates the role and potential mechanisms of EVs derived from endothelial cells (ECs) in regulating vascular smooth muscle cell (VSMC) calcification under high glucose (HG) condition, with a goal of developing effective prevention and treatment strategies for diabetic arterial calcification. Results The results showed that EVs derived from HG induced ECs (ECHG-EVs) exhibited a bilayer structure morphology with a mean diameter of 74.08 ± 31.78 nm, expressing EVs markers including CD9, CD63 and TSG101, but not express calnexin. ECHG-EVs was internalized by VSMCs and induced VSMC calcification by increasing Runx2 expression and mineralized nodule formation. The circ_0008362 was enriched in ECHG-EVs, and it can be transmitted to VSMCs to promote VSMC calcification both in vitro and in vivo. Mechanistically, miR-1251-5p might be one of the targets of circ_0008362 and they were co-localization in the cytoplasm of VSMCs. Runx2 was identified as the downstream target of miR-1251-5p, and circ_0008362 acted as a sponge, enhancing Runx2 expression and then promoted VSMC calcification. Besides, circ_0008362 could directly interact with Runx2 to aggravate VSMC calcification. Notably, DiR-labelled ECHG-EVs was detected in the vessels of mice. Meanwhile, the level of circ_0008362 and Runx2 were increased significantly, while the expression of miR-1251-5p was decreased significantly in calcified artery tissues of mice. However, inhibiting the release of EVs by GW4869 attenuated arterial calcification in diabetic mice. Finally, the level of circulation of plasma EVs circ_0008362 was significantly higher in patients with DM compared with normal controls. Elevated levels of plasma EVs circ_0008362 were associated with more severe coronary and aorta artery calcification in patients with DM. Conclusions Our findings suggested that circ_0008362 was enriched in EVs derived from ECs and promoted VSMC calcification under HG conditions, both by sponging miR-1251-5p to upregulate Runx2 expression and through direct interaction with Runx2. Furthermore, elevated levels of plasma EVs circ_0008362 were associated with more severe coronary and aorta artery calcification in patients with DM. These results may serve as a potential prevention and therapeutic target for diabetic arterial calcification. Graphical abstract

Abstract Ligusticum sinense cv. Chuanxiong (L. Chuanxiong), one of the widely used traditional Chinese medicines (TCM), is currently facing the problem of excessive cadmium (Cd) content. This problem has significantly affected the quality and safety of L. Chuanxiong and become a vital factor restricting its clinical application and international trade development. Currently, to solve the problem of excessive Cd, it is essential to research the response mechanisms of L. Chuanxiong to Cd stress. However, there are few reports on its physiological and biochemical responses under Cd stress. In this study, we conducted the hydroponic experiment under 25 μM Cd stress, based on the Cd content of the genuine producing areas soil. The results showed that 25 μM Cd stress not only had no significant inhibitory effect on the growth of L. Chuanxiong seedlings but also significantly increased the chlorophyll a content (11.79%) and root activity (51.82%) compared with that of the control, which might be a hormesis effect. Further results showed that the absorption and assimilation of NH4 + increased in seedlings under 25 μM Cd stress, which was associated with high photosynthetic pigments. Here, we initially hypothesized and confirmed that Cd exceedance in the root system of L. Chuanxiong was due to the thickening of the root cell wall, changes in the content of the cell wall components, and chelation of Cd by GSH. There was an increase in cell wall thickness (57.64 %) and a significant increase in cellulose (25.48%) content of roots under 25 μM Cd stress. In addition, L. Chuanxiong reduced oxidative stress caused by 25 μM Cd stress mainly through the GSH/GSSG cycle. Among them, GSH-Px (48.26%) and GR (42.64%) activities were significantly increased, thereby maintaining a high GSH/GSSG ratio. This study preliminarily reveals the response of L. Chuanxiong to Cd stress and the mechanism of Cd enrichment. It provides a theoretical basis for solving the problem of Cd excessive in L. Chuanxiong. Graphical Abstract Physiological and biochemical mechanisms of L. Chuanxiong seedlings under Cd stress.

Abstract BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.

Objective To explore the relationship between monocyte/high-density lipoprotein cholesterol ratio （MHR） and the progression and prognosis of type 2 diabetic kidney disease （DKD）. Methods From January 1， 2017 to December 31， 2022， 269 type 2 DKD patients were selected as DKD group while 269 healthy medical check-ups during the same period as healthy group. And the differences in MHR levels of two groups were compared. According to median MHR， DKD group were assigned into low-level MHR and high-level MHR sub-groups. General profiles， clinical data， the incidence rate of endpoint events and cumulative renal survival were compared two groups. Cox regression analysis was performed for exploring the independent risk factors for poor renal prognosis in DKD patients and drawing receiver operator characteristic curve （ROC） for exploring the diagnostic efficacy of MHR for poor prognosis of DKD. Results MHR level was higher in DKD group than that in healthy group [0.4918（0.3788，0.6818）×109/mmol vs 0.2984（0.1867，0.4112）×109/mmol] （P＜0.05）； high-level MHR group had higher levels of white blood cells （WBC） [7.70（6.40， 8.70）×109/L vs 6.50（5.40， 8.00）×109/L]， neutrophils （Ne） [4.60（3.60， 5.53）×109/L vs 3.99（3.18， 5.19）×109/L] and monocyte （Mono） [0.69（0.60， 0.70）×109/L vs 0.50（0.40， 0.60）×109/L]， urinary albumin to creatinine ratio （UACR） [1214.59（373.48， 3410.02）mg/g vs 1050.96（180.26， 3341.06） mg/g]， 24 h urine protein （24 hUP） [3.21（1.42， 5.51）g vs 2.66 （0.58， 4.56） g]， low-density lipoprotein cholesterol （LDL-C） [2.72（2.06， 3.40）mmol/L vs 2.23（1.63， 2.80）mmol/L]， serum creatinine （Scr） [152.10（95.20， 221.60）μmol/L vs 126.00（92.48， 186.55）μmol/L] than those in low-level MHR group； lymphocyte （Lym） [1.60（1.27， 2.20）×109/L vs 1.82（1.30， 2.40）×109/L]， high-density lipoprotein cholesterol （HDL-C） [0.94（0.83， 1.07）mmol/L vs 1.39（1.15， 1.65）mmol/L] and estimated glomerular filtration rate （eGFR） [39.69（25.19， 65.10）mL·min−1·（1.73 m²）−1 vs 47.12（28.86， 73.60）mL·min−1·（1.73 m²）−1] were lower than those in low-level MHR group； high-level MHR group had a cumulative kidney survival time and it was shorter than that in low level MHR group [63（39， 72）month vs 72（46， 72）month] （P＜0.05）； MHR was correlated positively with WBC， Ne， Mono， UACR， 24h UP， Scr and LDL-C （P＜0.05） and negatively with Lym， HDL-C， eGFR and cumulative renal survival time （P＜0.05）； the incidence of endpoint events was higher in high-level MHR group than that in low-level MHR group （52.59% vs 38.06%）（P＜0.05）； baseline MHR [0.5492（0.4030， 0.7235）×109/mmol vs 0.4255（0.3117， 0.5134）×109/mmol]， UACR [2062.65（752.80， 4234.80）mg/g vs 608.56（88.63. 1912.44）mg/g]， 24 hUP [3.79（2.54， 5.53）g vs 1.58（0.39， 4.85）g] and Scr [178.40（134.00， 234.23）μmol/L vs 100.95（74.25， 152.10）μmol/L] were higher than those in DKD patients without endpoint events； eGFR was lower than that in DKD patients without endpoint events [33.45（23.33， 46.41）mL·min−1·（1.73 m²）−1 vs 61.59（38.57， 95.98）mL·min−1·（1.73 m²）−1]（P＜0.05）. The results of Cox regression analysis indicated that MHR was an independent risk factor for a poor prognosis of DKD； The results of ROC curve showed that the area under the curve of MHR was 0.747 with a sensitivity of 0.820 and a specificity of 0.605. Conclusion DKD patients tend to have higher levels of MHR as compared with healthy individuals. As an independent risk for the progression of renal function in DKD patients， MHR has some diagnostic value for a poor prognosis of DKD. However， its specificity is not high.

Abstract Objective The aim of this study was to investigate sex-related differences in the clinical characteristics and hospital outcomes of patients undergoing surgery for acute type A aortic dissection (AAAD). Methods This study was a retrospective study. Patients who underwent surgery for AAAD at the Department of Cardiac Surgery, Fujian Medical University Union Hospital, from January 2014 to March 2023 were consecutively included. Data was extracted from electronic medical records. The primary outcome measure was in-hospital mortality, and secondary outcome measures included new-onset postoperative arrhythmia (POA), acute kidney injury (AKI), hepatic dysfunction, neurological complications, gastrointestinal hemorrhage, ICU length of stay, and hospital length of stay. Patients were divided into two groups based on sex, and data analysis was performed using SPSS 25.0 software. Results A total of 1137 subjects were included, with 863 males (75.9%) and 274 females (24.1%). There were statistically significant differences in age and BMI between the two groups (P 0.05). The rate of POA in females was 4.7%, higher than in males (2.2%), but AKI and gastrointestinal hemorrhage were both higher in males than in females (P

Abstract Background The aim of this study was to explore the relationships between teaching competence, career development, industrial orientation, and specialty construction in the case of intelligent medicine specialties in universities of traditional Chinese medicine, as well as the influencing factors of specialty construction. Methods Two-stage sampling with unequal probability was conducted to distribute self-administered questionnaires in the fieldwork. A structural equation model was built to investigate the influencing factors of specialty construction. Forty-two teachers were recruited and completed the questionnaire. Results The study found that teaching competence, career development, and industrial orientation positively affect specialty construction at a significant level. Career development and industrial orientation play chain mediating roles in the effect of teaching competence on specialty construction. Conclusions In the construction of intelligent medicine specialties, a professional curriculum system should be built that caters to industrial demand and is combined with industrial development, the traditional mode of teaching should be transformed, and the transformation of theoretical knowledge into practical ability should be promoted. Innovations in teaching modes should be achieved by introducing information technology, and the teacher evaluation system should be optimized.

Abstract Biocatalysis is an attractive approach for the synthesis of chiral pharmaceuticals and fine chemicals, but assessing and/or improving the enantioselectivity of biocatalyst towards target substrates is often time and resource intensive. Although machine learning has been used to reveal the underlying relationship between protein sequences and biocatalytic enantioselectivity, the establishment of substrate fitness space is usually disregarded by chemists and is still a challenge. Using 240 datasets collected in our previous works, we adopt chemistry and geometry descriptors and build random forest classification models for predicting the enantioselectivity of amidase towards new substrates. We further propose a heuristic strategy based on these models, by which the rational protein engineering can be efficiently performed to synthesize chiral compounds with higher ee values, and the optimized variant results in a 53-fold higher E-value comparing to the wild-type amidase. This data-driven methodology is expected to broaden the application of machine learning in biocatalysis research.

Abstract Background The impact of polycyclic aromatic hydrocarbons (PAHs) on lung function has garnered attention, but studies mostly focus on individual effect. This study investigates urinary PAH metabolites as biomarkers of exposure and assesses the relationships between single and combined exposures to nine urinary PAH metabolites and lung function in adults. Methods Data from 4040 adults in the 2007–2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Weighted generalized linear models estimated the effects of individual PAH metabolites on lung function. Additionally, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR) were employed to evaluate the combined impacts of multiple PAH metabolites. Results Analyses of individual PAH metabolites revealed negative associations with lung function, excluding forced vital capacity (FVC). The WQS, qgcomp, and BKMR models consistently showed that exposure to multiple PAH metabolites was associated with lung function decrease. WQS indicated that 2-hydroxynaphthalene (2-NAP) was the largest contributor to the reductions in forced expiratory volume in 1 s (FEV1), FVC, peak expiratory flow (PEF), and forced expiratory flow from 25 to 75% of FVC (PEF25-75%). Additionally, 1-hydroxypyrene (1-PYR) was the primary PAH metabolite contributing to the decreases in FEV1/FVC and fractional exhaled nitric oxide (FeNO). The combined effect of urinary PAH metabolites did not affect FVC in the current smokers or FeNO in nonsmokers, but decreased FEV1/FVC in current smokers. Conclusion This study strengthens the negative relationships between multiple PAH metabolites exposure and lung function in adults. Given the limitations of this study, including the lack of knowledge of other exposure pathways and the uncertainty of urinary metabolites, further research is necessary to explore the mechanisms underlying these associations and to address the limitations in exposure assessment.

Abstract Background To compare the differences in long-term quality of life (QoL) between survivors of paediatric and adult patients with nasopharyngeal carcinoma (NPC) and assess the clinical factors that predict long-term QoL. Methods We enrolled 420 long-term NPC survivors who were alive for at least 8 years after treatment, including 195 paediatric and 225 adult patients diagnosed and treated with intensity-modulated radiotherapy (IMRT) at Sun Yat-sen University Cancer Centre (SYSUCC) between 2011 and 2015. Data on clinical factors and EORTC QLQ-C30 were collected from all participants. The QoL of paediatric and adult NPC survivors was compared. Results The paediatric group had significantly better outcomes in global health status (paediatric: 80.2 ± 12.7; adult: 77.2 ± 11.5; P = 0.027), physical function (paediatric: 98.5 ± 4.6; adult: 95.1 ± 7.0; P

Abstract Inherently chiral medium-ring derivatives have important applications in many research fields, such as materials science, molecular recognition, and asymmetric catalysis. However, the enantioselective assembly of these molecules, especially by organocatalytic strategies, remains a formidable challenge, and few methods are available. Here, we report the enantioselective NHC-catalyzed (NHC: N-heterocyclic carbenes) formal high-order (5 + 3) annulation of 1-(2-indolyl)naphthalen-2-ols with ynals. In the presence of an NHC pre-catalyst, base, Lewis acid and oxidant, this protocol enables the catalytic formation of C–C and C-O bonds, providing practical and facile access to an array of inherently chiral saddle-shaped eight-membered lactones featuring an oxocin-2-one scaffold with structural diversity in good efficiency and excellent enantiocontrol. Moreover, the scale-up preparation and representative late-stage transformations of the eight-membered lactones further demonstrate the application potential of this synthetic technology.

Chin-Hsuan Yeh,1,&ast; Chia-Hsuan Lin,2,&ast; Tien-Li Ma,3 Tzu-Yu Peng,4 Thi Thuy Tien Vo,5 Wei-Ning Lin,6 Yu-Hsu Chen,7,8 I-Ta Lee4 1Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan; 2Department of Family Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan; 3School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; 4School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; 5Faculty of Dentistry, Nguyen Tat Thanh University, Ho Chi Minh City, 700000, Vietnam; 6Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan; 7Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan; 8Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: I-Ta Lee, School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan, 250 Wuxing St, Taipei, 11031, Taiwan, Tel +886-2-27361661 ext. 5162, Fax +886-2-27362295, Email itlee0128@tmu.edu.twAbstract: This integrative literature review evaluates the effectiveness of power toothbrushes (PTBs) compared to manual toothbrushes (MTBs) across various populations, focusing on plaque removal, gingival health, calculus reduction, and stain removal. PTBs equipped with advanced technologies such as oscillating-rotating and high-frequency sonic mechanisms have been examined for their potential to enhance oral hygiene. Special attention is given to vulnerable groups, including the elderly and individuals with intellectual disabilities, to assess how PTBs meet their specific oral health needs. A comprehensive literature search was conducted in databases including PubMed, Cochrane Library, Embase, and Google Scholar using keywords such as “power toothbrush”, “electric toothbrush”, “manual toothbrush”, “plaque removal”, “gingivitis”, “calculus”, “dental stains”, “oral hygiene”, “elderly”, and “intellectual disabilities”. Studies published between 2000 and 2024 were selected based on their relevance to the PTB and MTB comparison, with an emphasis on outcomes related to oral hygiene efficacy. As this review is narrative rather than systematic, it focuses on synthesizing existing knowledge without applying strict inclusion or exclusion criteria. The results indicate that PTBs generally outperform MTBs in reducing plaque, gingivitis, and stains, though the benefits for special populations are less pronounced but still significant. However, practical issues such as user experience and mechanical reliability of PTBs warrant further investigation. In conclusion, this review enhances the understanding of PTB effectiveness, guides consumer choices, and informs future technological advancements in dental care practices.Keywords: power toothbrushes, manual toothbrushes, plaque removal, gingival health, dental calculus, oral hygiene

Fueled by substantial advancements in deep learning, the domain of autonomous driving is swiftly advancing towards more robust and effective intelligent systems. One of the critical challenges in this field is achieving accurate 3D object detection, which is often hindered by data sparsity and occlusion. To address these issues, we propose a method centered around a multi-modal fusion strategy that leverages vehicle-road cooperation to enhance perception capabilities. Our approach integrates label information from roadside perception point clouds to harmonize and enrich the representation of image and LiDAR data. This comprehensive integration significantly improves detection accuracy by providing a fuller understanding of the surrounding environment. Rigorous evaluations of our proposed method on two benchmark datasets, KITTI and Waymo Open, demonstrate its superior performance, with our model achieving 87.52% 3D Average Precision (3D AP) and 93.71% Bird’s Eye View Average Precision (BEV AP) on the KITTI val set. These results highlight the effectiveness of our method in detecting sparse and distant objects, contributing to the development of safer and more efficient autonomous driving solutions.

Background: Mozart’s Sonata for Two Pianos in D Major (K448) is a classic double piano work. This study investigated its effect on children with epilepsy (EP) and analyzed the changes in electroencephalography (EEG) among children on the basis of acoustic quality. Methods: The clinical data of 150 children with EP in the Affiliated Hospital (Group) of Putian University from March 2020 to March 2023 were retrospectively analyzed. They were divided into group A (n = 73, antiepileptic drug therapy) and group B (n = 77, antiepileptic drug therapy + Mozart K448) in accordance with the treatment methods. The seizure frequency, frequency of epileptic discharges (EDs), and Quality of Life in Childhood Epilepsy Questionnaire-16 in both groups were compared before and after treatment. The changes in EEG before, during, and after music appreciation were observed. The effects of the acoustic characteristics (rhythm, root mean square value, roughness, and spectral flux) of Mozart K448 on EDs in children were explored. Results: After treatment, group A had a higher seizure frequency (P < 0.001), a higher frequency of EDs (P < 0.05), and significantly lower scores of cognition and emotion than group B (P < 0.001), without significant difference in the scores of social function and physical function (P > 0.05). The frequency of EDs before music appreciation was significantly higher than that during music appreciation (P < 0.01). Spearman correlation analysis showed that the rhythm, spectral flux, and roughness in Mozart K488 were related to the decrease in EDs among children with EP (P < 0.001). Conclusion: This study confirmed the application effect of Mozart K448 in children with EP. Mozart K448 can decrease the seizure frequency, reduce the ED occurrence, and improve the quality of life. The acoustic characteristics of K448 may be the reason for improving EP in children.

The indoor terahertz (THz) wave reflection and transmission characteristics were clarified as essential for the construction of an integrated channel model for terahertz integrated sensing and communication (ISAC). Measurement campaigns were carried out on seven indoor materials at 130~134 GHz using a vector network analyzer-based measurement platform, and the frequency dependence and incidence angle dependence of the terahertz channel reflection and transmission characteristics were analyzed, which were compared with the measurement results at 282~290 GHz, to have the reflection loss characteristics in the two frequency bands revealed. A quantum particle swarm optimization algorithm was used to extract the material electromagnetic parameters, and a joint frequency-incidence angle model of the reflection coefficient was proposed. The results are shown to indicate that the variation rule of the reflection coefficient with frequency and incidence angle can be accurately portrayed by the model. The material propagation coefficient database of the 130~134 GHz band is supplemented by the research results, the electromagnetic parameter dataset is enriched, and the reflection coefficient model is established. The data basis and model reference for the detection, identification, and environmental reconstruction of the terahertz ISAC system are provided.

Abstract Background The initial randomized, double‐blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first‐line therapy in epidermal growth factor receptor (EGFR)‐mutated advanced non‐small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. Methods Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double‐blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow‐up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological‐BICR). The primary endpoint for this subgroup analysis was CNS progression‐free survival (PFS). Results Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological‐BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17‐0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11‐0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non‐CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. Conclusions These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR‐mutated advanced NSCLC with baseline CNS metastases. Trial registration ClinicalTrials.gov number, NCT03849768

Abstract Intestinal fibrosis is the primary cause of disability in patients with Crohn’s disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.

Abstract Background The prognosis of breast cancer patients with visceral metastasis (VM) is significantly worse than that of patients without VM. We aimed to evaluate EZH2 (enhancer of zeste homolog 2) mutation as a biomarker associated with VM. Methods Data from forty-nine patients with metastatic breast cancer (MBC) pathologically confirmed at our hospital between March 2016 and September 2018 were collected. Metastatic tissue samples were obtained via ultrasound-guided needle biopsy, and paired peripheral blood samples were also collected. Tissue and blood samples were subjected to targeted next-generation sequencing via a 247-gene panel. Stably transfected MDA-MB-231 cells expressing wild-type EZH2 (EZH2WT) or a mutant form of EZH2 (EZH2K515R) were generated. Cell proliferation, colony formation ability, migration and invasion abilities and apoptosis were assessed using CCK-8 assays, plate colony formation assays, Transwell chamber assays and flow cytometry. Results The incidence of EZH2 mutations in the VM subgroup was greater than that in the non-VM subgroup in the entire cohort (n = 49, 42.3% vs. 13.0%, p = 0.024) and in the triple-negative breast cancer (TNBC) subgroup (n = 20, 50.0% vs. 10.0%, p = 0.05). Patients carrying EZH2 mutations had a significantly greater risk of developing VM than did those in the non-EZH2 mutation group in the entire cohort (HR 2.9) and in the TNBC subgroup (HR 6.45). Multivariate analysis revealed that EZH2 mutation was an independent prognostic factor for VM (HR 2.99, p = 0.009) in the entire cohort and in the TNBC subgroup (HR 10.1, p = 0.006). Data from cBioPortal also showed that patients with EZH2 mutations had a significantly greater risk of developing VM (HR 3.1), and the time to develop VM was significantly earlier in the EZH2 mutation group (31.5 months vs. 109.7 months, p = 0.008). Multivariate analysis revealed that EZH2 mutation (HR 2.73, p = 0.026) was an independent factor for VM after breast cancer surgery. There was no correlation between EZH2 mutations and BRCA1/2 mutations. Most of the patients (81.8%) in our cohort who developed VM carried the “c.1544A > G (p.K515R)” mutation. Compared with EZH2WT MDA-MB-231 cells, EZH2K515R MDA-MB-231 cells had greater colony formation rates (p

Abstract The global expansion of domesticated plant and animal species has profoundly impacted biodiversity and ecosystem functions. However, the spillover effect of non-native honey bees from mass-flowering crops into adjacent natural vegetation on pollination function within plant communities remains unclear. To address this, we conduct field experiments to investigate the ecological impacts of honey bees (Apis mellifera) and a mass-flowering crop (Brassica rapa var. oleifera) on pollinator communities, plant-pollinator interactions, and reproductive performance of wild plants in 48 pollinator-limited alpine grasslands. Our findings indicate that the transition of dominant pollinators from flies to honey bees enhances visitation fidelity of pollinator species and reconfigures pollination interactions due to an increase in competition between honey bees and native pollinator species. Additionally, honey bees increase, decrease or do not alter plant reproductive success, depending on the plant species. Here, we report the mixed effects of honey bees on pollination function in pollinator-limited alpine grasslands.

Abstract Ultrafast lasers have become powerful tools in various fields, and increasing their fundamental repetition rates to the gigahertz (GHz) level holds great potential for frontier scientific and industrial applications. Among various schemes, passive mode-locking in ultrashort-cavity fiber laser is promising for generating GHz ultrashort pulses (typically solitons), for its simplicity and robustness. However, its pulse energy is far lower than the critical value of the existing theory, leading to open questions on the mode-locking mechanism of GHz fiber lasers. Here, we study the passive mode-locking in GHz fiber lasers by exploring dynamic gain depletion and recovery (GDR) effect, and establish a theoretical model for comprehensively understanding its low-threshold mode-locking mechanism with multi-GHz fundamental repetition rates. Specifically, the GDR effect yields an effective interaction force and thereby binds multi-GHz solitons to form a counterpart of soliton crystals. It is found that the resulting collective behavior of the solitons effectively reduces the saturation energy of the gain fiber and permits orders of magnitude lower pulse energy for continuous-wave mode-locking (CWML). A new concept of quasi-single soliton defined in a strongly correlated length is also proposed to gain insight into the dynamics of soliton assembling, which enables the crossover from the present mode-locking theory to the existing one. Specifically, two distinguishing dynamics of Q-switched mode-locking that respectively exhibit rectangular- and Gaussian-shape envelopes are theoretically indicated and experimentally verified in the mode-locked GHz fiber laser through the measurements using both the standard real-time oscilloscope and emerging time-lens magnification. Based on the proposed criterion of CWML, we finally implement a GDR-mediated mode-locked fiber laser with an unprecedentedly high fundamental repetition rate of up to 21 GHz and a signal-to-noise ratio of 85.9 dB.

Abstract By analyzing e + e − annihilation data corresponding to an integrated luminosity of 2.93 fb −1 collected at a center-of-mass energy of 3.773 GeV with the BESIII detector, the first observation of the semileptonic decays D 0 → K S 0 π − π 0 e + ν e $$ {D}^0\to {K}_S^0{\pi}^{-}{\pi}^0{e}^{+}{\nu}_e $$ and D + → K S 0 π + π − e + ν e $$ {D}^{+}\to {K}_S^0{\pi}^{+}{\pi}^{-}{e}^{+}{\nu}_e $$ is reported. In the hypothesis that all events correspond to K 1(1270) decays, the branching fractions are measured to be B D 0 → K 1 1270 − → K S 0 π − π 0 e + ν e = 1.69 − 0.46 + 0.53 ± 0.15 × 10 − 4 $$ \mathcal{B}\left({D}^0\to {K}_1{(1270)}^{-}\left(\to {K}_S^0{\pi}^{-}{\pi}^0\right){e}^{+}{\nu}_e\right)=\left({1.69}_{-0.46}^{+0.53}\pm 0.15\right)\times {10}^{-4} $$ and B D + → K ¯ 1 1270 0 → K S 0 π + π − e + ν e = 1.47 − 0.40 + 0.45 ± 0.14 × 10 − 4 $$ \mathcal{B}\left({D}^{+}\to {\overline{K}}_1{(1270)}^0\left(\to {K}_S^0{\pi}^{+}{\pi}^{-}\right){e}^{+}{\nu}^e\right)=\left({1.47}_{-0.40}^{+0.45}\pm 0.14\right)\times {10}^{-4} $$ with statistical significance of 5.4σ and 5.6σ, respectively. When combined with measurements of the K 1(1270) → K + π − π decays, the absolute branching fractions are determined to be B D 0 → K 1 1270 − e + ν e = 1.08 − 0.13 − 0.10 + 0.14 + 0.08 ± 0.21 × 10 − 3 $$ \mathcal{B}\left({D}^0\to {K}_1{(1270)}^{-}{e}^{+}{\nu}_e\right)=\left({1.08}_{-0.13-0.10}^{+0.14+0.08}\pm 0.21\right)\times {10}^{-3} $$ and B D + → K ¯ 1 1270 0 e + ν e = 1.70 − 0.23 + 0.26 ± 0.13 ± 0.35 × 10 − 3 $$ \mathcal{B}\left({D}^{+}\to {\overline{K}}_1{(1270)}^0{e}^{+}{\nu}_e\right)=\left({1.70}_{-0.23}^{+0.26}\pm 0.13\pm 0.35\right)\times {10}^{-3} $$ . The first and second uncertainties are statistical and systematic, respectively, and the third uncertainties originate from the assumed branching fractions of the K 1(1270) → Kππ decays.

Abstract The aim of our study was to develop robust diagnostic and prognostic models for lung adenocarcinoma (LUAD) using machine learning (ML) techniques, focusing on early immune infiltration. Feature selection was performed on The Cancer Genome Atlas (TCGA) data using least absolute shrinkage and selection Operator (LASSO), random forest (RF), and support vector machine (SVM) algorithms. Six ML algorithms were employed to construct the diagnostic models, which were evaluated through receiver operating characteristic (ROC) curves, precision-recall curves (PRC), and classification error (CE), and validated on the GSE7670 dataset. Additionally, a lasso cox prognostic model was built on the TCGA-LUAD dataset and externally validated using independent Gene Expression Omnibus datasets (GSE30219, GSE31210, GSE50081, and GSE37745). Single-sample gene set enrichment analysis (ssGSEA) was performed to assess immune cell infiltration in stage I LUAD samples, revealing significant differences in immune cell types. These findings demonstrate a positive correlation between immune infiltration in stage I LUAD and Th2 cells, Tcm cells, and T helper cells, while a negative correlation was observed with Macrophages, Eosinophils, and Tem cells. These insights provide novel perspectives for clinical diagnosis and treatment of LUAD.

Abstract Computational models have made significant progress in predicting the effect of protein variants. However, deciphering numerous variants of uncertain significance (VUS) located within intrinsically disordered regions (IDRs) remains challenging. To address this issue, we introduce phase separation, which is tightly linked to IDRs, into the investigation of missense variants. Phase separation is vital for multiple physiological processes. By leveraging missense variants that alter phase separation propensity, we develop a machine learning approach named PSMutPred to predict the impact of missense mutations on phase separation. PSMutPred demonstrates robust performance in predicting missense variants that affect natural phase separation. In vitro experiments further underscore its validity. By applying PSMutPred on over 522,000 ClinVar missense variants, it significantly contributes to decoding the pathogenesis of disease variants, especially those in IDRs. Our work provides insights into the understanding of a vast number of VUSs in IDRs, expediting clinical interpretation and diagnosis.

Abstract Lymph node metastasis (LNM) is a typical marker in oral squamous cell carcinoma (OSCC) indicating poor prognosis. Pathological examination by artificial image acquisition and analysis, as the main diagnostic method for LNM, often takes a week or longer which may cause great anxiety of the patient and also retard timely treatment. However, there are few efficient fast LNM diagnosis methods in clinical applications currently. Our previous study profiled the proteomics of extracellular vesicles (EVs) derived from postoperative drainage fluid (PDF) and showed the potential of detecting specific EVs that expressed aspartate β-hydroxylase (ASPH) for LNM diagnosis in OSCC patients. Considering that the analysis of ASPH+ PDF-EVs is challenging due to their low abundance (counting less than 10% of total EVs in PDF) and the complex EV isolation process of ultra-centrifugation, we developed a facile platform containing two microfluidic chips filled with antibody-modified microbeads to isolate ASPH+ PDF-EVs, with both the capture and retrieval rate reaching around 90%. Clinical sample analysis based on our method revealed that a mean of 6 × 106 /mL ASPH+ PDF-EVs could be isolated from LNM+ OSCC patients compared to 2.5 × 106 /mL in LNM- OSCC ones. When combined with enzyme-linked immunosorbent assay (ELISA) technique that was commonly used in clinical laboratories in hospitals, this microfluidic platform could precisely distinguish postoperative OSCC patients with LNM or not in several hours, which were validated by a double-blind test containing 6 OSCC patients. We believe this strategy has promise for early diagnosis of LNM in postoperative OSCC patients and finally helps guiding timely and reasonable treatment in clinic.

Abstract Background Bisphosphonates (BPs) are widely used to inhibit excessive osteoclast activity. However, the potential to compromise bone defect healing has limited their broader application. To better understand the influence of BPs on bone regeneration, we established a bone grafting model with Zoledronate administration, aiming to deepen the understanding of bone remodeling and mineralization processes. Methods A bone grafting model was established in the distal femurs of male Sprague–Dawley rats. The experimental group received systemic administration of Zoledronate (ZOL, 0.2 mg/kg, administered twice). Histological analysis and immunohistochemistry (IHC) were employed to assess osteoblastic and macrophage activity, tartrate-resistant acid phosphatase (TRAP) staining was used to evaluate osteoclastogenesis. Mineralization was assessed through Micro-CT analysis, Raman spectroscopy, and back-scatter scanning electron microscopy (BSE-SEM). Additionally, the in vitro effects of ZOL on osteoblast and osteoclast activity were investigated to further elucidate its impact on bone regeneration. Results In vivo, the ZOL group showed increased bone mass, as observed in histological and radiological assessments. However, Micro-CT, Raman spectroscopy, and BSE-SEM detection revealed lower mineralization levels in ZOL group's regenerated bone. Acid-etched SEM analysis showed abnormal osteocyte characteristics in ZOL-group’s regenerated bone. Simultaneously, elevated osteopontin (OPN), F4/80 expression along with reduced TRAP expressing was found in the grafting region of ZOL group. In vitro, ZOL did not negatively impact osteogenetic activity (ALP, BMP4, OCN expression) at the tested concentrations (0.02–0.5 g/ml) but significantly impaired mineralization and inhibited osteoclast formation, even at the lowest concentration. Conclusions This study highlights a less recognized negative effect of ZOL on bone mineralization during bone regeneration. More research is needed to elucidate the underlying mechanism.

Abstract Introduction Since 2015, the Guanghua School of Stomatology has established an elective dental basic research course (EDBRC). To make all students benefit from the dental basic research course without causing excessive academic burden, the “flexible” compulsory dental basic research course (CDBRC) was settled in 2020. This study intends to introduce the “flexible” compulsory teaching module and assessment system of CDBRC, and analyze its effectiveness over 3 years. Materials and methods The grade point average (GPA), course pressure, level of basic research knowledge and skills, and students’ research achievements were collected and analyzed between EDBRC and CDBRC. The unpaired t test was used to analyze the difference. Results The “flexible” CDBRC has been successfully constructed with compulsory teaching module and hierarchical assessment system. The CDBRC has not caused significant course pressure to students compared with the EDBRC. Besides, the “flexible” CDBRC can improve the students’ GPA, basic research knowledge, and research achievements. Conclusions The “flexible” CDBRC can improve students’ academic performance and basic research abilities without causing significant course pressure, which can be conducted in dental schools with similar backgrounds. Trial registration Not applicable.