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Wenkai Chen,1,2,* Wenping Lin,3,* Naichun Yu,1,2,* Linlin Zhang,1,2,* Zuoxing Wu,2 Yongjie Chen,1,2 Zongguang Li,1,2 Fengqing Gong,1,2 Na Li,2 Xiaohui Chen,4 Xu He,3 Yue Wu,5 Xiangchen Zeng,1,2 Yuting Yueh,1,2 Ren Xu,2,4,6,* Guangrong Ji1,2,* 1Department of Orthopedic Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Xiamen Key Laboratory of Regeneration Medicine, Organ Transplantation Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 3Department of Spine Surgery, Shenzhen Pingle Orthopedic Hospital, Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, People’s Republic of China; 4Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China; 5Department of Pathology, Zhongshan Hospital, Xiamen University, Xiamen, People’s Republic of China; 6Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangrong Ji; Ren Xu, Department of Orthopedic Surgery, Xiang’an Hospital of Xiamen University, No. 2000, Xiang’an East Road, Xiang’an District, Xiamen, 361000, People’s Republic of China, Tel +86-15710667257, Fax +86592-2889000, Email jiguangrong@xmu.edu.cn; xuren526@xmu.edu.cnPurpose: To investigate induction of cell death in Osteosarcoma (OS) using the anti-tuberculosis drug, rifampicin, loaded into exosomes.Patients and Methods: BMSC-exosomes were isolated by ultracentrifugation and loaded ultrasonically with rifampicin. Nanoparticle exosome-rifampicin (EXO-RIF) was added to the OS cell-lines, 143B and MG63, in vitro, to observe the growth inhibitory effect. In vivo experiments were conducted by injecting fluorescently labeled EXO-RIF through the tail vein of 143B cell xenograft nude mice and tracking distribution. Therapeutic and toxic side-effects were analyzed systemically.Results: Sonication resulted in encapsulation of rifampicin into exosomes. Exosome treatment accelerated the entry of rifampicin into OS cells and enhanced the actions of rifampicin in inhibiting OS proliferation, migration and invasion. Cell cycle arrest at the G2/M phase was observed. Dynamin-related protein 1 (Drp1) was activated by EXO-RIF and caused mitochondrial lysis and apoptosis. Exosome treatment targeted rifampicin to the site of OS, causing OS apoptosis and improving mouse survival in vivo.Conclusion: The potent Drp1 agonist, rifampicin, induced OS apoptosis and exosome loading, improving OS targeting and mouse survival rates. EXO-RIF is a promising strategy for the treatment of diverse malignancies.Graphical Abstract: Keywords: bone tumor, drug delivery, exosomes, mesenchymal stem cells, survival

Southeast Asia has recently seen a number of developments and transformations that requires one to adjust to as the region’s skill requirements are evolving. For some these new changes brings new opportunities, however, for some greater levels of career adaptability is need to manage these new developments and transformations. The necessity of systematically reviewing articles on career adaptability in Southeast Asian nations is made apparent by this particular instance. A systematic review of career adaptability in Southeast Asia was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. About 22 eligible studies were identified. The findings indicated that the most prevalent groups in career adaptability studies were students, followed by working adults. Antecedents such as role modeling and cultural intelligence were identified. Four categories of predictors were identified such as personal, educational, career behavior, and environmental factor. Two categories were identified for the outcomes of career adaptability, namely, personal and career outcomes. Findings revealed that career adaptability offers several beneficial outcomes such as improved employability skills and life satisfaction. Discussion includes conditions faced in Southeast Asian countries and cultural differences. The dearth of studies within multicultural settings calls for further research in exploring career adaptability, as this broaden cultural understanding and awareness of educational and career behaviors pertaining to one’s career adaptability. This study offers important practical implications and recommendations for career counseling practices and policymakers in Southeast Asia that would potentially benefit students and working adults.

This study aimed to explore the experiences of Chinese EFL doctoral students in constructing their academic identities through critical argumentation in their thesis writing in an English as a Medium of Instruction (EMI) context. Data were collected through semi-structured interviews and document analysis. Narrative analysis was used to examine participants’ thesis writing to gain insights into their experiences of academic identity construction. The results revealed that Chinese EFL doctoral students face challenges in developing a critical voice and authorial position, synthesizing multiple sources, and positioning themselves rhetorically in their writing. Furthermore, the results open possibilities for a broader understanding of academic writing that values international graduate student’s educational background and cultural diversity in target English language discourse communities. While the narrative inquiry study on Chinese EFL doctoral students’ academic identity construction through critical argumentation is insightful, there are several limitations to consider, mainly due to the small sample size of only two female Chinese respondents.

The current study aims to examine lecturer readiness for English Medium Instruction (EMI) in higher educational institutions and the contextual influences of gender, age, academic qualification, teaching experience, EMI course teaching involvement, and EMI training. A quantitative research design was employed, and a survey questionnaire was completed by 227 lecturers (out of 250 invited participants) from private universities in Klang Valley, Malaysia to gauge self-ratings of personal knowledge, skills, abilities, and attitudes in educating EMI courses. The collected data were subsequently analysed via the Statistical Package for Social Sciences (SPSS) version 27.0 software before revealing the findings from the inferential statistics of the t-test and one-way analysis of variance (ANOVA) on lecturers' gender, age, academic qualification, teaching experience, EMI course teaching involvement, and EMI training. Resultantly, the important role of lecturers' knowledge, understanding, skills, abilities, and attitudes was highlighted to further enhance intercultural communicative competence in managing the increasingly diversified student body in EMI classrooms.

Metadiscourse refers to linguistic items, which functions to establish a connection with imagined readers of a text (Hyland, 2004). The use of metadiscourse has received much attention in various contexts, yet, little works are focusing on disciplinary metadiscourse, that has been carried out. To address this gap, this study explored, described, and compared the use of disciplinary metadiscourse by eight Malaysian first-year ESL doctoral students across four areas of study in education. The study reported in this article focuses on development or changes in writing over time. This study is quantitative in nature with a corpus-based approach utilizing AntConc (3.4.4) to examine the frequency of three dimensions of academic discourse in their writing, namely textual, engagement, and evaluative The results of this analysis show that (i) the engagement dimension (3.1%) was the lowest of all three dimensions in written work, reinforcing the argument that first-year ESL doctoral students are less experienced at using textual metadiscourse resources, and (ii) frequency of all three dimensions of academic discourse in their writing differs across time between first written drafts to the final written drafts. These are first-year ESL doctoral students, who are writing in different fields of educational research. The implication is that teaching and learning of disciplinary metadiscourse should involve explicit explanation, demonstration, and practice of its use, and development in the academic writing process. Academic writing; corpus analysis; ESL doctoral students; metadiscourse

Willingness to communicate (WTC) as introduced by McCroskey and Bear (1985) has developed and been perceived by many as a critical field. Unfortunately, there is a noticeable gap in research on the willingness to communicate (WTC) in English among ESL teachers in the Malaysian context. This study aims to investigate the ESL teachers’ willingness to communicate in English in terms of gender and school locations. The four constructs of communication in WTC are group discussions, interpersonal, public, and talking in meetings. Through both criterion and convenience sampling, 250 ESL teachers from twenty-five schools were chosen for this research. Survey questionnaire with a total of 20 items adopted from McCroskey (1992) was used as the data collection instrument. Findings reveal that ESL teachers' willingness to communicate in English is generally high and that the teachers were more willing to converse and exchange ideas orally in English during the meeting rather than in group or public. Female participants were significantly different in their overall willingness to communicate as they were more willing to communicate in groups and public. The within-group comparison also shows that school locations (urban and rural) affect ESL teachers' willingness to communicate in English. The findings also suggest that schools should encourage more ESL teachers to participate in activities such as debates, drama, public speaking, English language clubs/society, and empower them by providing professional development workshops or training.

X-linked retinoschisis (XLRS) is an inherited retinal disorder with severe retinoschisis and visual impairments. Multiomics approaches integrate single-cell RNA-sequencing (scRNA-seq) and spatiotemporal transcriptomics (ST) offering potential for dissecting transcriptional networks and revealing cell-cell interactions involved in biomolecular pathomechanisms. Herein, a multimodal approach is demonstrated combining high-throughput scRNA-seq and ST to elucidate XLRS-specific transcriptomic signatures in two XLRS-like models with retinal splitting phenotypes, including genetically engineered (Rs1 emR209C ) mice and patient-derived retinal organoids harboring the same patient-specific p.R209C mutation. Through multiomics transcriptomic analysis, the endoplasmic reticulum (ER) stress/eukryotic initiation factor 2 (eIF2) signaling, mTOR pathway, and the regulation of eIF4 and p70S6K pathways are identified as chronically enriched and highly conserved disease pathways between two XLRS-like models. Western blots and proteomics analysis validate the occurrence of unfolded protein responses, chronic eIF2α signaling activation, and chronic ER stress-induced apoptosis. Furthermore, therapeutic targeting of the chronic ER stress/eIF2α pathway activation synergistically enhances the efficacy of AAV-mediated RS1 gene delivery, ultimately improving bipolar cell integrity, postsynaptic transmission, disorganized retinal architecture, and electrophysiological responses. Collectively, the complex transcriptomic signatures obtained from Rs1 emR209C mice and patient-derived retinal organoids using the multiomics approach provide opportunities to unravel potential therapeutic targets for incurable retinal diseases, such as XLRS., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Cell shape reflects the spatial configuration resulting from the equilibrium of cellular and environmental signals and is considered a highly relevant indicator of its function and biological properties. For cancer cells, various physiological and environmental challenges, including chemotherapy, cause a cell state transition, which is accompanied by a continuous morphological alteration that is often extremely difficult to recognize even by direct microscopic inspection. To determine whether deep learning-based image analysis enables the detection of cell shape reflecting a crucial cell state alteration, we used the oral cancer cell line resistant to chemotherapy but having cell morphology nearly indiscernible from its non-resistant parental cells. We then implemented the automatic approach via deep learning methods based on EfficienNet-B3 models, along with over- and down-sampling techniques to determine whether image analysis of the Convolutional Neural Network (CNN) can accomplish three-class classification of non-cancer cells vs. cancer cells with and without chemoresistance. We also examine the capability of CNN-based image analysis to approximate the composition of chemoresistant cancer cells within a population. We show that the classification model achieves at least 98.33% accuracy by the CNN model trained with over- and down-sampling techniques. For heterogeneous populations, the best model can approximate the true proportions of non-chemoresistant and chemoresistant cancer cells with Root Mean Square Error (RMSE) reduced to 0.16 by Ensemble Learning (EL). In conclusion, our study demonstrates the potential of CNN models to identify altered cell shapes that are visually challenging to recognize, thus supporting future applications with this automatic approach to image analysis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hsieh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

NK2 Homeobox 1 (NKX2-1) is a well-characterized pathological marker that delineates lung adenocarcinoma (LUAD) progression. The advancement of LUAD is influenced by the immune tumor microenvironment through paracrine signaling. However, the involvement of NKX2-1 in modeling the tumor immune microenvironment is still unclear. Here, the downregulation of NKX2-1 is observed in high-grade LUAD. Meanwhile, single-cell RNA sequencing and Visium in situ capturing profiling revealed the recruitment and infiltration of neutrophils in orthotopic syngeneic tumors exhibiting strong cell-cell communication through the activation of CXCLs/CXCR2 signaling. The depletion of NKX2-1 triggered the expression and secretion of CXCL1, CXCL2, CXCL3, and CXCL5 in LUAD cells. Chemokine secretion is analyzed by chemokine array and validated by qRT-PCR. ATAC-seq revealed the restrictive regulation of NKX2-1 on the promoters of CXCL1, CXCL2, and CXCL5 genes. This phenomenon led to increased tumor growth, and conversely, tumor growth decreased when inhibited by the CXCR2 antagonist SB225002. This study unveils how NKX2-1 modulates the infiltration of tumor-promoting neutrophils by inhibiting CXCLs/CXCR2-dependent mechanisms. Hence, targeting CXCR2 in NKX2-1-low tumors is a potential antitumor therapy that may improve LUAD patient outcomes., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Major advances have been made in utilizing human-induced pluripotent stem cells (hiPSCs) for regenerative medicine. Nevertheless, the delivery and integration of hiPSCs into target tissues remain significant challenges, particularly in the context of retinal ganglion cell (RGC) restoration. In this study, we introduce a promising avenue for providing directional guidance to regenerated cells in the retina. First, we developed a technique for construction of gradient interfaces based on functionalized conductive polymers, which could be applied with various functionalized ehthylenedioxythiophene (EDOT) monomers. Using a tree-shaped channel encapsulated with a thin PDMS and a specially designed electrochemical chamber, gradient flow generation could be converted into a functionalized-PEDOT gradient film by cyclic voltammetry. The characteristics of the successfully fabricated gradient flow and surface were analyzed using fluorescent labels, time of flight secondary ion mass spectrometry (TOF-SIMS), and X-ray photoelectron spectroscopy (XPS). Remarkably, hiPSC-RGCs seeded on PEDOT exhibited improvements in neurite outgrowth, axon guidance and neuronal electrophysiology measurements. These results suggest that our novel gradient PEDOT may be used with hiPSC-based technologies as a potential biomedical engineering scaffold for functional restoration of RGCs in retinal degenerative diseases and optic neuropathies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hsiao-Hua Yu reports financial support was provided by National Science and Technology Council. Shih-Hwa Chiou reports financial support was provided by National Science and Technology Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: All-suture buttons (ASBs) and interference screw (IS) are commonly utilized in the inlay subpectoral biceps tendon tenodesis. However, the biomechanical characteristics of these two methods have not been compared directly. The aim of present study was to compare the biomechanical properties of ASB vs. IS for inlay subpectoral biceps tendon tenodesis in a human cadaveric model., Methods: Sixteen fresh-frozen human cadaveric shoulders were randomly divided into two experimental inlay biceps tenodesis groups: ASB or IS. After tenodesis, every specimen was preloaded at 5 N for 2 minutes, followed with a cyclic loading test from 5 to 70 N for 500 load cycles. Then the load-to-failure test was performed. Afterward, the humerus was placed in a cylinder tube and secured with anchoring cement. Lastly, a two-point bending test was performed to determine the strength of the humerus. Destructive axial force was applied, and the failure strength and displacement were recorded., Results: No difference in stiffness was observed between the two groups (ASB = 27.4 ± 3.5 N/mm vs. IS = 29.7 ± 3.0 N/mm; P = .270). Cyclic displacement was significantly greater in the ASB group (6.8 ± 2.6 mm) than the IS group (3.8 ± 1.1 mm; P = .021). In terms of failure load, there were no statistical differences among the two groups (P = .234). The ASB group was able to withstand significantly greater displacement (11.9 ± 1.6 mm) before failure than the IS group (7.8 ± 1.5 mm; P = .001). During the humeral bending test, the ASB group exhibited significantly greater maximal load (2354.8 ± 285.1 N vs. 2086.4 ± 296.1 N; P = .046) and larger displacement (17.8 ± 2.8 mm vs. 14.1 ± 2.8 mm; P = .027) before fracture., Conclusions: In inlay subpectoral bicep tenodesis, ASB fixation appears to offer comparable stiffness and failure load to that of IS fixation. Additionally, the ASB group exhibited greater resistance to load and displacement before humeral fracture. However, the ASB group did demonstrate increased cyclic displacement compared to IS group., (Copyright © 2024 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

The blood supply in the retina ensures photoreceptor function and maintains regular vision. Leber's hereditary optic neuropathy (LHON), caused by the mitochondrial DNA mutations that deteriorate complex I activity, is characterized by progressive vision loss. Although some reports indicated retinal vasculature abnormalities as one of the comorbidities in LHON, the paracrine influence of LHON-affected retinal ganglion cells (RGCs) on vascular endothelial cell physiology remains unclear. To address this, we established an in vitro model of mitochondrial complex I deficiency using induced pluripotent stem cell-derived RGCs (iPSC-RGCs) treated with a mitochondrial complex I inhibitor rotenone (Rot) to recapitulate LHON pathologies. The secretomes from Rot-treated iPSC-RGCs (Rot-iPSC-RGCs) were collected, and their treatment effect on human umbilical vein endothelial cells (HUVECs) was studied. Rot induced LHON-like characteristics in iPSC-RGCs, including decreased mitochondrial complex I activity and membrane potential, and increased mitochondrial reactive oxygen species (ROS) and apoptosis, leading to mitochondrial dysfunction. When HUVECs were exposed to conditioned media (CM) from Rot-iPSC-RGCs, the angiogenesis of HUVECs was suppressed compared to those treated with CM from control iPSC-RGCs (Ctrl-iPSC-RGCs). Angiogenesis-related proteins were altered in the secretomes from Rot-iPSC-RGC-derived CM, particularly angiopoietin, MMP-9, uPA, collagen XVIII, and VEGF were reduced. Notably, GeneMANIA analysis indicated that VEGFA emerged as the pivotal angiogenesis-related protein among the identified proteins secreted by health iPSC-RGCs but reduced in the secretomes from Rot-iPSC-RGCs. Quantitative real-time PCR and western blots confirmed the reduction of VEGFA at both transcription and translation levels, respectively. Our study reveals that Rot-iPSC-RGCs establish a microenvironment to diminish the angiogenic potential of vascular cells nearby, shedding light on the paracrine regulation of LHON-affected RGCs on retinal vasculature., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: To evaluate the correlation between suture contamination and rotator cuff tendon retear after arthroscopic rotator cuff repair., Methods: Patients undergoing primary arthroscopic rotator cuff repair from April 1, 2020, to September 30, 2022, were enrolled. Those younger than 18 years, with a history of shoulder surgeries or shoulder infection episodes, or who declined participation were excluded. A 5-cm section of the first-cut suture, originating from the anchor eyelet ends, in each rotator cuff repair surgery was subjected to bacteria culture and polymerase chain reaction analysis. Patients with positive culture findings were matched 1:1 to those with negative culture reports based on age, sex, tear size as well as involved tendons, preoperative fatty infiltration grade (Goutallier grade), and preoperative muscle atrophy grade (Warner score). Postoperative rotator cuff tendon retear assessments were conducted at the 6-month mark using the Sugaya classification via magnetic resonance imaging. The Wilcoxon signed-rank test was used for matched-pair comparisons between the groups., Results: A total of 141 patients (60 men and 81 women) with a mean age of 61.0 ± 8 years were finally enrolled. Twenty-six patients (18 men and 8 women) had a positive culture, while 115 patients (42 men and 73 women) had a negative culture. After the propensity score matching process, 24 culture-negative patients (16 men and 8 women) were selected as the culture-negative group. Age, fatty infiltration grade, and muscle atrophy grade were not significantly different between matched groups. The retear grade in the culture-positive group was significantly higher than that in the culture-negative group (P = .020) under the matched-pair comparison. Cutibacterium acnes was the most prevalent bacterial species responsible for suture contamination., Conclusions: The matched-pair analysis revealed that the presence of bacterial contamination on sutures was associated with a higher risk of retear on magnetic resonance imaging following arthroscopic rotator cuff repair., Level of Evidence: Level III, retrospective cohort study., Competing Interests: Disclosures The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was funded by National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH 10904008 and 11101005). All authors (C-K.H., K-L.H., F-C.K., Y.C., Y-T.L., P-F.T., P-L.C., W-R.S.) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Background: To identify and quantify the factors associated with the reparability of rotator cuff tears (RCTs)., Methods: PubMed, Scopus, and Web of Science databases were searched for clinical studies published in English focusing on RCT reparability by using the keywords "rotator cuff tear" and "reparability". A meta-analysis was conducted if ≥3 studies examined the same factor and provided enough data to assess RCT reparability. Quality assessment was completed using the quality assessment of diagnostic accuracy studies tool., Results: Eighteen studies (2700 patients) were enrolled and 26 factors were included in the meta-analysis. The dichotomous variables associated with irreparability were Patte stage 3 (odds ratio (OR): 8.0, 95% confidence interval [CI]: 4.3-14.9), massive tear vs. large tear (OR: 3.1, 95% CI: 1.3-7.2), Goutallier stage for each tendon, and tangent sign (OR: 11.1, 95% CI: 4.3-28.4). The continuous variables associated with irreparability were age (mean difference (MD): 3.25, 95% CI: 1.4-5.1), mediolateral tear size (MD: 12.3, 95% CI: 5.8-18.9), anteroposterior tear size (MD: 10.4, 95% CI: 5.2-15.6), acromiohumeral distance on X-ray (MD: -2.3, 95% CI: -3.0 to -1.6) and magnetic resonance imaging (MD: -1.8, 95% CI: -2.8 to -0.9), and inferior glenohumeral distance on magnetic resonance imaging (MD: 2.2, 95% CI: 1.4-3.0)., Conclusion: This study revealed that older age, larger tear size, severe fatty infiltration, muscle atrophy, and advanced superior migration of the humeral head were strongly associated with irreparable RCTs. Conversely, clinical symptoms provided limited information for predicting reparability. Additionally, the tangent sign emerged as a powerful and simple tool for individual prediction, and several quantitative scoring systems also proved useful., (Copyright © 2024 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate an extended self-adapting nnU-Net framework for detecting and segmenting brain metastases (BM) on magnetic resonance imaging (MRI)., Methods and Materials: Six different nnU-Net systems with adaptive data sampling, adaptive Dice loss, or different patch/batch sizes were trained and tested for detecting and segmenting intraparenchymal BM with a size ≥2 mm on 3 Dimensional (3D) post-Gd T1-weighted MRI volumes using 2092 patients from 7 institutions (1712, 195, and 185 patients for training, validation, and testing, respectively). Gross tumor volumes of BM delineated by physicians for stereotactic radiosurgery were collected retrospectively and curated at each institute. Additional centralized data curation was carried out to create gross tumor volumes of uncontoured BM by 2 radiologists to improve the accuracy of ground truth. The training data set was augmented with synthetic BMs of 1025 MRI volumes using a 3D generative pipeline. BM detection was evaluated by lesion-level sensitivity and false-positive (FP) rate. BM segmentation was assessed by lesion-level Dice similarity coefficient, 95-percentile Hausdorff distance, and average Hausdorff distance (HD). The performances were assessed across different BM sizes. Additional testing was performed using a second data set of 206 patients., Results: Of the 6 nnU-Net systems, the nnU-Net with adaptive Dice loss achieved the best detection and segmentation performance on the first testing data set. At an FP rate of 0.65 ± 1.17, overall sensitivity was 0.904 for all sizes of BM, 0.966 for BM ≥0.1 cm 3 , and 0.824 for BM <0.1 cm 3 . Mean values of Dice similarity coefficient, 95-percentile Hausdorff distance, and average HD of all detected BMs were 0.758, 1.45, and 0.23 mm, respectively. Performances on the second testing data set achieved a sensitivity of 0.907 at an FP rate of 0.57 ± 0.85 for all BM sizes, and an average HD of 0.33 mm for all detected BM., Conclusions: Our proposed extension of the self-configuring nnU-Net framework substantially improved small BM detection sensitivity while maintaining a controlled FP rate. Clinical utility of the extended nnU-Net model for assisting early BM detection and stereotactic radiosurgery planning will be investigated., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Blood flow restriction (BFR) resistance training has demonstrated efficacy in promoting strength gains beneficial for rehabilitation. Yet, the distinct functional advantages of BFR strength training using high-load and low-load protocols remain unclear. This study explored the behavioral and neurophysiological mechanisms that explain the differing effects after volume-matched high-load and low-load BFR training., Methods: Twenty-eight healthy participants were randomly assigned to the high-load blood flow restriction (BFR-HL, n = 14) and low-load blood flow restriction (BFR-LL, n = 14) groups. They underwent 3 weeks of BFR training for isometric wrist extension at intensities of 25% or 75% of maximal voluntary contraction (MVC) with matched training volume. Pre- and post-tests included MVC and trapezoidal force-tracking tests (0-75%-0% MVC) with multi-channel surface electromyography (EMG) from the extensor digitorum., Results: The BFR-HL group exhibited a greater strength gain than that of the BFR-LL group after training (BFR&#95;HL: 26.96 ± 16.33% vs. BFR&#95;LL: 11.16 ± 15.34%)(p = 0.020). However, only the BFR-LL group showed improvement in force steadiness for tracking performance in the post-test (p = 0.004), indicated by a smaller normalized change in force fluctuations compared to the BFR-HL group (p = 0.048). After training, the BFR-HL group activated motor units (MUs) with higher recruitment thresholds (p < 0.001) and longer inter-spike intervals (p = 0.002), contrary to the BFR-LL group, who activated MUs with lower recruitment thresholds (p < 0.001) and shorter inter-spike intervals (p < 0.001) during force-tracking. The discharge variability (p < 0.003) and common drive index (p < 0.002) of MUs were consistently reduced with training for the two groups., Conclusions: BFR-HL training led to greater strength gains, while BFR-LL training better improved force precision control due to activation of MUs with lower recruitment thresholds and higher discharge rates., (© 2024. The Author(s).)

Background and Objectives : This paper evaluates the efficacy and safety of ureteral access sheath (UAS) utilization in retrograde intrarenal surgery (RIRS). Materials and Methods : We searched PubMed, Embase, and the Cochrane Library up to 30 August 2023. The inclusion criteria comprised English-language original studies on RIRS with or without UAS in humans. The primary outcome was SFR, while the secondary outcomes included intraoperative and postoperative complications, the lengths of the operation and the hospitalization period, and the duration of the fluoroscopy. Subgroup analyses and a sensitivity analysis were performed. Publication bias was assessed using funnel plots and Egger's regression tests. Dichotomous variables were analyzed using odds ratios (ORs) with 95% confidence intervals (CIs), while mean differences (MDs) were employed for continuous variables. Results : We included 22 studies in our analysis. These spanned 2001 to 2023, involving 12,993 patients and 13,293 procedures. No significant difference in SFR was observed between the UAS and non-UAS groups (OR = 0.90, 95% CI 0.63-1.30, p = 0.59). Intraoperative (OR = 1.13, 95% CI 0.75-1.69, p = 0.5) and postoperative complications (OR = 1.29, 95% CI 0.89-1.87, p = 0.18) did not significantly differ between the groups. UAS usage increased operation times (MD = 8.30, 95% CI 2.51-14.10, p = 0.005) and fluoroscopy times (MD = 5.73, 95% CI 4.55-6.90, p < 0.001). No publication bias was detected for any outcome. Conclusions : In RIRS, UAS usage did not significantly affect SFR, complications, or hospitalization time. However, it increased operation time and fluoroscopy time. Routine UAS usage is not supported, and decisions should be patient-specific. Further studies with larger sample sizes and standardized assessments are needed to refine UAS utilization in RIRS.

Coronaviruses (CoVs) are enveloped single-stranded RNA viruses that predominantly attack the human respiratory system. In recent decades, several deadly human CoVs, including SARS-CoV, SARS-CoV-2, and MERS-CoV, have brought great impact on public health and economics. However, their high infectivity and the demand for high biosafety level facilities restrict the pathogenesis research of CoV infection. Exacerbated inflammatory cell infiltration is associated with poor prognosis in CoV-associated diseases. In this study, we used human CoV 229E (HCoV-229E), a CoV associated with relatively fewer biohazards, to investigate the pathogenesis of CoV infection and the regulation of neutrophil functions by CoV-infected lung cells. Induced pluripotent stem cell (iPSC)-derived alveolar epithelial type II cells (iAECIIs) exhibiting specific biomarkers and phenotypes were employed as an experimental model for CoV infection. After infection, the detection of dsRNA, S, and N proteins validated the infection of iAECIIs with HCoV-229E. The culture medium conditioned by the infected iAECIIs promoted the migration of neutrophils as well as their adhesion to the infected iAECIIs. Cytokine array revealed the elevated secretion of cytokines associated with chemotaxis and adhesion into the conditioned media from the infected iAECIIs. The importance of IL-8 secretion and ICAM-1 expression for neutrophil migration and adhesion, respectively, was demonstrated by using neutralizing antibodies. Moreover, next-generation sequencing analysis of the transcriptome revealed the upregulation of genes associated with cytokine signaling. To summarize, we established an in vitro model of CoV infection that can be applied for the study of the immune system perturbations during severe coronaviral disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Plant heterotrimeric G proteins respond to various environmental stresses, including high salinity. It is known that Gβ subunit AGB1 functions in maintaining local and systemic Na + /K + homeostasis to accommodate ionic toxicity under salt stress. However, whether AGB1 contributes to regulating gene expression for seedling's survival under high salinity remains unclear., Results: We showed that AGB1-Venus localized to nuclei when facing excessive salt, and the induction of a set of bZIP17-dependent salt stress-responsive genes was reduced in the agb1 mutant. We confirmed both genetic and physical interactions of AGB1 and bZIP17 in plant salinity response by comparing salt responses in the single and double mutants of agb1 and bzip17 and by BiFC assay, respectively. In addition, we show that AGB1 depletion decreases nuclei-localization of transgenic mRFP-bZIP17 under salt stress, as shown in s1p s2p double mutant in the Agrobacteria-mediated transient mRFP-bZIP17 expression in young seedlings., Conclusions: Our results indicate that AGB1 functions in S1P and/or S2P-mediated proteolytic processing of bZIP17 under salt stress to regulate the induction of salinity-responsive gene expression., (© 2024. The Author(s).)

Introduction: Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is related to the pathogenesis of various retinopathies including age-related macular degeneration (AMD). Oxidative stress is the major factor that induces degeneration of RPE cells associated with the etiology of AMD., Objectives: Sodium iodate (NaIO 3 ) generates intracellular reactive oxygen species (ROS) and is widely used to establish a model of AMD due to the selective induction of retinal degeneration. This study was performed to clarify the effects of multiple NaIO 3 -stimulated signaling pathways on EMT in RPE cells., Methods: The EMT characteristics in NaIO 3 -treated human ARPE-19 cells and RPE cells of the mouse eyes were analyzed. Multiple oxidative stress-induced modulators were investigated and the effects of pre-treatment with Ca 2+ chelator, extracellular signal-related kinase (ERK) inhibitor, or epidermal growth factor receptor (EGFR) inhibitor on NaIO 3 -induced EMT were determined. The efficacy of post-treatment with ERK inhibitor on the regulation of NaIO 3 -induced signaling pathways was dissected and its role in retinal thickness and morphology was evaluated by using histological cross-sections and spectral domain optical coherence tomography., Results: We found that NaIO 3 induced EMT in ARPE-19 cells and in RPE cells of the mouse eyes. The intracellular ROS, Ca 2+ , endoplasmic reticulum (ER) stress marker, phospho-ERK, and phospho-EGFR were increased in NaIO 3 -stimulated cells. Our results showed that pre-treatment with Ca 2+ chelator, ERK inhibitor, or EGFR inhibitor decreased NaIO 3 -induced EMT, interestingly, the inhibition of ERK displayed the most prominent effect. Furthermore, post-treatment with FR180204, a specific ERK inhibitor, reduced intracellular ROS and Ca 2+ levels, downregulated phospho-EGFR and ER stress marker, attenuated EMT of RPE cells, and prevented structural disorder of the retina induced by NaIO 3 ., Conclusions: ERK is a crucial regulator of multiple NaIO 3 -induced signaling pathways that coordinate EMT program in RPE cells. Inhibition of ERK may be a potential therapeutic strategy for the treatment of AMD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Background: Modifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required., Methods: Here we generated induced pluripotent stem cell-derived airway organoids (iPSC-AOs) that resemble the human native airway. Single-cell sequencing (ScRNAseq) and microscopic examination verified the cellular heterogeneity and microstructures of iPSC-AOs, respectively. We subjected iPSC-AOs to SARS-CoV-2 infection and investigated the treatment effect of lipid modifiers statin drugs on viral pathogenesis, gene expression, and the intracellular trafficking of the SARS-CoV-2 entry receptor angiotensin-converting enzyme-2 (ACE-2)., Results: In SARS-CoV-2-infected iPSC-AOs, immunofluorescence staining detected the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and bioinformatics analysis further showed the aberrant enrichment of lipid-associated pathways. In addition, SARS-CoV-2 hijacked the host RNA replication machinery and generated the new isoforms of a high-density lipoprotein constituent apolipoprotein A1 (APOA1) and the virus-scavenging protein deleted in malignant brain tumors 1 (DMBT1). Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2) and decreased N protein expression, leading to the reduction of SARS-CoV-2 entry and replication. The same lipid modifications suppressed the entry of luciferase-expressing SARS-CoV-2 pseudoviruses containing the S proteins derived from different SARS-CoV-2 variants, i.e. wild-type, alpha, delta, and omicron., Conclusions: Together, our data demonstrated that modifications of lipid pathways restrict SARS-CoV-2 propagation in the iPSC-AOs, which the inhibition is speculated through the translocation of ACE2 from the cell membrane to the cytosol. Considering the highly frequent mutation and generation of SARS-CoV-2 variants, targeting host metabolisms of cholesterol or other lipids may represent an alternative approach against SARS-CoV-2 infection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Background: In the post-coronavirus disease 2019 (COVID-19) era, remote diagnosis and precision preventive medicine have emerged as pivotal clinical medicine applications. This study aims to develop a digital health-monitoring tool that utilizes electronic medical records (EMRs) as the foundation for performing a non-random correlation analysis among different comorbidity patterns for heart failure (HF)., Methods: Novel similarity indices, including proportional Jaccard index (PJI), multiplication of the odds ratio proportional Jaccard index (OPJI), and alpha proportional Jaccard index (APJI), provide a fundamental framework for constructing machine learning models to predict the risk conditions associated with HF., Results: Our models were constructed for different age groups and sexes and yielded accurate predictions of high-risk HF across demographics. The results indicated that the optimal prediction model achieved a notable accuracy of 82.1% and an area under the curve (AUC) of 0.878., Conclusions: Our noninvasive HF risk prediction system is based on historical EMRs and provides a practical approach. The proposed indices provided simple and straightforward comparative indicators of comorbidity pattern matching within individual EMRs. All source codes developed for our noninvasive prediction models can be retrieved from GitHub., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Purpose: This study aimed to evaluate the effects and interactions of training level and different joints on the outcomes of cadaveric arthroscopic training courses for orthopaedic residents., Methods: This prospective study enrolled 16 orthopaedic residents who voluntarily participated in a cadaveric training programme involving the shoulder, elbow, wrist, knee and ankle joints. Outcomes were quantitatively assessed using task-specific checklists and the Arthroscopic Surgery Skill Evaluation Tool. Two-way analysis of variance (ANOVA) was conducted to determine the significance of the interactions between joint and years of training., Results: Resident scores significantly increased after the dedicated lectures in all five joints ( p  = 0.003 for the shoulder module, p  < 0.001 for the other joints). Two-way ANOVA revealed that the progress made after the dedicated lectures was significantly impacted by the joint ( p  = 0.006) and training level × joint interaction ( p  = 0.005) but not by the training level ( p  = 0.47). The simple effect of the joint was examined using Sidak's multiple comparison test. Among junior residents, the dedicated lectures resulted in more substantial progress in elbow and wrist arthroscopy when compared to shoulder arthroscopy ( p  = 0.020 and p  = 0.043, respectively)., Conclusions: The results suggest that, in cadaveric arthroscopic training courses for orthopaedic residents, training outcomes are primarily impacted by the specific joint being trained rather than the training level. Specifically, junior residents demonstrated greater improvement with training in procedures that are less commonly encountered during on-the-job training, such as elbow and wrist arthroscopy., Clinical Relevance: These findings suggest the need to prioritise wrist and elbow arthroscopic training for junior residents to optimise educational outcomes., Level of Evidence: Level III., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: Mesenchymal stem cells (MSCs) have promising potential in clinical application, whereas their limited amount and sources hinder their bioavailability. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have become prominent options in regenerative medicine as both possess the ability to differentiate into MSCs., Methods: Recently, our research team has successfully developed human leukocyte antigen (HLA)-homozygous iPSC cell lines with high immune compatibility, covering 13.5% of the Taiwanese population. As we deepen our understanding of the differences between these ESCs and HLA-homozygous iPSCs, our study focused on morphological observations and flow cytometry analysis of specific surface marker proteins during the differentiation of ESCs and iPSCs into MSCs., Results: The results showed no significant differences between the two pluripotent stem cells, and both of them demonstrated the equivalent ability to further differentiate into adipose, cartilage, and bone cells., Conclusion: Our research revealed that these iPSCs with high immune compatibility exhibit the same differentiation potential as ESCs, enhancing the future applicability of highly immune-compatible iPSCs., Competing Interests: Conflicts of interest: Dr. Shih-Hwa Chiou, an editorial board member at Journal of the Chinese Medical Association , had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Background: Leber hereditary optic neuropathy (LHON) is mainly the degeneration of retinal ganglion cells (RGCs) associated with high apoptosis and reactive oxygen species (ROS) levels, which is accepted to be caused by the mutations in the subunits of complex I of the mitochondrial electron transport chain. The treatment is still infant while efforts of correcting genes or using antioxidants do not bring good and consistent results. Unaffected carrier carries LHON mutation but shows normal phenotype, suggesting that the disease's pathogenesis is complex, in which secondary factors exist and cooperate with the primary complex I dysfunction., Methods: Using LHON patient-specific induced pluripotent stem cells (iPSCs) as the in vitro disease model, we previously demonstrated that circRNA&#95;0087207 had the most significantly higher expression level in the LHON patient-iPSC-derived RGCs compared with the unaffected carrier-iPSC-derived RGCs. To elaborate the underlying pathologies regulated by circRNA&#95;008720 mechanistically, bioinformatics analysis was conducted and elucidated that circRNA&#95;0087207 could act as a sponge of miR-548c-3p and modulate PLSCR1/TGFB2 levels in ND4 mutation-carrying LHON patient-iPSC-derived RGCs., Results: Using LHON iPSC-derived RGCs as the disease-based platform, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on targeted mRNA of miR-548c-3p showed the connection with apoptosis, suggesting downregulation of miR548c-3p contributes to the apoptosis of LHON patient RGCs., Conclusion: We showed that the downregulation of miR548c-3p plays a critical role in modulating cellular dysfunction and the apoptotic program of RGCs in LHON., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Dual-targeting anticancer agents 4-29 are designed by combining the structural features of purine-type microtubule-disrupting compounds and HDAC inhibitors. A library of the conjugate compounds connected by appropriate linkers was synthesized and found to possess HDACs inhibitory activity and render microtubule fragmentation by activating katanin, a microtubule-severing protein. Among various zinc-binding groups, hydroxamic acid shows the highest inhibitory activity of Class I HDACs, which was also reconfirmed by three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore prediction. The purine-hydroxamate conjugates exhibit enhanced cytotoxicity against MDA-MB231 breast cancer cells, H1975 lung cancer cells, and various clinical isolated non-small-cell lung cancer cells with different epidermal growth factor receptor (EGFR) status. Pyridyl substituents could be used to replace the C2 and N9 phenyl moieties in the purine-type scaffold, which can help to improve the solubility under physiological conditions, thus increasing cytotoxicity. In mice treated with the purine-hydroxamate conjugates, the tumor growth rate was significantly reduced without causing toxic effects. Our study demonstrates the potential of the dual-targeting purine-hydroxamate compounds for cancer monotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: The potential of induced pluripotent stem cells (iPSCs) in revolutionizing regenerative medicine cannot be overstated. iPSCs offer a profound opportunity for therapies involving cell replacement, disease modeling, and cell transplantation. However, the widespread application of iPSC cellular therapy faces hurdles, including the imperative to regulate iPSC differentiation rigorously and the inherent genetic disparities among individuals. To address these challenges, the concept of iPSC super donors emerges, holding exceptional genetic attributes and advantageous traits. These super donors serve as a wellspring of standardized, high-quality cell sources, mitigating inter-individual variations and augmenting the efficacy of therapy., Methods: In pursuit of this goal, our study embarked on the establishment of iPSC cell lines specifically sourced from donors possessing the HLA type (A33:03-B58:01-DRB1*03:01). The reprogramming process was meticulously executed, resulting in the successful generation of iPSC lines from these carefully selected donors. Subsequently, an extensive characterization was conducted to comprehensively understand the features and attributes of these iPSC lines., Results: The outcomes of our research were highly promising. The reprogramming efforts culminated in the generation of iPSC lines from donors with the specified HLA type. These iPSC lines displayed a range of distinctive characteristics that were thoroughly examined and documented. This successful generation of iPSC lines from super donors possessing advantageous genetic traits represents a significant stride towards the realization of their potential in therapeutic applications., Conclusion: In summary, our study marks a crucial milestone in the realm of regenerative medicine. The establishment of iPSC lines from super donors with specific HLA types signifies a paradigm shift in addressing challenges related to iPSC cellular therapy. The standardized and high-quality cell sources derived from these super donors hold immense potential for various therapeutic applications. As we move forward, these findings provide a solid foundation for further research and development, ultimately propelling the field of regenerative medicine toward new horizons of efficacy and accessibility., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Secondary polycythemia is a paraneoplastic syndrome observed in tumors with excessive erythropoietin (EPO) production. Renal cell carcinoma (RCC) and cerebellar hemangioblastoma are the 2 most well-known tumors to induce secondary polycythemia. Hemangioblastomas occurring in the kidney are rare. In this work we present a case of renal hemangioblastoma that caused erythrocytosis in a 19-year-old man. We demonstrated intratumoural EPO production by immunohistochemistry, and conducted whole-exome sequencing to evaluate possible genetic alterations that reported to induce tumor-related polycythemia. In spite of an indolent clinical behavior, renal hemangioblastoma is difficult to differentiate from RCC not only clinically, but also histopathologically. Given that RCC is the most well-known renal tumor to induce erythrocytosis, the uncommon manifestation of polycythemia in renal hemangioblastoma, as shown in our case, can cause further diagnostic challenges. Renal hemangioblastoma should be listed in the differential diagnoses of renal tumors presenting with erythrocytosis, apart from the most common RCC., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: A coracoclavicular (CC) fixation technique using an all-suture anchor with the assistance of fluoroscopy can prevent iatrogenic anterior deltoid detachment from the clavicle; however, soft anchor pullout has been reported as a complication., Purpose: To compare the biomechanical properties of conventional metallic and all-suture anchors for CC suture fixation., Study Design: Controlled laboratory study., Methods: A total of 24 fresh-frozen cadaveric specimens were divided into 2 groups: metal anchor group (group M) and all-suture anchor group (group A). In group M, 5.0-mm metallic suture anchors were used for CC fixation, whereas 2.8-mm all-suture anchors were used in group A. The prepared specimens were mounted on a materials testing machine. After preconditioning at 0 to 20 N for 10 cycles, the specimens were subjected to cyclic loading from 20 to 70 N for 1000 cycles. Finally, all the specimens were loaded to failure. Cyclic elongation, linear stiffness, ultimate load, and failure modes were recorded, and the Mann-Whitney U test was used to compare nonparametric parameters between the 2 groups., Results: All of the specimens completed the cyclic loading test. The elongation after cyclic loading in group M (1.6 ± 0.6 mm) was significantly smaller compared with that in group A (2.5 ± 1.2 mm) ( P = .02). No between-group differences were found in linear stiffness (42 ± 17 N/mm in group M and 41 ± 17 N/mm in group A). The ultimate failure load in group M (263 ± 66 N) was significantly greater than that in group A (177 ± 76 N) ( P = .02). All specimens failed because of suture anchor pullout., Conclusion: The use of all-suture anchors in CC fixation resulted in significantly greater cyclic displacement and smaller ultimate failure load than that of metallic anchors., Clinical Relevance: Understanding the most biomechanically sound suture anchor may assist in lowering the risk of clinical failure in CC fixation and repair., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: Research support was received from Skeleton Materials and Bio-compatibility Core Lab, Research Center of Clinical Medicine, National Cheng Kung University Hospital (NCKUH-11204010). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval was not sought for the present study., (© The Author(s) 2024.)

A maternal inheritance disorder called Leber's hereditary optic neuropathy (LHON) is the most common primary mitochondrial deoxyribonucleic acid (DNA) disorder. In most studies, there are more male patients than female patients, which contradicts the usual pattern in mitochondrial hereditary diseases. This suggests that nuclear DNA (nDNA) may influence the degeneration of retinal ganglion cells (RGCs) in LHON. The primary cause of this is dysfunction in complex I of the electron transport chain, leading to ineffective adenosine triphosphate (ATP) production. In addition to MT-ND4 or MT-ND1 mutations, genes such as PRICKLE3 , YARS2 , and DNAJC30 , which come from nDNA, also play a role in LHON. These three genes affect the electron chain transport differently. PRICKLE3 interacts with ATP synthase (complex V) at Xp11.23, while YARS2 is a tyrosyl-tRNA synthetase 2 involved in mitochondria . DNAJC30 mutations result in autosomal recessive LHON (arLHON). Understanding how genes impact the disease is crucial for developing new treatments. Idebenone has been approved for treating LHON and has shown safety and efficacy in clinical trials. Mesenchymal stem cell-based therapy has also emerged as a potential treatment for LHON by transferring mitochondria into target cells. Gene therapy research focuses on specific gene mutations, and the wild-type ND4 gene target in the adeno-associated viruses (AAV) vector has shown promise in clinical trials as a potential treatment for LHON., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)