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ULK1 is crucial for initiating autophagosome formation and its activity is tightly regulated by post-translational modifications and protein-protein interactions. In the present study, we demonstrate that TMEM189 (Transmembrane protein 189), also known as plasmanylethanolamine desaturase 1 (PEDS1), negatively regulates the proteostasis of ULK1 and autophagy activity. In TMEM189-overexpressed cells, the formation of autophagesome is impaired, while TMEM189 knockdown increases cell autophagy. Further investigation reveals that TMEM189 interacts with and increases the instability of ULK1, as well as decreases its kinase activities. The TMEM189 N-terminal domain is required for the interaction with ULK1. Additionally, TMEM189 overexpression can disrupt the interaction between ULK1 and TRAF6, profoundly impairs K63-linked polyubiquitination of ULK1 and self-association, leading to the decrease of ULK1 stability. Moreover, in vitro and in vivo experiments suggest that TMEM189 deficiency results in the inhibition of tumorigenicity of gastric cancer. Our findings provide a new insight into the molecular regulation of autophagy and laboratory evidence for investigating the physiological and pathological roles of TMEM189.

Patients with lung metastasis of colorectal cancer typically have a poor prognosis. Therefore, establishing an effective screening and diagnosis model is paramount. Our study seeks to construct and verify a predictive model utilizing machine learning (ML) that can evaluate the risk of lung metastasis with newly diagnosed colorectal cancer (CRC) using Shapley Additive exPlanations (SHAP). Using the Surveillance, Epidemiology, and End Results database, 39,674 were extracted for model development, all of whom had been pathologically diagnosed with CRC. The data spans from 2010 to 2015. Our study has constructed seven ML algorithms based on the data mentioned above, including Random Forest (RF), Decision Tree, Support Vector Machine, Naive Bayes, K-Nearest Neighbor, eXtreme Gradient Boosting, and Gradient Boosting Machine. We selected the best algorithm and visualized it using SHAP. We conducted a validation of the model utilizing data from a Chinese hospital to assess its practicality. Based on this, we have constructed an open web calculator. 39,674 patient data were included in our study, among whom 1369 (3.5%) presented with distant lung metastasis. The Random Forest (RF) algorithm demonstrated the highest predictive capability within the internal test set (AUC of 0.980, AUPR of 0.941). Furthermore, the random forest algorithm also exhibited excellent performance in external validation sets. Meanwhile, we have also established a web calculator ( http://121.43.117.60:8003/ ). The RF algorithm has demonstrated excellent predictive performance. It can assist clinicians in devising more personalized treatment plans.

The E3 ubiquitin ligase RING finger protein 115 (RNF115), also known as breast cancer-associated gene 2 (BCA2), has been linked with the growth of some cancers and immune regulation, which is negatively correlated with prognosis. Here, it is demonstrated that the RNF115 deletion can protect mice from acute liver injury (ALI) induced by the treatment of lipopolysaccharide (LPS)/D-galactosamine (D-GalN), as evidenced by decreased levels of alanine aminotransaminase, aspartate transaminase, inflammatory cytokines (e.g., tumor necrosis factor α and interleukin-6), chemokines (e.g., MCP1/CCL2) and inflammatory cell (e.g., monocytes and neutrophils) infiltration. Moreover, it was found that the autophagy activity in Rnf115 −/− livers was increased, which resulted in the removal of damaged mitochondria and hepatocyte apoptosis. However, the administration of adeno-associated virus Rnf115 or autophagy inhibitor 3-MA impaired autophagy and aggravated liver injury in Rnf115 −/− mice with ALI. Further experiments proved that RNF115 interacts with LC3B, downregulates LC3B protein levels and cell autophagy. Additionally, Rnf115 deletion inhibited M1 type macrophage activation via NF-κB and Jnk signaling pathways. Elimination of macrophages narrowed the difference in liver damage between Rnf115 +/+ and Rnf115 −/− mice, indicating that macrophages were linked in the ALI induced by LPS/D-GalN. Collectively, for the first time, we have proved that Rnf115 inactivation ameliorated LPS/D-GalN-induced ALI in mice by promoting autophagy and attenuating inflammatory responses. This study provides new evidence for the involvement of autophagy mechanisms in the protection against acute liver injury.

[1] Ring finger protein 115 (RNF115) is a RAB7 target protein also known as breast cancer-associated gene 2 (BCA2). In the present study, we report that RNF115 is a negative regulator of basal autophagy in hepatoma cells. Inactivating RNF115 promoted autophagic activity by enhancing RAB7–HOPS complex binding and ATG14 activities [Figure 1], which inhibited hepatoma cell growth in vivo and in vitro and provided an experimental foundation for hepatocellular carcinoma treatment by targeting RNF115. Zongming Zhang, Department of General Surgery, Beijing Electric Power Hospital, State Grid Corporation of China, Capital Medical University, Beijing 100073, China E-Mail: zhangzongming@mail.tsinghua.edu.cn; Bin Zhu, Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China E-Mail: zhubin@bjmu.edu.cn; Yingyu Chen, Center for Human Disease Genomics, Peking University, Beijing 100191, China E-Mail: yingyu_chen@bjmu.edu.cn How to cite this article:

Transmembrane protein 166 (TMEM166), an endoplasmic reticulum (ER)-resident membrane protein, exerts anticancer effects by inducing autophagy and apoptosis. Although tissues of various cancers downregulate its expression, the biological function of TMEM166 in hepatocellular carcinoma (HCC) remains unclear. Herein, we report that TMEM166 negatively regulates unfolded protein response (UPR) in HCC. TMEM166 was noted to interact with ACSL3 to maintain ACSL3 stability and facilitate lipid storage. TMEM166 deletion reduced ACSL3 expression and increased lipid utilisation in the mitochondria through fatty acid β-oxidation (FAO), ultimately boosting ATP production. Moreover, TMEM166 -knockout (KO) cells demonstrated accelerated protein synthesis via the AMPK–mTOR axis. These effects induced sublethal ER stress and UPR activation in TMEM166 -KO cells. Furthermore, TMEM166 KO promoted HCC cell proliferation and sorafenib resistance via UPR activity upregulation. We analysed the clinical significance of TMEM166-regulated UPR in human HCC cells and noted that TMEM166 expression was negatively correlated with the activities of UPR-related transcriptional factors such as ATF4, ATF6 and XBP1s in the cells. This study is the first to elucidate the relationship among TMEM166, ER stress, and HCC and may provide and indicate newer avenues for TMEM166 -targeted gene therapy strategies for HCC treatment.

Objectives This study aimed to determine the prevalence and independent risk factors of SDB, and explore its association with malocclusion among 6–11-year-old children in Shanghai, China. Methods A cluster sampling procedure was adopted in this cross-sectional study. Pediatric Sleep Questionnaire (PSQ) was applied to evaluate the presence of SDB. Questionnaires including PSQ, medical history, family history, and daily habits/environment were completed by parents under instruction, and oral examinations were implemented by well-trained orthodontists. Multivariable logistic regression was applied to identify independent risk factors for SDB. Chi-square tests and Spearman's Rank Correlation were used to estimate the relationship between SDB and malocclusion. Results A total of 3433 subjects (1788 males and 1645 females) were included in the study. The SDB prevalence was about 17.7%. Allergic rhinitis (OR 1.39, 95% CI 1.09–1.79), adenotonsillar hypertrophy (OR 2.39, 95% CI 1.82–3.19), paternal snoring (OR 1.97, 95% CI 1.53–2.53), and maternal snoring (OR 1.35, 95% CI 1.05–1.73) were independent risk factors for SDB. The SDB prevalence was higher in children with retrusive mandibles than in proper or excessive ones. No significant difference was observed in the correlation between SDB and lateral facial profile, mandible plane angle, constricted dental arch form, the severity of anterior overjet and overbite, degree of crowding and spacing, and the presence of crossbite and open bite. Conclusions The prevalence of SDB in primary students in the Chinese urban population was high and highly associated with mandible retrusion. The independent risk factors included Allergic rhinitis, adenotonsillar hypertrophy, paternal snoring, and maternal snoring. More efforts should be made to enhance public education about SDB and related dental-maxillofacial abnormalities.

The intricate and protracted process of dentin formation has been extensively explored, thanks to the significant advancements facilitated by the use of animal models and related techniques. Despite variations in their effectiveness, taking into account factors such as sensitivity, visibility, and reliability, these models or techniques are indispensable tools for investigating the complexities of dentin formation. This article focuses on the latest advances in animal models and related technologies, shedding light on the key molecular mechanisms that are essential in dentin formation. A deeper understanding of this phenomenon enables the careful selection of appropriate animal models, considering their suitability in unraveling the underlying molecular intricacies. These insights are crucial for the advancement of clinical drugs targeting dentin-related ailments and the development of comprehensive treatment strategies throughout the duration of the disease.

Purpose: Sevoflurane is the preferred anesthetic agent for induction and maintenance of ambulatory surgery due to its property of fast onset and recovery. However, it has been recognized as one of the major contributors of emergence delirium. The aim of this study was to evaluate the preventive effect of intranasal dexmedetomidine on the occurrence of emergence delirium in pediatric patients under general anesthesia with sevoflurane. Patients and Methods: Ninety pediatric patients undergoing dental rehabilitation under sevoflurane anesthesia were enrolled in this study. The patients were divided into three groups (n=30 each in the 2 [micro]g/kg dexmedetomidine, 1 [micro]g/kg dexmedetomidine, and control with saline groups). The same volume (0.02mL/kg) of the mixed solution was dropped into the nasal cavity of the children 30 minutes before surgery. We used the Pediatric Anesthesia Emergence Delirium Scale (PAED) to assess the level and incidence of delirium in the post-anesthesia care unit. Results: Compared with the control group, prophylactic use of different dosages of intranasal dexmedetomidine significantly reduces the incidence of ED and severe ED in PACU (P<0.001). Intranasal administration of 2 [micro]g/kg dexmedetomidine was associated with a better acceptance of mask induction and a better tolerance of separation with parents. Conclusion: Both 2 [micro]g/kg and 1 [micro]g/kg intranasal dexmedetomidine can achieve ED preventive effects in PACU in dental rehabilitation under general anesthesia. A dosage of 2 [micro]g/kg is more effective in preventing severe ED and providing better mask acceptance. Keywords: intranasal dexmedetomidine, emergence delirium, sevoflurane anesthesia, pediatric patients, dental rehabilitation

IntroductionOrthodontic treatment and adenotonsillectomy (AT) are both conventional treatments for paediatric obstructive sleep apnoea (OSA). Each approach has distinct treatment advantages; however, there is currently a lack of solid evidence to support their efficacy comparison. We hypothesise that the objective effect of orthodontic treatment is not inferior to AT in children with moderate OSA and mandibular retrognathia, but orthodontic treatment has the advantage of promoting dentofacial growth.Methods and analysisThis is a randomised, open-label, parallel-group, active controlled trial that will study the efficacy of orthodontic treatment versus AT in children with moderate OSA accompanied by tonsillar adenoid hypertrophy and mandibular retrognathia. A total of 98 patients will be enrolled and randomised in a 2:1 ratio to either orthodontic treatment or AT group. Participants will be recruited at Shanghai Stomatological Hospital, Shanghai Children’s Hospital of Shanghai Jiaotong University and Children’s Hospital of Fudan University, which are all located in Shanghai, China. The primary endpoint is the per cent change in the obstructive apnoea–hypopnoea index from baseline (month 0) to the primary endpoint (month 7), and the mean reduction in A point, nasion and B point angle on cephalometric measurements by lateral X-ray films. Important secondary efficacy endpoints include sleep duration with oxygen saturation below 90% according to polysomnography and subjective symptoms (assessed by the OSA-20 questionnaire), etc. Safety endpoints will also be evaluated.Ethics and disseminationThe study was approved by the ethics committees of Shanghai Stomatological Hospital (approval no. (2021)002), Shanghai Children’s Hospital of Shanghai Jiaotong University (approval no. 2021R046-F01) and Children’s Hospital of Fudan University (approval no. (2021)136). Before enrolment, a qualified clinical research assistant will obtain written informed consent from both the participants and their guardians after full explanation of this study. The results will be presented at national or international conferences and published in peer-reviewed journals.Trial registration numberChiCTR2000037288.

Polypharmacology is emerging as the next paradigm in drug discovery. However, considerable challenges still exist for polypharmacology modeling. In this study, we developed a rational design to identify highly potential targets (HPTs) for polypharmacological drugs, such as berberine. All the proven co-crystal structures locate berberine in the active cavities of a redundancy of aromatic, aliphatic, and acidic residues. The side chains from residues provide hydrophobic and electronic interactions to aid in neutralization for the positive charge of berberine. Accordingly, we generated multi-target binding motifs (MBM) for berberine, and established a new mathematical model to identify HPTs based on MBM. Remarkably, the berberine MBM was embodied in 13 HPTs, including beta-secretase 1 (BACE1) and amyloid-β (Aβ ). Further study indicated that berberine acted as a high-affinity BACE1 inhibitor and prevented Aβ aggregation to delay the pathological process of Alzheimer's disease. Here, we proposed a MBM-based drug-target space model to analyze the underlying mechanism of multi-target drugs against polypharmacological profiles, and demonstrated the role of berberine in Alzheimer's disease. This approach can be useful in derivation of rules, which will illuminate our understanding of drug action in diseases.