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In this study, the "particle in a box" idea, which was broadly developed in semiconductor quantum dot research, was extended into mid-infrared (IR) cavity modes by applying lateral confinement in an optical cavity. The discrete cavity modes hybridized with molecular vibrational modes, resulting in a quartet of polariton states that can support multiple coherence states in the IR regime. We applied tailored pump pulse sequences to selectively prepare these coherences and verified the multi-coherence existence. The simulation based on Lindblad equation showed that because the quartet of polariton states resided in the same cavity, they were specifically robust toward decoherence caused by fluctuations in space. The multiple robust coherences paved the way for entangled states and coherent interactions between cavity polaritons, which would be critical for advancing polariton-based quantum information technology.
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Ciencia de la Información , Puntos Cuánticos , Simulación por Computador , Tecnología de la Información , SemiconductoresRESUMEN
In most species studied, energy deficits inhibit female reproductive behavior, but the location and nature of energy sensors and how they affect behavior are unknown. Progress has been facilitated by using Drosophila melanogaster, a species in which reproduction and food availability are closely linked. Adult males and females were either fed or food deprived (FD) and then tested in an arena with a fed, opposite-sex conspecific with no food in the testing arena. Only FD females (not FD males) significantly decreased their copulation rate and increased their copulation latency, and the effects of FD were prevented in females fed either yeast alone or glucose alone, but not sucralose alone, cholesterol alone, or amino acids alone. It is well-known that high-fat diets inhibit copulation rate in this species, and the effects of FD on copulation rate were mimicked by treatment with an inhibitor of glucose but not free fatty acid oxidation. The availability of oxidizable glucose was a necessary condition for copulation rate in females fed either yeast alone or fed a nutritive fly medium, which suggests that the critical component of yeast for female copulation rate is oxidizable glucose. Thus, female copulation rate in D. melanogaster is sensitive to the availability of oxidizable metabolic fuels, particularly the availability of oxidizable glucose or substrates/byproducts of glycolysis.NEW & NOTEWORTHY Copulation rate was decreased in food-deprived female but not in male adults when tested without food in the testing arena. Copulation rate was 1) maintained by feeding glucose alone, yeast alone, nutritive medium lacking yeast, but not sucralose, amino acids, or cholesterol alone; 2) decreased by inhibition of glycolysis in females fed either nutritive medium or yeast alone; and 3) not affected by inhibition of fatty acid oxidation. Thus, female copulation rate was linked to glycolytic status.
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Drosophila melanogaster , Privación de Alimentos , Conducta Sexual Animal , Femenino , Animales , Drosophila melanogaster/fisiología , Privación de Alimentos/fisiología , Conducta Sexual Animal/fisiología , Redes y Vías Metabólicas/fisiología , Masculino , Factores Sexuales , DietaRESUMEN
BACKGROUND AND AIMS: NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element-binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway. APPROACH AND RESULTS: Here, we identify a potent SREBP inhibitor, 25-hydroxylanosterol (25-HL). 25-HL binds to insulin-induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25-HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25-HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down-regulating the expression of lipogenic genes. Furthermore, 25-HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet-treated Ldlr-/- mice, and reduces the formation of cholesterol crystals and associated crown-like structures of Kupffer cells. Notably, 25-HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25-HL shows a good safety and pharmacokinetics profile. CONCLUSIONS: This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25-HL in human NASH and demonstrates the critical role of SREBP-controlled lipogenesis in the progression of NASH by pharmacological inhibition.
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Insulinas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Lipogénesis/fisiología , Proteínas de Unión a los Elementos Reguladores de Esteroles , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Hígado/metabolismo , Triglicéridos/metabolismo , Colesterol/metabolismo , Lovastatina/metabolismo , Insulinas/metabolismo , Ratones Endogámicos C57BLRESUMEN
Moiré fringe is an effective approach to realize nano-alignment. However, affected by short periodicity and phase unwrapping, moiré fringe technology has small alignment ranges and redundant algorithms, making it difficult to meet practical application requirements. To solve the problem, we propose a large-range lithography nano-alignment method without phase unwrapping by a dual-frequency moiré fringe heterodyne. This method obtains four sets of moiré fringes from the main and differential alignment marks and then calculates the misalignment information using the heterodyne method. In this approach, both large alignment range and high alignment accuracy are achieved while avoiding the phase unwrapping process. The experimental results verified the rationality and feasibility of the proposed method.
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Extracellular vesicles (EVs) are a group of secretory vesicles with cell-derived membrane and contents. Due to the cargo delivery capability, EVs can be designed as drug delivery platforms for cancer therapy. Biocompatibility and immune compatibility endow EVs with unique advantages compared with other nanocarriers. With the development of this field, multiple ingenious modification methods have been developed to obtain engineered EVs with desired performance. Application of engineered EVs in cancer therapy has gradually shifted from monotherapy to combinational therapy to fight against heterogeneous cancer cells and complex tumor microenvironment. In addition, the strong plasticity and load capacity of engineered EV make it potential to achieve various combinations of cancer treatment methods. In this review, we summarize the existing schemes of cancer combination therapy realized by engineered EVs, highlight the mechanisms and representative examples of these schemes and provide guidance for the future application of engineered EVs to design more effective cancer combination treatment plans.
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Vesículas Extracelulares , Neoplasias , Comunicación Celular , Terapia Combinada , Sistemas de Liberación de Medicamentos/métodos , Humanos , Neoplasias/tratamiento farmacológico , Microambiente TumoralRESUMEN
Chronic stress, a characteristic of modern time, has a significant impact on general health. In the context of psychiatric disorders, insufficient coping behavior under chronic stress has been linked to higher rates of (1) depressive symptoms among subjects of the general population, (2) relapse among patients under treatment for clinical depression, and (3) negative symptoms among subjects with an elevated vulnerability to psychosis. In this normative study we assessed basic coping behavior among 461 Chinese freshman university students along with their consumption behavior and general health in terms of regular exercises, physical health, psychosomatic disturbances, and mental health. The assessments relied on two instruments that have already demonstrated their capability of (1) reliably detecting insufficient coping behavior under chronic stress and (2) reliably quantifying the interrelation between coping behavior and mental health in the Western world. Thus, we aimed to complement existing data and to develop a generally available, socioculturally independent tool that can be used for the early detection of subjects with an elevated risk of mental health problems. Structural analyses yielded essentially the same scales "activity" and "defeatism" as previous studies on 2,500 students from Switzerland, Italy, Spain, the USA, and Argentina. These scales explained 74.3% of the observed variance in coping behavior among the 461 Chinese students. We found highly significant correlations (p < 0.0001) between the "defeatism" scale on the one hand, and the scales "regular use of medicine," "psychosomatic disturbances," and "impaired mental health" on the other. Particularly intriguing was the finding that a neural net classifier could be constructed to identify students with the highest contributions to the interrelation between "coping behavior" and "mental health," yielding a correlation coefficient as high as r = 0.597 for the respective subgroup. Based on the normative data, an online tool for risk assessments was developed with immediate feedback to users. This study provided another piece of evidence regarding the close link between basic coping behavior and mental health, across cultures and ethnicities. In consequence, our approach to quantifying basic coping behavior, along with other risk factors, can be expected to clear the way for an "early" detection of students with an elevated risk of stress-related mental health problems, nota bene prior to the development of clinically relevant symptoms. The socioeconomic impact of the potential prevention of depressive -disorders, and psychiatric disorders in general, may be enormous.
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Diagnóstico Precoz , Salud Mental/normas , Trastornos Psicofisiológicos/diagnóstico , Psicoterapia/métodos , Estrés Psicológico/psicología , Estudiantes/psicología , Adolescente , Adulto , Femenino , Humanos , Masculino , Factores de Riesgo , Universidades , Adulto JovenRESUMEN
Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.
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Acrilamidas/síntesis química , Receptores ErbB/antagonistas & inhibidores , Fenilendiaminas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Compuestos de Anilina , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Ratones , Ratones Desnudos , Mutación , Neoplasias/tratamiento farmacológico , Fenilendiaminas/farmacología , Fenilendiaminas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Trasplante HeterólogoRESUMEN
A novel method has been developed for the synthesis of 1-methyl-4,5-diaryl-1H-imidazoles through Fe(II)-catalyzed cyclization of 2H-azirines and N,N-dimethylformamide (DMF) as an amine source. This transformation involves the cleavage of C-N and CîN double bonds and the construction of new C-N and CîN double bonds. The reaction has readily available starting materials, a wide range of substrates and mild reaction conditions. In addition, the reaction also facilitated the convenient synthesis of 1-methyl-2,4,5-triaryl-1H-imidazoles.
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Purpose: Congenital accessory navicular bone (ANB) is a common variant in the foot and is prone to cause several clinical symptoms. Wearing custom-made foot orthosis is considered a desirable option; however, there is limited evidence of its effectiveness. This study aims to report the mid-term effect of foot orthosis for symptomatic pediatric ANBs. Methods: School-age children with symptomatic ANBs combined with flexible flatfoot in the authors' institute were recruited and got custom-made foot orthosis treatment. They were followed up over 4 years. The general characteristics of these children were collected before treatment, including age, gender, and body mass index (BMI). The indicators of foot symptoms, including frequency and location of pain, visual analogue scale (VAS), arch index (AI), and hind foot valgus angle (HVA), were measured during pretreatment and at the last follow-up. Results: Twenty-seven children were recruited for this study. After 4 years of custom-made foot orthosis treatment, significant improvements showed in pain frequency, VAS, AI, and HVA (P < 0.001). Type II ANBs showed a higher pain index pretreatment (P < 0.001) and reduced after treatment (P < 0.001). Conclusion: Mid-term effect of custom-made foot orthosis is inspiring in clinical symptoms of pediatric congenital ANBs combined with flexible flatfoot and may be an optional nonoperative treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-024-01210-7.
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Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA/PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance.
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Neoplasias de la Mama , Proliferación Celular , Fosfatidilinositol 3-Quinasa Clase I , Resistencia a Antineoplásicos , Lapatinib , Proteolisis , Receptor ErbB-2 , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Lapatinib/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Resistencia a Antineoplásicos/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Animales , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Proteolisis/efectos de los fármacos , Mutación , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Ratones Desnudos , TiazolesRESUMEN
With the development of educational cognitive neuroscience, language instruction is no longer perceived as mechanical teaching and learning. Individual cognitive proficiency has been found to play a crucial role in language acquisition, particularly in the realm of reading comprehension. The primary objective of this study was to investigate two key aspects: firstly, to assess the predictive effects of the central executive (CE) on the Chinese reading comprehension scores of Chinese primary school students, and secondly, to explore the influence of CE training on the Chinese reading comprehension performance of Chinese primary school students. Chinese primary school students were recruited as participants. Experiment 1 used a Chinese N-back task, a Chinese Stroop task, and a number-pinyin conversion task to investigate the predictive effect of the CE components on Chinese reading comprehension. Experiment 2, based on the results of Experiment 1, used the Chinese character N-back training to explore the influence of updating training on Chinese reading comprehension. The findings from Experiment 1 underscored that CE had a predictive effect on Chinese reading comprehension scores. And updating had a prominent role in it. Experiment 2 revealed that the experimental group exhibited an enhancement in their updating performance following N-back training. Although the reading comprehension performance of the two groups after training did not produce significant differences in total scores, the experimental group showed maintained and higher microscopic reading comprehension scores than the control group in the more difficult post-test. In summary, this study yields two primary conclusions: (1) CE was able to predict Chinese reading comprehension scores. Updating has an important role in prediction. (2) Updating training enhances students' updating performance and positively influences students' Chinese microscopic reading comprehension performance.
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Objective: This study aimed to explore the effects of working memory updating training on primary school students' writing ability and performance. Methods: A total of 46 fourth-grade Chinese primary school students were recruited; their performance in the Chinese character N-back training task, the Writing Ability Questionnaire, and a time-limited writing task was assessed. Results: The paired-sample t-test revealed that working memory updating training significantly improved the experimental group's working memory level. After training, a repeated measures ANOVA revealed that the experimental group's performance on the Writing Ability Questionnaire improved and was higher than that of the control group. In the time-limited writing task, independent-sample t-tests revealed that the experimental group's writing fluency increased and was higher than that of the control group, while the latter's grammatical accuracy and complexity decreased and were lower than those of the former. Conclusion: Working memory updating training can be used as auxiliary cognitive training to improve primary school students' working memory level, thereby promoting their writing development.
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Social media and online navigation bring us enjoyable experiences in accessing information, and simultaneously create information cocoons (ICs) in which we are unconsciously trapped with limited and biased information. We provide a formal definition of IC in the scenario of online navigation. Subsequently, by analyzing real recommendation networks extracted from Science, PNAS, and Amazon websites, and testing mainstream algorithms in disparate recommender systems, we demonstrate that similarity-based recommendation techniques result in ICs, which suppress the system navigability by hundreds of times. We further propose a flexible recommendation strategy that addresses the IC-induced problem and improves retrieval accuracy in navigation, which are demonstrated by simulations on real data and online experiments on the largest video website in China. This paper quantifies the challenge of ICs in recommender systems and presents a viable solution, which offer insights into the industrial design of algorithms, future scientific studies, as well as policy making.
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This Viewpoint responds to the analysis of 2D IR spectra of vibration cavity polaritons in the study reported in The Journal of Physical Chemistry Letters (Duan et al. 2021, 12, 11406). That report analyzed 2D IR spectra of strongly coupled molecules, such as W(CO)6 and nitroprusside anion, based on subtracting a background signal generated by polariton filtered free space signals. They assigned the resulting response as being due to excited polaritons. We point out in this Viewpoint that virtually all of the response can be properly reproduced using the physics of transmission through an etalon containing a material modeled with a complex dielectric function describing the ground- and excited-state absorber populations. Furthermore, such a coupled system cannot be described as a scaled sum of the bare molecular and cavity responses.
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Ibrutinib is a first-line drug for the treatment of B-cell malignancies. BTKC481S mutation has led to drug resistance during clinical application. Herein, a novel BTK-targeting PROTAC molecule with better solubility and bioavailability was developed. Compound 15-271 has better solubility than ibrutinib and some reported BTK PROTACs. 15-271 has better liver microsomal stability than its analogues in multiple species. More importantly, 15-271 has a longer half-life and better bioavailability in vivo. The development strategy of compound 15-271 can be a general procedure for the optimization of other PROTACs.
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Background: It is uncommon for young children to suffer an intercondylar fracture of the distal humerus. Although many approaches have been described to manage, there is no specific and accepted treatment protocol for such fracture patterns. This study aimed to identify the incidence of intercondylar fracture of the distal humerus in the pediatric population and report the clinical outcome of external fixation and percutaneous pinning in such injury patterns. Methods: Pediatric patients under the age of 14 years who had an intercondylar fracture of the distal humerus treated with external fixation and percutaneous pinning between January 2013 and December 2018 at the author's Wuhan Union Hospital were retrospectively evaluated. The detailed baseline information of the patients, operating time, time to union time, and carrying angle difference (CAD) of the injured extremity were collected. During the follow-up visit, clinical results were evaluated using the Mayo Elbow Performance Score (MEPS) and the Flynn criteria. Results: A total of eight patients (2 women and 6 men) with an average age of 8 years (5-12 years) who had an intercondylar fracture of the distal humerus (1 C2 and 7 C1) were included. All the patients achieved union, and the average MEPS score was 95 points 24 months after the surgery. Conclusion: The intercondylar fracture of the distal humerus in children is rare, and closed reduction and external fixation is a viable treatment option, especially for the C1 type of fracture pattern.
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Membrane vesicles, a group of nano- or microsized vesicles, can be internalized or interact with the recipient cells, depending on their parental cells, size, structure and content. Membrane vesicles fuse with the target cell membrane, or they bind to the receptors on the cell surface, to transfer special effects. Based on versatile features, they can modulate the functions of immune cells and therefore influence immune responses. In the field of tumor therapeutic applications, phospholipid-membrane-based nanovesicles attract increased interest. Academic institutions and industrial companies are putting in effort to design, modify and apply membrane vesicles as potential tumor vaccines contributing to tumor immunotherapy. This review focuses on the currently most-used types of membrane vesicles (including liposomes, bacterial membrane vesicles, tumor- and dendritic-cell-derived extracellular vesicles) acting as tumor vaccines, and describes the classification, mechanism and application of these nanovesicles.
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Vibrational strong coupling (VSC) between molecular vibrations and microcavity photons yields a few polaritons (light-matter modes) and many dark modes (with negligible photonic character). Although VSC is reported to alter thermally activated chemical reactions, its mechanisms remain opaque. To elucidate this problem, we followed ultrafast dynamics of a simple unimolecular vibrational energy exchange in iron pentacarbonyl [Fe(CO)5] under VSC, which showed two competing channels: pseudorotation and intramolecular vibrational-energy redistribution (IVR). We found that under polariton excitation, energy exchange was overall accelerated, with IVR becoming faster and pseudorotation being slowed down. However, dark-mode excitation revealed unchanged dynamics compared with those outside of the cavity, with pseudorotation dominating. Thus, despite controversies around thermally activated VSC modified chemistry, our work shows that VSC can indeed alter chemistry through a nonequilibrium preparation of polaritons.
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Background: Flatfoot is common among children. Symptomatic flexible flatfoot is one of the various types which needs treatment. Wearing insoles is considered one of the conservative therapies, but its effects are still uncertain. This study aims to provide evidence for the efficacy of insoles treatment among school-aged children with symptomatic flexible flatfoot. Methods: Patient who were Children who were diagnosed with symptomatic flexible flatfoot and received insoles treatment in authors' institute were retrospectively included. Their ages, body mass index, pain positions, pain frequency, valgus angle, arch index and visual analogue scale (VAS) score were collected before and after insole treatment. Results: A total of 32 children were included in this study. The results showed that wearing insoles for 2 years caused a significant improvement in pain frequency, valgus angle, arch index and VAS score. Conclusions: This study indicated that pediatric symptomatic flexible flatfoot could be relieved by wearing insoles for 2 years. Insole treatment might be a workable option for pediatric symptomatic flexible flatfoot in children older than 6 years old.
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INTRODUCTION: Workplace violence against psychiatric professionals is a growing problem, yet nationally representative data in China are lacking. This study examines workplace violence against psychiatrists and psychiatric nurses in China as well as its association with workforce stability and well-being . METHODS: Data came from a 2019 national survey of 14,264 participants (including 4,520 psychiatrists and 9,744 nurses) from 41 psychiatric hospitals across China. The occurrence of physical and verbal assaults among psychiatrists and psychiatric nurses was reported. Logistic regression models were constructed to examine the participants' characteristics associated with encountering workplace violence and the association of encountering violence with self-reported quality of life, health status, turnover intention, and career satisfaction. Analyses were performed during 2020. RESULTS: In 2019, among 14,264 psychiatrists and psychiatric nurses in China, 81% reported encountering workplace violence during the past year. Psychiatrists were 0.68 (95% CI=0.55, 0.83) times less likely to report an encounter of violence than nurses. Male and younger nurses were 2.20 (95% CI=1.72, 2.81) and 1.21 (95% CI=1.01, 1.45) times more likely to report violence. Psychiatrists who had a higher educational degree or a higher professional rank were more vulnerable to violence. Encountering violence was significantly associated with poor quality of life, less satisfaction with health status, greater intention to leave the current job, and career dissatisfaction. CONCLUSIONS: Workplace violence against psychiatrists and psychiatric nurses are common in China, indicating that China's psychiatric professionals are facing a significant threat to occupational safety. To maintain psychiatric workforce stability, actions are needed to reduce the prevalence of workplace violence at the system, institutional, and individual levels.