Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8⁺ T-cell-mediated antitumor immunity both in vivo and in vitro. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8⁺ T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.

Metabolic reprogramming plays a central role in tumors. However, the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood. Here, we try to identify the mechanism by which histone acetyltransferase 1 (HAT1) confers reprogramming of gluconeogenesis/lipogenesis in liver cancer. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl₄)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice. Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver. Protein phosphatase 2 scaffold subunit alpha (PPP2R1A) promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1 (PCK1) serine 90 dephosphorylation to suppress the tumor growth. HAT1 succinylated PPP2R1A at lysine 541 (K541) to block the assembly of protein phosphatase 2A (PP2A) holoenzyme and interaction with PCK1, resulting in the depression of dephosphorylation of PCK1. HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation, leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1 (SREBP1) nuclear accumulation-induced lipogenesis gene expression, which enhanced the tumor growth. In conclusion, succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer. Our finding provides new insights into the mechanism by which post-translational modifications (PTMs) confer the conversion of tumor suppressor function to oncogene.

Temporomandibular joint osteoarthritis (TMJ-OA) is a common disease often accompanied by pain, seriously affecting physical and mental health of patients. Abnormal innervation at the osteochondral junction has been considered as a predominant origin of arthralgia, while the specific mechanism mediating pain remains unclear. To investigate the underlying mechanism of TMJ-OA pain, an abnormal joint loading model was used to induce TMJ-OA pain. We found that during the development of TMJ-OA, the increased innervation of sympathetic nerve of subchondral bone precedes that of sensory nerves. Furthermore, these two types of nerves are spatially closely associated. Additionally, it was discovered that activation of sympathetic neural signals promotes osteoarthritic pain in mice, whereas blocking these signals effectively alleviates pain. In vitro experiments also confirmed that norepinephrine released by sympathetic neurons promotes the activation and axonal growth of sensory neurons. Moreover, we also discovered that through releasing norepinephrine, regional sympathetic nerves of subchondral bone were found to regulate growth and activation of local sensory nerves synergistically with other pain regulators. This study identified the role of regional sympathetic nerves in mediating pain in TMJ-OA. It sheds light on a new mechanism of abnormal innervation at the osteochondral junction and the regional crosstalk between peripheral nerves, providing a potential target for treating TMJ-OA pain.
Animals ; Osteoarthritis/physiopathology* ; Mice ; Sympathetic Nervous System/physiopathology* ; Temporomandibular Joint Disorders/physiopathology* ; Arthralgia ; Sensory Receptor Cells ; Disease Models, Animal ; Norepinephrine ; Male ; Temporomandibular Joint/physiopathology* ; Pain Measurement

Enamel demineralization, the formation of white spot lesions, is a common issue in clinical orthodontic treatment. The appearance of white spot lesions not only affects the texture and health of dental hard tissues but also impacts the health and aesthetics of teeth after orthodontic treatment. The prevention, diagnosis, and treatment of white spot lesions that occur throughout the orthodontic treatment process involve multiple dental specialties. This expert consensus will focus on providing guiding opinions on the management and prevention of white spot lesions during orthodontic treatment, advocating for proactive prevention, early detection, timely treatment, scientific follow-up, and multidisciplinary management of white spot lesions throughout the orthodontic process, thereby maintaining the dental health of patients during orthodontic treatment.
Humans ; Consensus ; Dental Caries/etiology* ; Dental Enamel/pathology* ; Tooth Demineralization/etiology* ; Tooth Remineralization

ObjectiveTo explore the clinical features and causative genes of short stature children with unknown etiology， providing evidence for precise clinical diagnosis and treatment. MethodsThe study recruited children with suspected but undiagnosed short stature from the pediatric endocrinology department in our hospital between January 2018 and August 2022. A retrospective analysis was performed on the clinical manifestations， laboratory test and whole exome sequencing （WES） results. Causative genes were classified and analyzed according to different pathogenic mechanisms. ResultsA total of 48 children （30 boys and 18 girls） were enrolled， aged 7.73 ± 3.97 years， with a height standard deviation score （ HtSDS） of -3.63 ± 1.67. Of the patients， 33 （68.8%） suffered from facial anomalies， 31 （64.6%） from skeletal abnormalities， 26 ［54.2%， 61.5% of whom born small for gestational age （SGA）］ from perinatal abnormalities， 24 ［50.0%， 87.5% of whom with growth hormone （GH） peak concentration below normal］ from endocrine disorders and 21（43.8%） had a family history of short stature. Laboratory tests showed that GH peak concentration following stimulation test was （9.72 ± 7.25） ng/mL， IGF-1 standard deviation score was -0.82 ± 1.42， the difference between bone age and chronological age was -0.93 ± 1.39 years. Of the 25 cases with mutant genes found by WES， 14 （56.0%） had pathogenic mutation， 6 （24.0%） likely pathogenic mutation， and 5 （20.0%） mutation of uncertain significance. Pathogenic and likely pathogenic variants were identified in 14 genes， including 10 affecting intracellular signaling pathways （PTPN11， RAF1， RIT1， ARID1B， ANKRD11， CSNK2A1， SRCAP， CUL7， SMAD4 and FAM111A） and 4 affecting extracellular matrix （ECM） components or functions （ACAN， FBN1， COL10A1 and COMP）. ConclusionsA rare monogenic disease should be considered as the possible etiology for children with severe short stature accompanied by facial anomalies， disproportionate body types， skeletal abnormalities， SGA， GH peak concentration below normal and a family history of short stature. WES played an important role in identifying the monogenic causes of short stature. This study indicated that affecting growth plate cartilage formation through intracellular signaling pathways and ECM components or functions was the main mechanism of causative genes leading to severe short stature in children. Further research may help discover and study new pathogenic variants and gene functions.

Objective:To analyze plaque characteristics of non-culprit coronary lesions with cholesterol crystals in patients with acute myocardial infarction(AMI) by using optical coherence tomography(OCT). We also investigated the potential association between cholesterol crystals with plaque rupture and healed plaque at non-culprit segment.Methods:This study was a retrospective cohort study. Between January 2017 and December 2017, patients with AMI who underwent 3-vessel OCT imaging were included in this study. Patients were divided into two groups according to the presence or absence of cholesterol crystals at the non-culprit lesions. All patients underwent coronary angiography and OCT examination, and non-culprit plaque characteristics were compared between the two groups. The generalized estimating equation log-binomial multirariate regression model was used to assess the relationship between non-culprit lesions with cholesterol crystals and plaque rupture and plaque healing. The follow-up data collection ended in October 2023. Kaplan-Meier survival curves were plotted, and log-rank tests were used to compare the cumulative incidence of major adverse cardiovascular events between the two groups.Results:A total of 173 AMI patients were included (aged (56.8±11.6) years; 124 men (71.7%)). Among 710 non-culprit lesions identified by OCT, there were 102 (14.4%) in cholesterol crystals group and 608 (85.6%) in non-cholesterol crystals group. Compared with non-culprit lesions without cholesterol crystals, those with cholesterol crystals had smaller minimum lumen diameter, severer diameter stenosis, and longer lesion length (all P<0.01). The prevalence of plaque rupture (17.6% (18/102) vs. 4.9% (30/608), P=0.001) and thin-cap fibroatheroma (31.4% (32/102) vs. 11.5% (70/608), P<0.01) was higher in the cholesterol crystals groups than in the non-cholesterol crystals group. In addition, vulnerable plaque characteristics such as (44.1% (45/102) vs. 25.8% (157/608), P<0.01), macrophages were more frequently observed in non-culprit lesions with cholesterol crystals. The generalized estimating equation log-binomial multivariate regression analyses showed that non-culprit cholesterol crystals were positively correlated with healed plaque ( OR=1.583, 95% CI: 1.004-2.495, P=0.048). Conversely, cholesterol crystals were not associated with plaque rupture ( OR=1.632, 95% CI: 0.745-3.576, P=0.221). The follow-up time was 2 142 (1 880, 2 198) days. Non-culprit cholesterol crystals were not related to the major adverse cardiovascular events in patients with AMI (log-rank P=0.558). Conclusions:Among AMI patients, non-culprit lesions with cholesterol crystals presented with severer luminal stenosis and increased plaque vulnerability. The presence of non-culprit cholesterol crystals was associated with rather than plaque rupture.

Objective:To evaluate the effect of electroacupuncture on the heme oxygenase-1 (HO-1)/PTEN-induced putative kinase 1 (PINK1)/Parkin signaling pathway during acute kidney injury in endotoxemic rats.Methods:Twenty-four SPF healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 180-220 g, were divided into 4 groups ( n=6 each) by a random number table method: control group(group C), endotoxemia group(group E), acupoint electroacupuncture+ endotoxemia group(group EE), and non-acupoint electroacupuncture+ endotoxemia group(group NE). The endotoxemia model was developed by intraperitoneal injection of lipopolysaccharide 10 mg/kg. The equal volume of normal salinewas injected in group C. LPS 10 mg/kg was intraperitoneally injected in group E. In group EE, 30-min electroacupuncture was performed at bilateral Zusanli and Shenshu acupoints using disperse-dense waves with a frequency of 2/15 Hz to induce slight muscle tremor once a day starting from 5 days before developing the model, and the needle was retained until 6 h after injection. Electroacupuncture was performed at the points 0.5 cm lateral to the acupoints of Zusanli and Shenshu in group NE. The rats were anesthetized at 6 h after lipopolysaccharide injection, and blood samples from the femoral vein were obtained for determination of the serum creatinine (Cr) and urea nitrogen (BUN) concentrations(with a biochemical analyzer) and concentrations of neutrophil gelatinase-associated lipid transport protein (NGAL), interleukin-6 (IL-6), tumor necrosis factor (TNF-α) and kidney injury molecule-1(KIM-1) in serum (by enzyme-linked immunosorbent assay). Then the rats were sacrificed and kidney tissues were taken for determination of histological score of kidneys (HSK, using HE staining) and expression of HO-1, PINK1, Parkin, mitochondrial fusion protein 2(Mfn2), optic atrophy protein 1(OPA1) and mitochondrial dynamic-related protein 1 (Drp1) (by Western blot). Results:Compared with group C, serum concentrations of Cr, BUN, KIM-1, NGAL, IL-6 and TNF-α and HSK score of renal tissues were significantly increased, the expression of HO-1, PINK1, Parkin and Drp1 was up-regulated, and the expression of Mfn2 and OPA1 was down-regulated in E, EE and NE groups ( P<0.05). Compared with group E, serum concentrations of Cr, BUN, KIM-1, NGAL, IL-6 and TNF-α and HSK score of renal tissues were significantly decreased, and the expression of HO-1, PINK1, Parkin, Mfn2 and OPA1 was up-regulated, and Drp1 expression was down-regulated in group EE( P<0.05), and no significant change was found in the parameters mentioned above in group NE ( P>0.05). Conclusions:The mechanism by which electroacupuncture alleviates acute kidney injury is associated with activation of HO-1/PINK1/Parkin signaling pathway in endotoxemic rats.

Objective:To evaluate the effect of ozone preconditioning on splenic natural killer (NK) cells in septic mice.Methods:Twenty-four SPF-grade male C57BL/6 mice, aged 6-8 weeks, weighing 18-22 g, were divided into 4 groups ( n=6 each) according to the random number table method: control group (group C), lipopolysaccharide (LPS)group, ozone+ LPS group (O 3+ LPS) and air+ LPS group (Air+ LPS). The sepsis was induced by intraperitoneal injection of LPS 10 mg/kg. Ozone preconditioning was started at 5 days before developing the model: ozone 1 mg/kg was intraperitoneally injected once a day for 5 consecutive days, the equal volume of air was injected in Air+ LPS group. The survival was observed within 72 h after LPS injection, and sepsis score and ear temperature (once every 2 h, an average was calculated) were recorded. The posterior orbital venous blood samples were taken at 6 and 24 h after LPS injection for determination of serum interferon-γ (IFN-γ) and interleukin-10 (IL-10) concentrations using enzyme-linked immunosorbent assay. The spleen was then taken, and a single cell suspension of the spleen was prepared for measurement of the percentage of NK cells in the spleen by flow cytometry. Results:Compared with C group, the ear temperature, sepsis score and 72-h survival rate were significantly decreased, serum IFN-γ and IL-10 concentrations were increased at each time point after LPS injection, and the percentage of splenic NK cells was increased at 6 h after LPS injection and decreased at 24 h after LPS injection in LPS, Air+ LPS and O 3+ LPS groups ( P<0.05). Compared with LPS group, the ear temperature, sepsis score and 72-h survival rate were significantly increased, serum IFN-γ concentrations were decreased at each time point after LPS injection, serum IL-10 concentrations were increased at each time point after LPS injection, and the percentage of splenic NK cells was decreased at 6 h after LPS injection and increased at 24 h after LPS injection in O 3+ LPS group ( P<0.05), and no significant change was found in the parameters mentioned above in Air+ LPS group ( P>0.05). Conclusions:The mechanism by which ozone preconditioning reduces sepsis may be related to reduction of inflammatory responses and regulation of splenic NK cell levels in septic mice.

It's the duty of contemporary teachers to cultivate students' independent learning, independent thinking, and self-management ability. This paper reviews the significance of independent learning for cultivating medical students with forward-looking learning ability and cutting-edge medical knowledge. It focuses on the strategies and ideas of cultivating medical students' independent learning ability from the aspects of strategy and evaluation, and tries to provide inspiration and reference for the application of independent learning teaching method in the cultivation of medical students.

Objective:To investigate the safety and efficacy of remimazolam combined with afentanyl for fiberoptic bronchoscopy.Methods:Sixty patients admitted to Chifeng Hospital for fiberbronchoscopy from January to April 2022 were selected and divided into two groups by random number table method: remimazolam group (group R) and propofol group (group P), 30cases in each group. After intravenous injection of alfentanil for anesthesia induction, group R was sedated by intravenous injection of remidazolam besylate, and group P was sedated by intravenous injection of propofol emulsion. When sufficient sedation was achieved, fiberoptic bronchoscopy was performed. The patients were scored with the Mini-Mental State Examination (MMSE) before examination and before leaving the room. The recovery rate of sedation and the recovery rate of drugs during operation were compared. Blood pressure, heart rate (HR), bispectral index (BIS), SpO 2 value and Modified Observer′s Assessment of Alertness/Sedation (MOAA/S) score were compared before induction (T 0), at the beginning of examination (T 1), immediately when fiber bronchoscope reached juga (T 2), at the end of surgery (T 3), immediately, when patients regained consciousness (T 4). Drug onset and recovery time (time out of hospital) as well as the incidence of intraoperative and postoperative adverse reactions were recorded in both groups. Results:There was no statistically significant difference in general condition, MMSE score and examination time between the two groups (all P>0.05). There was no statistically significant difference between the two groups in the success rate of sedation and the number of sedative remedy times (all P>0.05). The number of additional drugs in group R was significantly higher than that in group P ( P<0.05). The systolic blood pressure, diastolic blood pressure and BIS values of patients in group P at T 1 and T 2 were significantly lower than those in group R (all P<0.05). After administration, the MOAA/S score of the two groups began to decrease, and the decrease of the P group was significantly greater than that of the R group, and the MOAA/S value of the patients was the lowest at the 3rd and 4th minutes after administration, respectively. The time from the beginning of administration to the MOAA/S score ≤3 in group P was significantly shorter than that in group R (all P<0.05). The incidence of pain and respiratory depression after injection in group P was significantly higher than that in group R ( P<0.05). Conclusions:The application of afentanil combined with remimazolam in the patients undergoing fiberoptic bronchoscopy has good sedative effect and high anesthesia quality, and has no obvious effect on cognitive function and few adverse reactions, so it is safe and effective.