Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
Humans ; Acetylation ; Carcinoma, Hepatocellular/genetics* ; Liver Neoplasms/genetics* ; Pyruvate Dehydrogenase Complex/genetics* ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Cell Line, Tumor ; Protein Processing, Post-Translational ; Histones/metabolism* ; Disease Progression

OBJECTIVE To investigate the protective effect of interleukin-35(IL-35)mRNA-lipid nanoparticles(LNP)against lipopolysaccharide(LPS)-induced acute lung injury(ALI)in mice.METHODS Fifity-six mice were randomly divided into 7 groups with 8 mice in each,including the normal control group,IL-35 mRNA-LNP(250 μg·kg-1)group,LPS group,LPS+IL-35 mRNA-LNP(50,125 and 250 μg·kg-1)group and LPS+Dexamethasone(DXM)group.Except for the normal control group and IL-35 mRNA-LNP(250 μg·kg-1)group and ALI model was established by tracheal infusion of LPS in each of the other groups.IL-35 mRNA-LNP(250 μg·kg-1)group and LPS+IL-35 mRNA-LNP(50,125 and 250 μg·kg-1)group were injected with a corresponding dose of LNP encapsulated mRNA complex via the tail vein while the LPS+DXM group was injected with DXM via the tail vein.Lung coefficient and the wet to dry weight ratio(W/D)of lung tissue were recorded.The mRNA levels of inflammatory cytokines tumor necrosis factor-α(TNF-α),Interleukin-6(IL-6)and IL-1βof lung homogenates were detected by real-time fluorescence quantitative PCR(RT-qPCR).LDH activity of lung homogenates and the protein levels of IL-35,TNF-α,IL-6 and IL-1β in lung homogenate were detected by corresponding kits.Hematoxylin-eosin(HE)staining was used to observe and analyze the pathological injury to lung tissue.The expres-sion of Lymphocyte antigen 6G(Ly6G)was detected by Immunofluorescence to reflect the infiltration of neutrophils.RESULTS Compared with the normal control group,LPS group and LPS+DXM group,IL-35 protein expression levels in lung homogenates of the other groups were more significant(P<0.01).Compared with the normal control group,lung coefficient,W/D ratio of lung tissue,LDH activity,mRNA levels and the protein levels of TNF-α,IL-6 and IL-1β in lung homogenates were significantly increased in the LPS group(P<0.01),accompanied by alveolar hemorrhage,alveolar wall thickening and neutro-phils infiltration.After IL-35 mRNA-LNP administration,lung coefficient,W/D ratio of lung tissue,LDH activity,mRNA levels and the protein levels of TNF-α,IL-6 and IL-1β in lung homogenates were signifi-cantly decreased(P<0.01),and alveolar hemorrhage,alveolar wall thickening and neutrophil infiltration were obviously improved.CONCLUSION IL-35 mRNA-LNP can express IL-35 protein in lung tissue of mice,and effectively improve LPS-induced ALI in mice by inhibiting the expression of proinflammatory factors.

OBJECTIVE:There are many kinds of biological agents for the treatment of rheumatoid arthritis in clinic,but the differences in therapeutic efficacy and safety are still unclear.The purpose of this study is to compare the differences in effectiveness and safety of different biological agents for the treatment of rheumatoid arthritis. METHODS:CNKI,VIP,WanFang,China Biomedical Literature System,PubMed,Cochrane Library,Web of Science,and Embase databases were searched to collect the randomized controlled trials on biological agents for rheumatoid arthritis that meet the requirements from inception to October 1,2022.The literature was selected by EndNote software,and the quality of the included literature was evaluated by RevMan 5.3 software.The software Stata 14.2 was used for direct meta-analysis and network meta-analysis of ACR20(American College of Rheumatology 20%response),ACR50(American College of Rheumatology 50%response),ACR70(American College of Rheumatology 70%response),erythrocyte sedimentation rate,and adverse reactions. RESULTS:Totally 39 articles were included,including 5 low-risk articles,4 high-risk articles,and the remaining 30 articles contained unknown risk bias,with a total of 13 treatment measures.The results of network meta-analysis:(1)In ACR20,infliximab combined with methotrexate(OR=5.54,95%CI:1.33-23.01,P<0.05),abatacept+methotrexate tablets(OR=3.21,95%CI:1.13-9.10,P<0.05),and tocilizumab(OR=2.95,95%CI:1.61-5.44,P<0.05)were better than methotrexate tablets.The probabilistic ranking of ACR20 was:infliximab+methotrexate tablets>abatacept+methotrexate tablets>tocilizumab>certlizumab>etanercept+methotrexate tablets.(2)In the aspect of ACR50,etanercept combined with methotrexate tablets(OR=4.04,95%CI:2.13-7.66,P<0.05),infliximab combined with methotrexate tablets(OR=4.79,95%CI:1.19-19.26,P<0.05),and tocilizumab combined with methotrexate tablets(OR=3.54,95%CI:1.36-9.22,P<0.05)had better therapeutic effects than methotrexate tablets.The probabilistic ranking of ACR50 was:etanercept+methotrexate tablets>infliximab+methotrexate tablets>tocilizumab+methotrexate tablets>tocilizumab>certlizumab+methotrexate tablets.(3)In terms of ACR70,the therapeutic effects of infliximab combined with methotrexate tablets(OR=8.00,95%CI:2.31-27.69,P<0.05),etanercept combined with methotrexate tablets(OR=4.26,95%CI:2.51-7.21,P<0.05),and tocilizumab combined with methotrexate tablets(OR=3.51,95%CI:1.82-6.80,P<0.05)were better than methotrexate tablets.The probabilistic ranking of ACR70 was infliximab+methotrexate tablets>etanercept+methotrexate tablets>tocilizumab+methotrexate tablets>certlizumab>adalimumab+methotrexate tablets.(4)In erythrocyte sedimentation rate,etanercept combined with methotrexate tablets(SMD=-9.23,95%CI:-16.55 to-1.92,P<0.05)was better than etanercept and methotrexate tablets(SMD=14.59,95%CI:7.28-21.91,P<0.05).The probabilistic ranking of erythrocyte sedimentation rate was etanercept+methotrexate tablets>infliximab+methotrexate tablets>etanercept>adalimumab+methotrexate tablets>methotrexate tablets.(5)In terms of adverse reactions,placebo(OR=0.62,95%CI:0.39-0.99,P<0.05)was better than infliximab and certlizumab(OR=0.44,95%CI:0.25-0.78,P<0.05).The probabilistic ranking of adverse reactions was placebo>infliximab>etanercept+methotrexate tablets>certlizumab>etanercept. CONCLUSION:Based on evidence from 39 randomized controlled trials,infliximab combined with methotrexate tablets(highly recommended)can be the first choice in clinic,and etanercept combined with methotrexate tablets(highly recommended)can be the second choice in terms of good effectiveness and safety.

Difficulty in swallowing is a common symptom in stroke patients, and nasogastric tubes are routinely used to solve the nutritional support problem of these patients. The existing nasogastric tube have the disadvantages of causing aspiration pneumonia and patient discomfort. The traditional transoral gastric tube has no one-way valve switch and gastric content storage device, and cannot be fixed in the stomach, resulting in reflux of gastric contents, inability to fully understand the digestion and absorption of gastric contents, and accidental dislocation of the gastric tube, affecting further feeding and gastric content detection. For these reasons, the medical staff of the department of gastroenterology and colorectal surgery of Jilin University China-Japan Union Hospital designed a new transoral gastric tube that can extract and store gastric contents, and was granted a national utility model patent of China (ZL 2020 2 1704393.1). The device consists of collection, cannula and fixation modules. The collection module includes three parts. Gastric contents storage capsule, which can clearly visualize the gastric contents; three-way switch, which can be controlled by rotating the pathway, makes the pathway exist in different states, which is convenient for medical personnel to extract gastric juice, as well as perform intermittent oral tube feeding on the patient or close the pipeline, and reduce contamination and prolong the service life of the gastric tube; one-way valve, which can effectively avoid the contents of the reflux back into the stomach. The tube insertion module includes three parts. A graduated tube, which can enable the medical staff to effectively identify the insertion depth; a solid guide head, which makes the insertion of the tube through the mouth more smoothly; the gourd-shaped passageway, which effectively avoids the blockage of the tube. The fixation module is a water-filled balloon, which is properly filled with water and air. After the pipe is inserted through the mouth, it can be injected with water and gas properly to avoid accidental withdrawal of the gastric tube. Intermittent oroesophageal tube feeding of patients with dysphagia after stroke through a transoral gastric tube that can extract and store gastric contents can not only accelerate the recovery process of patients and shorten the hospitalization time, but also transoral enteral nutrition can effectively promote the recovery of patients' systemic systems, which has certain clinical use value.
Humans ; Enteral Nutrition ; Aircraft ; Cannula ; China ; Drug Contamination

Pleomorphic adenoma (PA) is the most common benign tumour in the salivary gland and has high morphological complexity. However, the origin and intratumoral heterogeneity of PA are largely unknown. Here, we constructed a comprehensive atlas of PA at single-cell resolution and showed that PA exhibited five tumour subpopulations, three recapitulating the epithelial states of the normal parotid gland, and two PA-specific epithelial cell (PASE) populations unique to tumours. Then, six subgroups of PASE cells were identified, which varied in epithelium, bone, immune, metabolism, stemness and cell cycle signatures. Moreover, we revealed that CD36⁺ myoepithelial cells were the tumour-initiating cells (TICs) in PA, and were dominated by the PI3K-AKT pathway. Targeting the PI3K-AKT pathway significantly inhibited CD36⁺ myoepithelial cell-derived tumour spheres and the growth of PA organoids. Our results provide new insights into the diversity and origin of PA, offering an important clinical implication for targeting the PI3K-AKT signalling pathway in PA treatment.
Humans ; Adenoma, Pleomorphic/genetics* ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins c-akt ; Transcriptome ; Myoepithelioma

Objective:To investigate the clinical efficacy of 3D printed individual model combined with hyperbaric oxygen（HBO）therapy in treating complex ankle fracture，and to evaluate the therapy’s effect on prognosis.Methods:The clinical data of 45 patients with complex ankle fractures treated in the Department of Orthopedics of Penglai People’s Hospital from January 2017 to January 2021 were analyzed retrospectively. According to different treatment methods，they were divided into 3D model group（ n=21）and combined group（ n=24）. In addition，other 37 complex ankle fracture patients，who were treated in the Department of Orthopedics of Penglai People’s Hospital from January 2014 to December 2016 and had complete clinical data and detailed follow-up records，were selected as control group（conventional group）. The conventional group was given traditional surgery for complex ankle fractures，i.e.，after fracture reduction，the medial malleolus was fixed with steel wire tension band or screws，and the lateral malleolus was fixed with screws and steel plates. In the 3D model group，the strategy and approach of surgical operation were simulated and designed based on 3D printed individual models before operation. The combined group was additionally treated with HBO on the basis of the treatment of the 3D model group. The operation time，hospital length-of-stay，time to first ambulation，clinical fracture healing time，and the intraoperative bleeding loss of the three groups were observed and recorded，so as to compare the therapeutic effects of the three groups. All patients were followed up for one year. The functional recovery of postoperative ankle fracture was evaluated by Olerud-Molander Ankle Score（OMAS）. The incidences of postoperative complications were recorded. Results:The total effective rate of the 3D model group（95.24%）and the combined group（100.00%）were significantly higher than that of the conventional group（72.97%）（ P<0.05）. Regarding the operation time，hospital length-of-stay，time to first ambulation，clinical fracture healing time，and intraoperative bleeding loss，the results of the 3D model group and the combined group were significantly shorter or lower than those of the conventional group（ P<0.05）；the time to first ambulation and clinical fracture healing time of the combined group were significantly shorter than those of the control group（ P<0.05）；there was no statistically significant difference in the operation time，hospital length-of-stay，and intraoperative bleeding loss between the 3D model group and the combined group（ P>0.05）. All patients were followed up with a follow-up rate of 100.0%. The OMAS outcomes of the 3D model group and the combined group at the 1st，3rd，6th，and 12th month after operation were significantly higher than those of the conventional group at the same time points（ P<0.05），and the OMAS outcomes of the combined group at the 1st，3rd，6th，and 12th month after operation were significantly higher than those of 3D model group at the same time points（ P<0.05）. The incidence of postoperative complications was 16.22% in the conventional group，the incidence of deep venous thrombosis（DVT）was 4.8% in the 3D model group，and no complication was found in the combined group. Conclusion:The 3D printed individual model combined with HBO therapy has sound clinical efficacy and prognosis in treating complex ankle fracture. It can shorten the clinical fracture healing time and facilitate the rapid recovery of ankle function，therefore，it should be widely promoted in clinical practices.

Objective:To investigate the clinical efficacy of 3D printed individual model combined with hyperbaric oxygen（HBO）therapy in treating complex ankle fracture，and to evaluate the therapy’s effect on prognosis.Methods:The clinical data of 45 patients with complex ankle fractures treated in the Department of Orthopedics of Penglai People’s Hospital from January 2017 to January 2021 were analyzed retrospectively. According to different treatment methods，they were divided into 3D model group（ n=21）and combined group（ n=24）. In addition，other 37 complex ankle fracture patients，who were treated in the Department of Orthopedics of Penglai People’s Hospital from January 2014 to December 2016 and had complete clinical data and detailed follow-up records，were selected as control group（conventional group）. The conventional group was given traditional surgery for complex ankle fractures，i.e.，after fracture reduction，the medial malleolus was fixed with steel wire tension band or screws，and the lateral malleolus was fixed with screws and steel plates. In the 3D model group，the strategy and approach of surgical operation were simulated and designed based on 3D printed individual models before operation. The combined group was additionally treated with HBO on the basis of the treatment of the 3D model group. The operation time，hospital length-of-stay，time to first ambulation，clinical fracture healing time，and the intraoperative bleeding loss of the three groups were observed and recorded，so as to compare the therapeutic effects of the three groups. All patients were followed up for one year. The functional recovery of postoperative ankle fracture was evaluated by Olerud-Molander Ankle Score（OMAS）. The incidences of postoperative complications were recorded. Results:The total effective rate of the 3D model group（95.24%）and the combined group（100.00%）were significantly higher than that of the conventional group（72.97%）（ P<0.05）. Regarding the operation time，hospital length-of-stay，time to first ambulation，clinical fracture healing time，and intraoperative bleeding loss，the results of the 3D model group and the combined group were significantly shorter or lower than those of the conventional group（ P<0.05）；the time to first ambulation and clinical fracture healing time of the combined group were significantly shorter than those of the control group（ P<0.05）；there was no statistically significant difference in the operation time，hospital length-of-stay，and intraoperative bleeding loss between the 3D model group and the combined group（ P>0.05）. All patients were followed up with a follow-up rate of 100.0%. The OMAS outcomes of the 3D model group and the combined group at the 1st，3rd，6th，and 12th month after operation were significantly higher than those of the conventional group at the same time points（ P<0.05），and the OMAS outcomes of the combined group at the 1st，3rd，6th，and 12th month after operation were significantly higher than those of 3D model group at the same time points（ P<0.05）. The incidence of postoperative complications was 16.22% in the conventional group，the incidence of deep venous thrombosis（DVT）was 4.8% in the 3D model group，and no complication was found in the combined group. Conclusion:The 3D printed individual model combined with HBO therapy has sound clinical efficacy and prognosis in treating complex ankle fracture. It can shorten the clinical fracture healing time and facilitate the rapid recovery of ankle function，therefore，it should be widely promoted in clinical practices.

With thousands of sequenced 16 S rRNA genes available,and advancements in oligonucleotide microarray technology,the detection of microorganisms in microbial communities consisting of hundreds of species may be possible.The existing algorithms developed for sequence-specific probe design are not suitable for applications in large-scale bacteria detection due to the lack of coverage,flexibility and efficiency.Many other strategies developed for group-specific probe design focus on how to find a unique group-specific probe that can specifically detect all target sequences of a group.Unique group-specific probe for each group can not always be found.Hence,it is necessary to design non-unique probes.Each probe can specifically detect target sequences of a different subgroup.Combination of multiple probes can achieve higher coverage.However,it is a time-consuming task to evaluate all possible combinations.A feasible algorithm using relative entropy and genetic algorithm (GA) to design group-specific non-unique probes was presented.

Objective To analyze distribution of intracranial and extracranial arteriostenosis in patients with ischemic stroke. Methods 306 patients with ischemic stroke were collected during January 2002 to March 2005. All patients underwent color ultrasonography of carotid, TCD, MRA and DSA. According to NASCET, arteriostenosis was grouped into five grades: normal artery, mild stenosis(29%), moderate stenosis (30%—69%), severe stenosis(70%—90%) and occlusion(100%). Results (1) As for incidence of intracranial and extracranial arteriostenosis, 149 were of intracranial stenosis, 25 extracranial stenosis and 33 both. (2) As for incidence of single or dual stenosis, among 207 with arteriostenosis, single stenosis amounted to 129 and dual to 78. (3) Stenosis occurred in middle cerebral artery, distal vertebral artery, basilar artery, extracranial part of internal carotid artery, anterior cerebral artery, posterior cerebral artery, siphon part of internal carotid artery and onset part of vertebral artery in an order of decreased frequency. (4) DSA analysis revealed that, among 316 narrow blood vessels of 207 patients, 87 vessels were shown as severe stenosis or obstruction, accounting for 27.5%. (5) Among 164 cases, infarction occured in the corresponding stenostic vessel in 157 patients, accounting for 95.7%. ConclusionsIntracranial arteriostenosis is the most frequently encountered in those with ischemic stroke. Thereto, frequency of stenosis in middle cerebral artery is the highest, distal vertebral artery and basilar artery are next.