Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

eIF3a is a N ⁶-methyladenosine (m⁶A) reader that regulates mRNA translation by recognizing m⁶A modifications of these mRNAs. It has been suggested that eIF3a may play an important role in regulating translation initiation via m⁶A during infection when canonical cap-dependent initiation is inhibited. However, the death of animal model studies impedes our understanding of the functional significance of eIF3a in immunity and regulation in vivo. In this study, we investigated the in vivo function of eIF3a using eIF3a knockout and knockdown mouse models and found that eIF3a deficiency resulted in splenic tissue structural disruption and multi-organ damage, which contributed to severe sepsis induced by Lipopolysaccharide (LPS). Ectopic eIF3a overexpression in the eIF3a knockdown mice rescued mice from LPS-induced severe sepsis. We further showed that eIF3a maintains a functional and healthy immune system by regulating B cell function and quantity through m⁶A modification of mRNAs. These findings unveil a novel mechanism underlying sepsis, implicating the pivotal role of B cells in this complex disease process regulated by eIF3a. Furthermore, eIF3a may be used to develop a potential strategy for treating sepsis.

Taking chronic atrophic gastritis （CAG） as an example， the frontier technologies in data science have been introduced into the inheritance， innovation and development of traditional Chinese medicine （TCM）， providing reference for conducting real-world clinical research on specialized diseases of TCM. This paper put forward the construction of CAG data science system by elaborating the connotation of data science and its application value in TCM， and discussed the path to build CAG data science system， namely through "data acquisition-knowledge expression-knowledge reasoning" to establish CAG database， knowledge base and develop diagnosis platform differentiating diseases and syndromes. Besides， this paper analyzed the prospects of CAG data science in improving data governance ability and knowledge discovery efficiency， deepening the level of knowledge sharing， promoting interdisciplinary integration， and strengthening the integration process of industry， academia and research.

Objective To identify clinical risk factors for early major adverse cardiovascular events (MACEs) following surgical correction of supravalvar aortic stenosis (SVAS). Methods Patients who underwent SVAS surgical correction between 2002 and 2019 in Beijing and Yunnan Fuwai Cardiovascular Hospitals were included. The patients were divided into a MACEs group and a non-MACEs group based on whether MACEs concurring during postoperative hospitalization or within 30 days following surgical correction for SVAS. Their preoperative, intraoperative, and postoperative clinical data were collected for multivariate logistic regression. Results This study included 302 patients. There were 199 males and 103 females, with a median age of 63.0 (29.2, 131.2) months. The incidence of early postoperative MACEs was 7.0% (21/302). The multivariate logistic regression model identified independent risk factors for early postoperative MACEs, including ICU duration (OR=1.01, 95%CI 1.00-1.01, P=0.032), intraoperative cardiopulmonary bypass (CPB) time (OR=1.02, 95%CI 1.01-1.04, P=0.014), aortic annulus diameter (OR=0.65, 95%CI 0.43-0.97, P=0.035), aortic sinus inner diameter (OR=0.75, 95%CI 0.57-0.98, P=0.037), and diameter of the stenosis (OR=0.56, 95%CI 0.35-0.90, P=0.016). Conclusion The independent risk factors for early postoperative MACEs include ICU duration, intraoperative CPB time, aortic annulus diameter, aortic sinus inner diameter, and diameter of the stenosis. Early identification of high-risk populations for MACEs is beneficial for the development of clinical treatment strategies.

To summarize the nursing experience of a patient with cardiac resynchronization therapy defibrillator(CRT-D)implantation who was about to deplete battery due to repeated discharge after implantation and underwent left ventricular assist device implantation combined with cryoablation.Key points of care were as follows.To begin with,we actively managed arrhythmias and electric storm.Secondly,we carried refined capacity management to avoid water and sodium retention.Thirdly,we formulated personalized anticoagulation programs to reduce the risk of bleeding and thrombosis.Then,the pump line infection should be prevented as early as possible.At the whole stage,we provided psychological counseling to improve emotional state.After discharge,regular follow-up was carried out through online and offline method to ensure quality of life in the long term.After careful treatment and nursing care,23 days after surgery,the patient was discharged smoothly,and good follow-up after discharge.

Objective:To analyze the biological characteristics, phylogenic features and clinical significance of SQ219 and SQ220 isolated from clinical sputum and midstream urine specimens.Methods:The culture and biochemical characteristics of the two strains were observed. VITEK2 System, drug sensitivity testing and MALDI-TOF mass spectrometry were used for bacterial identification. Phylogenetic analysis based on 16S rRNA and core genome was performed. The average nucleotide identity (ANI) based on whole genome sequences was calculated.Results:SQ219 and SQ220 were Gram-stain-negative, aerobic, catalase- and oxidase-positive, and non-motile bacteria. Their optimum growth was observed in NaCl-free medium at 30℃ and pH7. Flexirubin-type pigments were produced by SQ220 on Colombia blood agar, but not by SQ219. Both SQ219 and SQ220 were resistant to aztreonam, amikacin, tobramycin and colistin, which was consistent with the drug resistance phenotype of genus Chryseobacterium. The genome sequences of SQ219 and SQ220 were 5.08 Mb and 4.80 Mb in length, and the G+ C contents were 36.72% and 36.36%, respectively. Both strains carried β-lactam resistance gene ( blaCGA). 16S rRNA phylogenetic analysis showed that SQ219 and SQ220 were closely related to Chryseobacterium gambrini DSM18014 T with the similarities of 98.93% and 98.36%, respectively. Core genome phylogenetic analysis revealed that SQ219 and SQ220 were highly homologous to Chryseobacterium gambrini DSM18014 T. However, the ANI values between the two strains and Chryseobacterium gambrini DSM18014 T were 92.49% and 93.27%, respectively, below the threshold for prokaryotic species identification. Conclusions:Based on the phenotypic and phylogenetic data, SQ219 and SQ220 represent a novel species of the genus Chryseobacterium. This study would help promote the understanding of the evolution of Chrysobacterium and provide reference for the identification of new species of Chrysobacterium.

Glioma is a common primary malignant brain tumor. At present, the main clinical treatment is surgical resection combined with radiotherapy and chemotherapy. Due to the selective permeability of the blood-brain barrier and the characteristics of multi-drug resistance of tumor cells, the therapeutic effect is not ideal. In recent years, studies have found that borneol could open the blood-brain barrier and promote the infiltration of chemotherapy drugs. When borneol is combined with or co-carried with chemotherapy drugs, chemotherapy drugs could target more glioma tissues and increase efficacy. The preclinical studies on the combination of borneol and chemotherapy drugs in recent years were reviewed in this article, in order to provide useful reference for the treatment of glioma.

More than 85% of patients with uveal melanoma (UM) carry a GNAQ or GNA11 mutation at a hotspot codon (Q209) that encodes G protein α subunit q/11 polypeptides (Gα_q/11). GNAQ/11 relies on palmitoylation for membrane association and signal transduction. Despite the palmitoylation of GNAQ/11 was discovered long before, its implication in UM remains unclear. Here, results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells. Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11^Q209L-induced malignant transformation in NIH3T3 cells. Importantly, the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells, which are much more dependent on Gα_q/11 signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations. Furthermore, the palmitoylation inhibitor, 2-bromopalmitate, also specifically disrupted Gα_q/11 downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor, ABT-199, in vitro. The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.
Humans ; Mice ; Animals ; Lipoylation ; NIH 3T3 Cells ; Uveal Neoplasms/genetics* ; Melanoma/genetics* ; Cell Proliferation ; Proto-Oncogene Proteins c-bcl-2 ; GTP-Binding Protein alpha Subunits, Gq-G11/genetics*

Objective: To investigate oral health related quality of life and associated factors of adolescents between 12 and 15 years old, and to provide countermeasures and suggestions for oral health promotion of adolescents. Methods: This cross-sectional study recruited 3 840 adolescents aged 12-15 through multi-stage stratified cluster sampling method. The oral clinical examination and oral health questionnaire were conducted. Descriptive analysis, non-parametric testing and logistic regression analysis were used to analyze the oral health-related quality of life and associated factors. Results: Oral problems showed moderate to severe impact on quality of life,especially on eating (27.1%). Ordinal Logistic regression analysis showed that low sugar intake frequency, few teeth with gingival bleeding, no history of dental pain in the past 12 months,no history of tooth injuries, and administrative region of residence (Nanhai, Shunde) were associated with higher oral health-related quality of life,(OR=0.6-0.8，P<0.05). Conclusion The oral health-related quality of life of adolescents in Foshan was slightly better than the average national level. It is recommended to accurately formulate and ensure the full implementation of oral public health measures based on the comprehensive analysis of the local area, and combine various efforts to strengthen education on reducing excessive intake of sugar, prevent gingival bleeding, relieve and treat toothache in time, pay attention to adolescents with histories of dental trauma, and update the concepts of receiving oral health examination for the adolescents themselves, parents and teachers, and help adolescents develop the habit of regular oral examinations.

Objective:To investigate the effect of early acupuncture treatment on limb function in patients with acute cerebral infarction (ACI).Methods:A total of 114 patients with first-episode ACI in our hospital from March 2018 to March 2019 were selected and randomly divided into three groups, 38 cases in each group. The control group was treated with conventional western medicine therapy, while the experimental group A and group B were given acupuncture treatment on the basis of the control group. The group A started treatment at 3rd days and the group B started at 10th day after admission. All three groups were treated for 2 weeks. The National Institute of Health Stroke Scale (NIHSS) was used to evaluate the degree of neurological deficit. The Fugl Meyer assessment of motor function (FAM) was used to evaluate the motor function. The Barthel Index (BI) was used to evaluate the activities of daily living, and the rehabilitation status was evaluated according to muscle strength grading. The levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were detected by ELISA to evaluate the clinical efficacy.Results:The total effective rate was 94.7% (36/38) in group A, 84.2% (30/38) in group B and 73.7% (22/38) in control group. The difference was statistically significant ( χ2=14.748, P<0.01). After treatment, NIHSS scores of three groups were significantly decreased ( F=97.619, P<0.01), and the scores of FAM, BI and muscle strength in group A were significantly lower than those in the group B ( t=12.580, P<0.01); FAM, BI scores and muscle strength of three groups were significantly increased ( F=134.525, 35.100, 164.160, all Ps<0.001), and those of group A were significantly higher than those in group B ( t=8.634, 7.260, 20.305, all Ps<0.001). After treatment, serum NGF (148.80 ± 22.17 pg/ml, 132.14 ± 20.40 pg/ml vs. 125.82 ± 18.31 pg/ml, F=12.926), BDNF (5.01 ± 1.14 ng/ml, 4.10 ± 1.09 ng/ml vs. 3.92 ± 0.95 ng/ml, F=11.481) in the group A and group B were significantly higher than those in the control group ( P<0.01), and serum NGF, BDNF in group A were significantly lower than those in the group B ( t=5.046, 5.277, all Ps<0.01). Conclusions:Early acupuncture treatment can increase the levels of serum NGF and BDNF, promote the recovery of nerve factors and limb function, and the curative effect of acupuncture treatment starting at 3rd days after admission is better than 10th day.