The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has posed a global challenge to the control of the coronavirus disease 2019 (COVID-19) pandemic. Therefore, developing countermeasures that broadly protect against SARS-CoV-2 and related sarbecoviruses is essential. Herein, we have developed a lipid nanoparticle (LNP)-encapsulated mRNA (mRNA-LNP) encoding the full-length Spike (S) glycoprotein of SARS-CoV-2 (termed RG001), which confers complete protection in a non-human primate model. Intramuscular immunization of two doses of RG001 in Rhesus monkey elicited robust neutralizing antibodies and cellular response against SARS-CoV-2 variants, resulting in significantly protected SARS-CoV-2-infected animals from acute lung lesions and complete inhibition of viral replication in all animals immunized with low or high doses of RG001. More importantly, the third dose of RG001 vaccination elicited effective neutralizing antibodies against current epidemic XBB and JN.1 strains and similar cellular response against SARS-CoV-2 Omicron variants (BA.1, XBB.1.16, and JN.1) were observed in immunized mice. All these results together strongly support the great potential of RG001 in preventing the infection of SARS-CoV-2 variants of concern (VOCs).

JMJD1C (Jumonji Domain Containing 1C), a member of the lysine demethylase 3 (KDM3) family, is universally required for the survival of several types of acute myeloid leukemia (AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.
Core Binding Factor Alpha 2 Subunit/genetics* ; Humans ; Leukemia, Myeloid, Acute/pathology* ; Jumonji Domain-Containing Histone Demethylases/chemistry* ; Gene Expression Regulation, Leukemic ; Oxidoreductases, N-Demethylating/genetics* ; Cell Line, Tumor

Objective To develop an ultra-sensitive nanoparticle contrast agent for magnetic resonance angiography(MRA),to establish a highly sensitive imaging method for complicated vascular structures,and to provide imaging evidence for precision diagnosis,treatment,prognosis,and individualized treatment of ischemic stroke.Methods A dual-modality MRA contrast agent was prepared through ligand exchange of ultra-small NaGdF4 nanocrystals synthesized via a high temperature method,with biocompatible polyethylene glycol(PEG-dp)ligands.The basic structure,morphology,size distribution,and relaxation rate of the NaGdF4 nano contrast agent were characterized using transmission electron microscopy(TEM),a particle size potential analyzer,and a 7.0 T small-animal MRI scanner.A total of 6 healthy male SPF-grade BALB/c mice were selected and randomly divided into two groups,a NaGdF4 group and a Gd-DTPA group.The mice in the two groups were injected with NaGdF4 nanoparticle contrast agent or clinical Gd-DTPA contrast agent(0.1 mmol Gd3+/kg)via the tail vein.MRA images were obtained using a 7.0 T small animal magnetic resonance imaging system before and after the injection.A total of 6 healthy male SPF-grade Sprague Dawley(SD)rats were selected to establish a right middle cerebral artery occlusion(rMCAO)model to simulate ischemic stroke.The rats were injected with NaGdF4 nano-contrast agent(0.1 mmol Gd3+/kg)via the tail vein.Before and after the injection,brain MRI images of the rats were obtained using a 7.0 T small animal magnetic resonance imaging system.The in vitro and in vivo biological safety of the nano contrast agent was verified through cytotoxicity and hemolysis experiments and HE staining.Results Uniform spherical oil-phase NaGdF4 nanocrystals with an average particle size of approximately(4.43±0.46)nm were successfully prepared.After ligand exchange,biocompatible water-phase nanocrystals were obtained with a hydrodynamic size of 16.1 nm and a surface potential of-1.9 mV.The relaxation performance of this nanocrystal contrast agent was significantly superior to that of the clinical contrast agent Gd-DTPA.The longitudinal molar relaxivity rate(r1)of the NaGdF4 nano contrast agent was 8.84 mM-1s-1,while the transverse molar relaxivity rate(r2)was 27.36 mM-1s-1,which were 1.96 times(4.52 mM-1s-1)and 3.37 times(8.13 mM-1s-1)those of Gd-DTPA,respectively.It also demonstrated excellent biocompatibility.NaGdF4-enhanced MRA achieved high-resolution vascular imaging and effectively enabled the differentiation of the ischemic area,infarct core,and ischemic penumbra in an animal model of ischemic stroke.Conclusion The multi-parameter MRA based on NaGdF4 nanoparticles provides critical imaging evidence for the clinical diagnosis and prognosis of ischemic stroke.

To investigate the malignant progression and molecular mechanism of KHSRP regulating esophageal squamous cell carcinoma(ESCC) through the JAK1/STAT3 signaling axis.

Objective To explore the mechanism by which soybean isoflavone(SI)reduces calcium overload induced by cerebral ischemia-reperfusion(I/R).Methods Forty-eight SD rats were randomized into 4 groups to receive sham operation,cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion(I/R model group),or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+signaling pathway.Calcium levels and pathological changes in the ischemic penumbra(IP)were measured using calcium chromogenic assay and HE staining,respectively.Another 72 SD randomly allocated for sham operation,I/R modeling,or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter,and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining,and ROS level,Ca2+level,cell apoptosis,and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry;the protein expressions of Wnt5a,Frizzled-2,and P-CaMK II in the IP were detected with Western blotting and immunohistochemistry.Results In rats with cerebral I/R,Frizzled-2 knockdown significantly lowered calcium concentration(P<0.001)and the expression levels of Wnt5a,Frizzled-2,and P-CaMK II in the IP area.In soy isoflavones-pretreated rats,calcium concentration,ROS and MDA levels,cell apoptosis rate,cerebral infarct volume,and expression levels of Wnt/Ca2+signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group.Conclusion Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+signaling pathway.

Objective To explore the mechanism by which soybean isoflavone(SI)reduces calcium overload induced by cerebral ischemia-reperfusion(I/R).Methods Forty-eight SD rats were randomized into 4 groups to receive sham operation,cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion(I/R model group),or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+signaling pathway.Calcium levels and pathological changes in the ischemic penumbra(IP)were measured using calcium chromogenic assay and HE staining,respectively.Another 72 SD randomly allocated for sham operation,I/R modeling,or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter,and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining,and ROS level,Ca2+level,cell apoptosis,and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry;the protein expressions of Wnt5a,Frizzled-2,and P-CaMK II in the IP were detected with Western blotting and immunohistochemistry.Results In rats with cerebral I/R,Frizzled-2 knockdown significantly lowered calcium concentration(P<0.001)and the expression levels of Wnt5a,Frizzled-2,and P-CaMK II in the IP area.In soy isoflavones-pretreated rats,calcium concentration,ROS and MDA levels,cell apoptosis rate,cerebral infarct volume,and expression levels of Wnt/Ca2+signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group.Conclusion Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+signaling pathway.

Objective Using network pharmacology to explore the mechanism of action of tripterygium wilfordii-white peony in the treatment of rheumatoid arthritis(RA)and validating it using an adjuvant arthritis rat model.Methods Obtain the effective ingredients of tripterygium wilfordii and white peony through TCMSP database and predict the action targets;Obtain the disease targets of RA using DisGeNET and GeneCards online database;Draw the network of"tripterygium wilfordii-white peony-active ingredient-RA"and screen the core effective components using the software Cytoscape 3.9.1;Construct the protein-protein interaction(PPI)network using String database and screen the core targets using the CytoNCA plug-in,using the Metascape database for gene enrichment analysis of common targets,and using Auto Dock Tools and Pymol software for molecular docking of core active ingredients and targets.Enzyme linked immunosorbent assay(ELISA)detection of serum tumor necrosis factor-α(TNF-α),interleukin(IL)-4,IL-6,and IL-17 levels in adjuvant arthritis rats,Western blot was used to detect the expression of phosphorylated phosphatidylinositol 3-hydroxy kinase(p-PI3K)and phosphorylated AKT protein(p-AKT),validate the results of network pharmacology analysis.Results There were a total of 61 effective ingredients in the treatment of RA with tripterygium wilfordii-white peony,with 116 targets and 191 signaling pathways involved.Animal experiments have shown that compared with the model group rats,the serum cytokine TNF-α,IL-6 and IL-17 of rats in tripterygium wilfordii-white peony group and tripterygium wilfordii extract group were significantly decreased(P<0.05),IL-4 significantly increased(P<0.05);The expression of p-PI3K and p-AKT in synovial tissue was significantly reduced(P<0.05);Compared with rats in tripterygium wilfordii extract group,the TNF-α,IL-6,IL-17,p-PI3K and p-AKT of rats in tripterygium wilfordii-white peony group were significantly reduced(P<0.05),while IL-4 was significantly increased(P<0.05).Conclusion Tripterygium wilfordii-white peony can inhibit the overexpression of phosphatidylinositol 3-hydroxy kinase(PI3K)/protein kinase B(AKT)signaling pathway,regulate cytokine release,exert anti-inflammatory effects,and ultimately treat RA through multiple active ingredients and targets.

ObjectiveTo investigate the effect of Xinfeng capsules on immunoinflammatory indicators in patients with rheumatoid arthritis （RA） due to spleen deficiency and dampness exuberance. MethodA total of 102 patients were randomly divided into control group and observation group according to the random number table method， with 51 cases in each group. All patients were treated with methotrexate tablets， while those in the observation group received additional Xinfeng capsules. The course of treatment in both groups was 12 weeks. The 28-joint disease activity score （DAS28）， visual analogue scale （VAS） scores， morning stiffness time， erythrocyte sedimentation rate （ESR）， high-sensitivity C-reactive protein （hs-CRP）， rheumatoid factor （RF）， anti-cyclic citrullinated peptide （anti-CCP） antibody， vascular endothelial growth factor （VEGF）， and serum amyloid A （SAA） of the two groups before and after treatment were compared. The efficacy and incidence of adverse events were compared between the two groups. The Apriori association rule model and random walk model were constructed to evaluate the effect of Xinfeng capsules in improving hs-CRP， ESR， RF， SAA， VEGF， and anti-CCP. ResultThere were no dropouts in this study. There was no statistical difference in the indicators between the two groups before treatment. After 12 weeks of treatment， the total effective rate in the observation group was 90.19% （46/51）， which was higher than 74.51% （38/51） in the control group （χ²＝4.320，P<0.05）. DAS28， VAS score， and morning stiffness time in the observation group were improved compared with those in the control group （P<0.05）. Apriori association rule model results showed that the application of Xinfeng capsules in the observation group had a strong correlation with the reduction of RF， ESR， hs-CRP， SAA， and VEGF. The results of the random walk model showed that the improvement coefficients of hs-CRP， ESR， RF， SAA， and VEGF in the observation group were all better than those of the control group， and the improvement coefficient of anti-CCP in the control group was better than that of the observation group. The improvement degree of hs-CRP， ESR， RF， SAA， and VEGF in the observation group was superior to that of the control group （P<0.05）. The incidence of adverse reactions in the observation group was lower than in the control group （χ²＝4.057，P<0.05）. ConclusionOn the basis of the treatment with methotrexate tablets， Xinfeng capsules can effectively improve the immunoinflammatory level in RA due to spleen deficiency and dampness exuberance and reduce the incidence of adverse reactions.

Objective:To investigate the effects of urinary nickel exposure on insulin resistance, islet function and diabetes risk in adults aged 18 years and above in China.Methods:Based on the China National Human Biomonitoring from 2017 to 2018, a total of 500 diabetes patients were randomly selected as the case group, and the matched euglycemic control were selected by 1∶1 matching ratio. The urinary and venous blood samples of the subjects were collected, and the urinary nickel levels and serum glucose metabolism indexes such as fasting blood glucose and fasting insulin were detected, and the insulin resistance index (HOMA-IR), β cell function index (HOMA-β), and adjusted HOMA-β were calculated by using homeostasis model assessment. A multivariate logistic regression model was used to analyze the association between urinary nickel level and diabetes risk. Multiple linear regression models were used to evaluate the association of urinary nickel level with HOMA-IR, HOMA-β and adjusted HOMA-β.Results:The sex ratio of controls and cases was 1∶1. The multivariate logistic regression model showed that after adjusting for factors such as education level, smoking status, alcohol consumption, rice and meat intakes, family history of diabetes, BMI, total cholesterol level, hypertension, and urinary creatinine, compared with T1 group, the ORs of diabetes risk in the T2 and T3 groups were 1.36 (95% CI: 0.98-1.89) and 1.60 (95% CI: 1.14-2.24), respectively. The multiple linear regression model showed a positive association between urinary nickel levels and the elevated HOMA-IR, the β value of HOMA-IR in the T3 group was 0.12 (95% CI: 0.01-0.25) compared with the T1 group and each one-unit increase in the log-transformed urinary nickel level (2.71 μg/L) was associated with a 0.06 elevation in HOMA-IR (95% CI: 0.02-0.10). Meanwhile, the urinary nickel levels were negative associated with the adjusted HOMA-β, the β value of adjusted HOMA-β in the T3 group were -0.26 compared with the T1 group (95% CI: -0.41- -0.11), and each one-unit increase in the log-transformed urinary nickel level (2.71 μg/L) was associated with a -0.09 decrease in adjusted HOMA-β(95% CI: -0.14- -0.04). Conclusion:Higher urinary nickel level is positively correlated with elevated insulin resistance and diabetes risk while negatively correlated with the function of pancreatic islet β cells in adults in China.

Objective:To investigate the diagnostic value of thyroid imaging report and data system (TIRADS) combined with BRAF V600E mutation detection in differentiating uncertain thyroid nodules by using fine needle aspiration cytology (FNAC), and to analyze the role of TIRADS classification in screening the nodules needed to be routinely detected for BRAF V600E mutation.Methods:The clinicopathological data of 337 thyroid nodules patients diagnosed with TIRADS classification, FNAC Bethesda classification, BRAF V600E mutation detection and postoperative histopathology from the Second Hospital of Hebei Medical University between January 2018 and August 2021 were retrospectively analyzed. The role of TIRADS classification, FNAC Bethesda classification and BRAF V600E mutation detection alone and the combined detection in the differentiation of benign and malignant thyroid nodules was also analyzed.Results:The postoperative histopathological result was regarded as the gold standard. The sensitivity of TIRADS classification, FNAC Bethesda classification and BRAF V600E mutation for thyroid cancer diagnosis was 76.0%, 88.1% and 80.4% respectively, and the corresponding specificity was 84.0%, 96.0% and 100.0%, respectively. Histologically, 37 (62.7%) of 59 nodules with FNAC uncertainty were malignant nodules after the surgery. The sensitivity and accuracy of BRAF V600E mutation detection in the diagnosis of FNAC uncertain nodules were 51.4% and 69.5%, respectively, while the sensitivity and accuracy of BRAF V600E mutation detection combined with TIRADS classification were 86.5% and 84.7%, respectively. The sensitivity and accuracy of BRAF V600E mutation detection combined with TIRADS classification were both improved ( P values were 0.002 and 0.049, respectively). The positive rate of BRAF V600E mutation in thyroid nodules increased step by step with the rise of risk degree in TIRADS classification, and the type 3 cases were lower than those in type 4a cases [14.3% (1/7) vs. 68.6% (24/35), P = 0.012], and there were no statistically significant differences among the adjacent groups above 4a (all P > 0.05). Conclusions:TIRADS combined with BRAF V600E mutation detection can improve the sensitivity and accuracy in the diagnosis of FNAC uncertain thyroid nodules. The BRAF V600E mutation rate of TIRADS 4a and above nodules is high, so routine detection is recommended.