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.

Objective:To explore effect of IgG receptor FcγRⅡB on neuronal injury and imbalance of Th17/Treg in experi-mental autoimmune encephalomyelitis(EAE)model mice.Methods:C57BL/6 mice were randomly divided into control group,EAE group,FcγRⅡB group and EAE+FcγRⅡB group,with 15 mice in each group.EAE model was induced by subcutaneous injection of MOG35-55 peptide and treated with FcγRⅡB lentiviral solution.After modeling was established,body weight of mice was weighed every day,and neurological function was scored for 30 d;after 30 days,mice were sacrificed.HE staining was used to observe patho-logical changes of brain tissue,LFB staining was used to assess structural changes of spinal cord myelin,and immunofluorescence staining was used to detect spinal cord cerebral cortex neuron nuclear antigen(NeuN)and Caspase-3 expressions,TUNEL staining was used to detect apoptosis of neurons,ELISA was used to detect serum IL-6,IL-17,IL-10 and TGF-β levels,flow cytometry was used to analyze proportion of Th17 and Treg cells in spleen,Western blot was used to determine protein expressions of retinoic acid-related orphan receptor γt(RORγt)and Forkhead family transcription factor 3(Foxp3)in spinal cord tissue.Results:Compared with control group,mice in EAE group had decreased body weight,increased neurological function scores,obvious infiltration of inflamma-tory cells in brain tissue,and signs of demyelination in spinal cord,fluorescence expression intensity of NeuN was weakened and fluorescence expression intensity of Caspase-3 was enhanced,there were more TUNEL-positive stained cells,number of apoptotic cells was increased,levels of IL-6 and IL-17 in serum were increased,and levels of IL-10 and TGF-β were decreased,proportion of Th17 cells in spleen was increased,proportion of Treg was decreased,expression of RORγt protein in spinal cord tissue was up-regu-lated while relative expression of Foxp3 protein was down-regulated(P<0.05);compared with EAE group,weight of mice in EAE+FcγRⅡB group was increased,neurological function score was decreased,infiltration of inflammatory cells in brain tissue was reduced,demyelination of spinal cord was improved,fluorescence expression intensity of NeuN was enhanced,and fluorescence expression intensity of Caspase-3 was weakened,there were fewer TUNEL-positive stained cells,number of apoptotic cells was decreased,levels of IL-6 and IL-17 in serum were decreased,while levels of IL-10 and TGF-β were increased,at the same time,proportion of Th17 cells in spleen was decreased and proportion of Treg was increased,expression of RORγt protein in spinal cord tissue was down-regulated,while expression of Foxp3 protein was up-regulated(P<0.05).Conclusion:FcγRⅡB has neuroprotective effect on EAE mice,and can reduce infiltration of inflammatory cells and demyelination in brain tissue,whose mechanism may be related to regulation of cytokine levels and immune balance of Th17/Treg cells.

Objective:To investigate the effect of glucocorticoids on brain injury in rats with Streptococcus pneumoniae(SP)meningitis,as well as the changes of cerebrospinal fluid immunoglobulin levels under this effect.Methods:A total of 40 SD rats were divided into control group,model group,low-dose methylprednisolone sodium succinate group(Low-MSS)and high-dose methylpred-nisolone sodium succinate group(High-MSS)according to random table method,with 10 rats in each group.Except for the control group,SP meningitis models were established in other groups.Rats in Low-MSS group and High-MSS group were injected with methyl-prednisolone sodium succinate by tail vein at doses of 5 mg/kg and 10 mg/kg,respectively,once a day for 21 days.Neurobehavioral scores of rats after modeling were performed by Loeffler method;contents of immunoglobulin IgA,IgM and IgG in cerebrospinal fluid of rats were detected by immunoturbidimetry;levels of inflammatory cytokines TNF-α,IL-6 and IFN-γ in supernatant of rats brain ho-mogenate were determined by ELISA;HE staining was used to detect pathological changes of rats brain tissue;Nissl staining was used to detect the number of neuronal cells in rats brain tissue;TUNEL staining was used to detect the number of apoptotic cells in rats brain tissue;immunofluorescence staining was used to detect expressions of GFAP and S-100b,the marker proteins of rat brain tissue injury.Results:Before SP injection,there was no difference in neurobehavioral scores between control group and model group(P>0.05),at 24 h,48 h and 72 h after SP injection,neurobehavioral scores in model group were significantly lower than those in control group(P<0.05).Compared with control group,contents of IgA,IgM and IgG in cerebrospinal fluid of rats in model group were in-creased,and contents of TNF-α,IL-6 and IFN-γ in supernatant of the brain homogenate were also increased,the tissue was obviously damaged,accompanied by a large number of inflammatory cells infiltration,the number of neuronal cells were decreased,the number of apoptotic cells were increased,and the fluorescence density values of S-100b and GFAP were increased(P<0.05);compared with model group,contents of IgA,IgM and IgG in cerebrospinal fluid of rats in Low-MSS group and High-MSS group were decreased,and contents of TNF-α,IL-6 and IFN-γ in brain homogenate supernatant were also decreased(P<0.05),brain tissue damage was alleviated,inflammatory cell infiltration was significantly reduced,neuronal cells were increased,the number of apoptotic cells were decreased,and the fluorescence density values of S-100b and GFAP were also decreased(P<0.05).In addition,the improvement effect of various indexes and brain tissue damage in High-MSS group was better than that in Low-MSS group,and the difference were statistically signifi-cant(P<0.05).Conclusion:Glucocorticoid methylprednisolone sodium succinate can effectively improve the brain tissue damage in SP meningitis rats,regulate the levels of immunoglobulin IgA,IgM and IgG,and has a protective effect on SP meningitis rats.

The process of embryo implantation is a multifaceted and intricate dynamic event that includes the development of endometrial receptivity, embryo localization, adhesion, and invasion. Adhesion molecules, acting as crucial mediators of communication between cells or between cells and the extracellular matrix, are essential for the maintenance of endometrial receptivity and the regulation of embryo localization, adhesion, and invasion. However, the mechanisms by which adhesion molecules of maternal and embryo are organized to regulate key events in the peri-implantation period have yet to be fully explored. Based on recent research findings, this review provides a summary of the functions of different adhesion molecules at the maternal-fetal interface and their potential regulatory mechanisms according to the key progress of embryo implantation. In particular, we discussed the interactions between decidual immune cells and other cells mediated by adhesion molecules during the invasion process, which will provide novel perspectives into the role of adhesion molecule dysfunction in contributing to implantation failure.

The process of embryo implantation is a multifaceted and intricate dynamic event that includes the development of endometrial receptivity, embryo localization, adhesion, and invasion. Adhesion molecules, acting as crucial mediators of communication between cells or between cells and the extracellular matrix, are essential for the maintenance of endometrial receptivity and the regulation of embryo localization, adhesion, and invasion. However, the mechanisms by which adhesion molecules of maternal and embryo are organized to regulate key events in the peri-implantation period have yet to be fully explored. Based on recent research findings, this review provides a summary of the functions of different adhesion molecules at the maternal-fetal interface and their potential regulatory mechanisms according to the key progress of embryo implantation. In particular, we discussed the interactions between decidual immune cells and other cells mediated by adhesion molecules during the invasion process, which will provide novel perspectives into the role of adhesion molecule dysfunction in contributing to implantation failure.

Objective:To analyze the epidemiological characteristics and genotypes of human rhinovirus (HRV) in patients with upper respiratory tract infection in Qingdao in the winter of 2020.Methods:Throat swab samples were collected from 101 patients with upper respiratory tract infection in Qingdao from November 2020 to January 2021. Quantitative PCR was used to detect 15 common respiratory viruses in the samples. HRV-positive samples were further analyzed with RT-PCR to amplify and sequence HRV VP4/VP2 gene. A phylogenetic tree was constructed based on the sequencing results and homology analysis was conducted.Results:Six common respiratory viruses were detected in the 101 patients. Thirty-four cases (34/101, 33.66%) were single pathogen infection and two cases were multiple infection (2/101, 1.98%). The positive rate of HRV was the highest (21.78%, 22/101). Twenty HRV VP4/VP2 sequences were successfully amplified. Phylogenetic analysis showed that there were 16 strains of HRV-A subtype and four strains of HRV-C subtype and 14 serotypes were involved.Conclusions:HRV was one of the leading viral pathogens causing upper respiratory tract infection in Qingdao in the winter of 2020 and the predominant subtype was HRV-A.

Objective:To Isolate and identify human rhinovirus (HRV) in hospitalized children with pneumonia in Qingdao in 2020.Methods:A total of 98 throat swab samples were collected from hospitalized children with pneumonia in 2020. Common respiratory viruses were screened through RT-qPCR. The HRV positive samples were inoculated into H1-HeLa cells. Viruses with typical cytopathic effect (CPE) were identified by HRV specific RT-PCR. Subsequently, sequences of HRV-VP4/VP2 gene were used to construct phylogenetic trees and analyze homology with sequences of reference strains through MEGA software.Results:Among 98 hospitalized children with pneumonia, 11 samples were HRV positive in 98 throat swab samples. After the typical CPE appeared in HeLa cells, two strains of HRV were identified by specific RT-PCR. The HRV-A28 and HRV-A58 were confirmed by comparison and analysis of VP4/VP2 sequence. Phylogenetic tree found that the isolated HRV-A28 strain was genetically close to strains of Singapore in 2011, of Tunisia in 2017, and Kenya in 2017. The isolated HRV-A58 strain was genetically close to the strains of Australia in 2009, Venezuela in 2011, Mongolia in 2011, and the United States in 2014.Conclusions:The HRV-A28 and HRV-A58 strains were isolated from the throat swabs of children patients with pneumonia in Qingdao.

Objective To investigate the efficacy of hyperbaric oxygen ( HBO ) combined with ganglioside on diffuse axonal injury and effects on serum-related indicators and prognosis. Methods Eighty-two patients with diffuse axonal injury admitted into our department were equally divided into 2 groups ( n=41 ) , according to different treatment methods. The control group was given such symptomatic supportive treatment as hormone, hemostasis, reduction of intracranial pressure via dehydration, nerve nutrition, maintenance of electrolyte balance, fluid infusion and routine nursing care. The study group was treated with HBO therapy combined with ganglioside in addition to the treatment received by the control group. The rate of consciousness and mean conscious recovery time, serum-related indicators, cognitive function and prognosis after treatment were compared between the patients of the 2 groups. Results After treatment, the rate of consciousness (80. 5％) and mean conscious recovery time of the study group ( 9. 3 ± 1. 4days ) were all superior to (56. 1％)and (16. 1 ± 3. 3 days) of the control group (χ2 =5. 632, t=6. 349, P<0. 05). After treatment, the levels of neuron-specific enolase (NSE) (11. 1 ± 2. 3 μg/L), S100 calcium binding protein B (S100B) (1. 1 ± 0. 1 ng/L) and myelin basic protein (MBP) (6. 6 ± 1. 2μg/L) were all significantly better than (16. 7 ±3.1)μg/L,(1.6±0.2)ng/L and(8.5 ±1.0)μg/L of the control group (t1 =4.684, t2 =5.219, t3 =4. 352, P<0. 05). Following treatment, the MMSE scores (28. 3 ± 5. 3) and ADL scores (25. 1 ± 1. 1) of the study group were significantly better than the MMSE scores (25. 2 ± 4. 1) and ADL scores (33. 6 ± 1. 5) of the control group (t1 =4. 429, t2 =5. 642, P<0. 05). Six months after treatment, the prognosis rate of the study group (73. 2％) was significantly higher than that of the control group (41. 5％) (χ2 =8. 424, P<0. 05). Conclusion HBO combined with ganglioside could produce better therapeutic effects in the treatment of diffuse axonal injury. In the meantime, it could avoid deterioration of secondary brain injury to the largest extent and promote recovery of nerve function, and ultimately improve the prognosis of patients. For this reason, it is worth further clinical application.

Objective To investigate the efficacy of hyperbaric oxygen ( HBO ) combined with ganglioside on diffuse axonal injury and effects on serum-related indicators and prognosis. Methods Eighty-two patients with diffuse axonal injury admitted into our department were equally divided into 2 groups ( n=41 ) , according to different treatment methods. The control group was given such symptomatic supportive treatment as hormone, hemostasis, reduction of intracranial pressure via dehydration, nerve nutrition, maintenance of electrolyte balance, fluid infusion and routine nursing care. The study group was treated with HBO therapy combined with ganglioside in addition to the treatment received by the control group. The rate of consciousness and mean conscious recovery time, serum-related indicators, cognitive function and prognosis after treatment were compared between the patients of the 2 groups. Results After treatment, the rate of consciousness (80. 5％) and mean conscious recovery time of the study group ( 9. 3 ± 1. 4days ) were all superior to (56. 1％)and (16. 1 ± 3. 3 days) of the control group (χ2 =5. 632, t=6. 349, P<0. 05). After treatment, the levels of neuron-specific enolase (NSE) (11. 1 ± 2. 3 μg/L), S100 calcium binding protein B (S100B) (1. 1 ± 0. 1 ng/L) and myelin basic protein (MBP) (6. 6 ± 1. 2μg/L) were all significantly better than (16. 7 ±3.1)μg/L,(1.6±0.2)ng/L and(8.5 ±1.0)μg/L of the control group (t1 =4.684, t2 =5.219, t3 =4. 352, P<0. 05). Following treatment, the MMSE scores (28. 3 ± 5. 3) and ADL scores (25. 1 ± 1. 1) of the study group were significantly better than the MMSE scores (25. 2 ± 4. 1) and ADL scores (33. 6 ± 1. 5) of the control group (t1 =4. 429, t2 =5. 642, P<0. 05). Six months after treatment, the prognosis rate of the study group (73. 2％) was significantly higher than that of the control group (41. 5％) (χ2 =8. 424, P<0. 05). Conclusion HBO combined with ganglioside could produce better therapeutic effects in the treatment of diffuse axonal injury. In the meantime, it could avoid deterioration of secondary brain injury to the largest extent and promote recovery of nerve function, and ultimately improve the prognosis of patients. For this reason, it is worth further clinical application.

Objective To investigate the added value of CTAC for improving image quality and diagnostic efficiency of bone imaging in SPECT/CT.Methods Seventy-five patients (47 males,28 females,(56.6± 12.8) years) with abnormal uptake in planar whole-body bone scintigraphy underwent SPECT/CTfor differentiation of malignant from benign spinal lesions.NAC and CTAC SPECT images were classified based on 5-point scale (5:excellent,4:good,3:adequate,2:suboptimal,1:inadequate).The diagnostic confidence for both NAC and CTAC SPECT images were classified based on 4-point scale (4:definite,3:certain,2:equivocal,1:uninterpretable).The pathological results after surgery were used as gold standard to evaluate the added diagnostic value of CTAC for spinal lesions.Wilcoxon-signed rank sum test was used for data analysis.Results CTAC improved the image quality in 37.3％ (28/75) of patients,and downgraded in 2.7％ (2/75) of patients.The remaining 45 patients were unchanged (60.0％,45/75).SPECT with CTAC could significantly improve the image quality (z=-4.747,P＜0.001),but the overall diagnostic confidence was not increased (z=-1.000,P＞0.05).Conclusion CTAC can improve the image quality of spinal SPECT,especially useful in imaging with poorer quality,but it has no significant incremental value in diagnostic confidence.