Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, which increases the incidence of colorectal cancer (CRC). In the pathophysiology of IBD, ubiquitination/deubiquitination plays a critical regulatory function. Josephin domain containing 2 (JOSD2), a deubiquitinating enzyme, controls cell proliferation and carcinogenesis. However, its role in IBD remains unknown. Colitis mice model developed by dextran sodium sulfate (DSS) or colon tissues from individuals with ulcerative colitis and Crohn's disease showed a significant upregulation of JOSD2 expression in the macrophages. JOSD2 deficiency exacerbated the phenotypes of DSS-induced colitis by enhancing colon inflammation. DSS-challenged mice with myeloid-specific JOSD2 deletion developed severe colitis after bone marrow transplantation. Mechanistically, JOSD2 binds to the C-terminal of inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) and preferentially cleaves K63-linked polyubiquitin chains at the K134 site, suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B (NF-κB) and inflammation in macrophages. It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane (AOM)/DSS-induced CRC, and AAV6-mediated JOSD2 overexpression in macrophages prevented the development of colitis in mice. These outcomes reveal a novel role for JOSD2 in colitis through deubiquitinating IMPDH2, suggesting that targeting JOSD2 is a potential strategy for treating IBD.

Objective:To evaluate the efficacy and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with HIV-1 or chronic HBV infection through observing the dynamic changes in antibody responses to two-dose inactivated SARS-CoV-2 vaccines.Methods:This cohort study recruited 169 people (including 39 with HIV-1 infection, 36 with chronic HBV infection and 94 individuals without chronic diseases) who completed two doses (prime and boost) of inactivated SARS-CoV-2 vaccination from January to December 2021. The levels of SARS-CoV-2 IgM and IgG antibodies at 14 d, one month and two months after boosting and neutralizing antibodies at one month were detected by chemiluminescence immunoassay and competitive ELISA method.Results:The positive rates of antibodies against SARS-CoV-2 in the HIV-1 and HBV groups were higher at one month after booster immunization, but significantly decreases at two months. The double-negative rate of SARS-CoV-2 IgM and IgG antibodies was higher in the HIV-1 and HBV groups than in the control group. The single positive rate of IgG antibody at one month in the control group was 2.01-fold higher than that of the HIV-1 group and 3.17-fold higher than that of the HBV group. The single positive rate of IgG antibody in people aged 18-39 years in each group was higher than that in the 40-59 age group. The antibody persistence was better in the HBV group than in the HIV-1 group, and the levels of IgG antibody in the HBV group was higher than that in the HIV-1 group. The neutralizing capacity of serum antibodies was significantly lower in the HIV-1 group than in the other groups ( P<0.000 1). The inhibition rate of serum neutralizing antibodies in the HBV group was lower than that in the control group among people aged 18-39 years [(34.050±6.031)% vs (64.220±3.845)%, t=4.43, P<0.000 1]. SARS-CoV-2-specific antibody responses were induced in 73.08% (19/26) of the patients aged 18-39 years in the HIV-1 group and 80.00% (4/5) in the HBV group. Conclusions:There were differences in the antibody responses to inactivated SARS-CoV-2 vaccines between different age groups, and infectious diseases affected the positive rates of antibodies and the neutralizing capability against SARS-CoV-2.

The influence of angled abutments on stress of peri-implant bone is a controversial issue. It is widely accepted that the use of angled abutments will increase adverse stress distributions on implants and surrounding bones. However, comparisons of clinical success rates of implants restored with angled and straight abutments indicate no significant differences. This review summarized the clinical application and biomechanical research associated with angled abutments. The use of angled abutments did not detrimentally affect the retention of dental implants, and tt was possible that the magnitude of stress within peri-implant bone increased or decreased under different conditions. Therefore, further researches should be conducted to confirm that favorable peri-implant stress levels may be induced if suitable angulation of abutments is selected.

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Animals ; Antiviral Agents ; pharmacology ; therapeutic use ; Betacoronavirus ; drug effects ; physiology ; Binding Sites ; drug effects ; Cell Line ; Coronavirus Infections ; drug therapy ; virology ; Crotonates ; pharmacology ; Cytokine Release Syndrome ; drug therapy ; Drug Evaluation, Preclinical ; Gene Knockout Techniques ; Humans ; Influenza A virus ; drug effects ; Leflunomide ; pharmacology ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae Infections ; drug therapy ; Oseltamivir ; therapeutic use ; Oxidoreductases ; antagonists & inhibitors ; metabolism ; Pandemics ; Pneumonia, Viral ; drug therapy ; virology ; Protein Binding ; drug effects ; Pyrimidines ; biosynthesis ; RNA Viruses ; drug effects ; physiology ; Structure-Activity Relationship ; Toluidines ; pharmacology ; Ubiquinone ; metabolism ; Virus Replication ; drug effects

Objective To investigate the expression of peripheral programmed death (PD)-1hiCXCR5-CD4+T cells and its clinical significance in systemic lupus erythematosus (SLE). Methods Peripheral blood PD-1hiCXCR5-CD4+ T cells from 21 SLE patients and 16 healthy controls were examined by flow cytometry. The levels of serum anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies were determined using immunoradiometric as-say. Data were analyzed with t test and Pearson's correlation test. Results The per-centages of PD-1hiCXCR5- cells within CD4+ T cell were significantly higher in SLE patients [(2.1 ±2.0)％] compared to normal controls [(0.3±0.3)％] (t=2.959, P<0.01). The percentages of PD-1hiCXCR5-cells within CD4+T cells in moderate to severe active SLE patients (3.0 ±2.0)％ was significantly increased compared to patients with mild or inactive (1.0±1.4)％(t=2.574, P<0.05) and normal controls (0.3±0.3)％ (t=5.149, P<0.01). The percentages of PD-1hiCXCR5- cells within CD4+ T cells from SLE patients were positively related with systemic lupus erythematosus disease activity index (SLEDAI) (r=0.475, P=0.0297). SLE patients in serum anti-dsDNA antibodies positive group (2.7±2.1)％displayed a higher percentage of PD-1hiCXCR5-cells within CD4+T cells than patients in serum anti-dsDNA antibodies negative group (0.6 ±0.5)％ (t=2.303, P<0.05). The percentages of PD-1hiCXCR5-cells within CD4+T cells from SLE patients were positively correlated with anti-dsDNA antibody titers. Conclusion The percentages of PD-1hiCXCR5- cells within CD4+ T cells from SLE patients are increased and are positively correlated with SLEDAI and anti-dsDNA antibody levels. Increased percentage of PD-1hiCXCR5-cells within CD4+T cells might play an important role in the pathogenesis of SLE.

Objective To discuss the outcomes of transvaginal repair and transabdominal repair for complex vesicovaginal fistula (VVF).Methods The data of complex VVF patients undergoing surgical repair in Peking University First Hospital were retrospectively collected between January 2009 and December 2016.The surgical modalities for complex VVF included transvaginal repair with layered closure and transabdominal repair with full thick vascular peritoneal interposition.The subtype distribution of complex VVF in transabdominal repair group and transvaginal repair group were recorded.The present study included 63 complex VVF patients with the median age of 46 years (range 26-60 years).There were 32 cases undergoing transvaginal repair with layered closure and 31 cases undergoing transabdominal repair with full thick vascular peritoneal interposition.The proportion of cases having failed previous repairs was significantly higher in transvagical repair group (30/32 vs.23/31,P =0.034).Compared with patients with transvaginal repair,patients with transabdominal repair tended to have multiple VVF without statistic significance (18.8％ vs.29.0％,P =0.338).Patients with transabdominal repair had larger VVF than patients with transvaginal repair (median:1.0cm vs.0.5cm,P ＜ 0.001).Results There were 2 cases suffering from fat liquefaction of surgical incision and 1 case suffering from adhesive intestinal obstruction in patients undergoing transabdominal repair.In the median follow-up duration of 24 months (range 8-102 months)and 29 months (range 8-78 months),the successful rates of transvaginal repair and transabdominal repair were 75％ (24/32) and 93.5％ (29/31).Severe lower urinary tract symptoms occurred in one patient who had urine leakage after transabdomnal repair.The bladder volume of patients in transabdominal group recovered at postoperative 3-6 months.Conclusions In consideration of surgical invasion and fistula condition,transvaginal repair with layered closure and transabdominal repair with full thick vascular peritoneal interposition should be performed individually for complex VVF.Meanwhile,the surgeons need pay attention to other perioperative management.

Objective    To investigate the effect and mechanism of calcitonin gene-related peptide (CGRP) on the prevention and treatment of transplant vein graft disease. Methods    The 25 New Zealand white rabbits were divided into three groups: an experimental group [n=8, the rabbit jugular veins transfected with adeno-associated virus vector tipe 2/1 containing CGRP gene (AAV2/1-CGRP)], a carrier group [n=9, transfected with mosaic adeno-associated virus vector tipe 2/1 containing LacZ gene (AAV2/1-LacZ)] and a control group (n=8, saline) and then the cervical veins were implantated into the ipsilateral carotid artery by reverse end-side anastomosis. At 4 weeks after surgery, the pathology of the specimens, CD68 immunohistochemistry, in situ β-galactosidase staining were obtained. The expression of CGRP gene was detected by reverse transcription-polymerase chain reaction (RT-PCR). Monocyte chemoattractant protein-1(MCP- 1), tumour necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-9 (MMP-9) were detected by real-time polymerase chain reaction (real-time PCR). Results    The CGRP and LacZ gene expression was positive at postoperative 4 weeks. The intima/media ratio was significantly inhibited in the experimental group. Macrophage infiltration and expression of inflammatory mediators including MCP-1, TNF-α, iNOS and MMP-9 were also significantly inhibited in the experimental group. Conclusion    Transfection of AAV2/1-CGRP inhibits inflammatory mediator expression, macrophage infiltration and neointimal hyperplasia in experimental vein graft disease.

Objective To explore influences of the fistula's location on the procedure and outcome of a transvaginal vesicovaginal (VVF) repair.Methods The medical data of patients undertaken transvaginal VVF repairs in Peking University First Hospital between Janurary 2009 and Auguest 2016 were retrospectively collected,including age,past history,causes of the fistula,disease course,past treatment,outcomes of the cystoscopy and imaging test and surgical information.The follow-ups were performed.Patients who had incomplete clinical data and lost to follow-up were not included.The present study included 68 VVF subjects with the median age of 46 years (range:24-64 years).The univariate analysis was performed to figure out potential risk factors for the VVF repair outcome.The duration and blood loss of VVF repairs were compared among the subjects with the fistulae located at bladder neck,trigone and supra-trigone region.Results There were 5,23 and 40 cases having VVFs located at bladder neck,trigone and supratrigone region respectively.The overall repair success rate was 88.2％ (60/68).According to results of the univariate analysis,subjects with more past repair times had significantly lower success rates.There were no significant differences in success rates of surgical repairs for VVFs located at bladder neck (80.0％,4/5),trigone (91.3％,21/23) and supra-trigone region (87.5％,35/40).And the location of VVFs had no significant association with the duration and blood loss during the VVF repair.Conclusions The location of VVFs had no influences on the procedure and outcomes of the transvaginal repairs.The VVF repair approach may not be determined based on the fistula's location alone.