Antibiotic resistance is spreading at a faster rate than new antibiotic agents applied for clinical remedies. It is an urgent need to discover potential compounds to combat multidrug-resistant (MDR) bacteria. Marine fungi offer a promising avenue for mining antibiotic-like molecules with chemical diversity. To discover structurally novel and antibiotic metabolites, we screened the in-house marine fungus genome library and found a fungus Stephanonectria keithii LZD-10-1 containing a non-ribosomal peptide synthetase (NRPS) cluster with 18 modules to synthesize a new subfamily of peptaibols with effective eradication against MDR pathogens. Targeting isolation of the cultured fungus afforded six new peptaibols, which exhibit the ability to kill MDR bacteria by targeting bacterial membrane phospholipids, especially phosphatidylglycerol (PG), leading to the dysfunction of bacterial membranes. Furthermore, their efficacies against methicillin-resistant Staphylococcus aureus (MRSA) in both Galleria mellonella and mouse wound infection models were observed. This study underscores the significance of employing genome-guided approaches to identify untapped marine fungi as potential sources for novel antibiotic candidates with unique scaffolds.

ObjectiveTo explore the clinical features and causative genes of short stature children with unknown etiology， providing evidence for precise clinical diagnosis and treatment. MethodsThe study recruited children with suspected but undiagnosed short stature from the pediatric endocrinology department in our hospital between January 2018 and August 2022. A retrospective analysis was performed on the clinical manifestations， laboratory test and whole exome sequencing （WES） results. Causative genes were classified and analyzed according to different pathogenic mechanisms. ResultsA total of 48 children （30 boys and 18 girls） were enrolled， aged 7.73 ± 3.97 years， with a height standard deviation score （ HtSDS） of -3.63 ± 1.67. Of the patients， 33 （68.8%） suffered from facial anomalies， 31 （64.6%） from skeletal abnormalities， 26 ［54.2%， 61.5% of whom born small for gestational age （SGA）］ from perinatal abnormalities， 24 ［50.0%， 87.5% of whom with growth hormone （GH） peak concentration below normal］ from endocrine disorders and 21（43.8%） had a family history of short stature. Laboratory tests showed that GH peak concentration following stimulation test was （9.72 ± 7.25） ng/mL， IGF-1 standard deviation score was -0.82 ± 1.42， the difference between bone age and chronological age was -0.93 ± 1.39 years. Of the 25 cases with mutant genes found by WES， 14 （56.0%） had pathogenic mutation， 6 （24.0%） likely pathogenic mutation， and 5 （20.0%） mutation of uncertain significance. Pathogenic and likely pathogenic variants were identified in 14 genes， including 10 affecting intracellular signaling pathways （PTPN11， RAF1， RIT1， ARID1B， ANKRD11， CSNK2A1， SRCAP， CUL7， SMAD4 and FAM111A） and 4 affecting extracellular matrix （ECM） components or functions （ACAN， FBN1， COL10A1 and COMP）. ConclusionsA rare monogenic disease should be considered as the possible etiology for children with severe short stature accompanied by facial anomalies， disproportionate body types， skeletal abnormalities， SGA， GH peak concentration below normal and a family history of short stature. WES played an important role in identifying the monogenic causes of short stature. This study indicated that affecting growth plate cartilage formation through intracellular signaling pathways and ECM components or functions was the main mechanism of causative genes leading to severe short stature in children. Further research may help discover and study new pathogenic variants and gene functions.

Objective To explore the prognostic impact and clinical application value of therapeutic plasma exchange(TPE)intervention timing and liver injury periodization in patients with exertional heat stroke(EHS).Methods Data of 127 EHS patients from the First Medical Center of the General Hospital of the People′s Liberation Army from January 2011 to December 2023 were collected,then divided into the death group and the survival group based on therapeutic outcomes and into 5 stages according to the dynamic changes of ALT,AST,TBIL and DBIL.According to propensity score matching analysis,11 patients in the survival group and 12 patients in the death group were included in the statistical analysis,and 20 of them were treated with TPE.The changes in indicators and clinical outcomes before and after TPE were observed,in order to evaluate the impact of intervention timing on prognosis.Results Among the 23 patients,14 had no liver injury or could progress to the repair phase,resulting in 3 deaths(with the mortality rate of 21.43%),while 9 patients failed to pro-gress to the repair phase,resulting in 9 deaths(with the mortality rate of 100%),with significant differences(P＜0.05).The mortality rate of the first TPE intervention before the third stage of liver injury was 23.08%(3/13),while that of interven-tion after reaching or exceeding the third stage was 85.71%(6/7),and the difference was statistically significant(P＜0.05).Conclusion TPE should be executed actively in EHS patients combined with liver injury before the third phase to lock its pathological and physiological processes,thereby improving prognosis and reducing mortality.

AIM:To investigate the interaction mechanisms of estrogen receptor β(ERβ),nuclear factor-κB(NF-κB)and activator protein-1(AP-1)in colorectal cancer by analyzing the transcriptome data after tumor necrosis fac-tor α(TNF-α)treatment and combining it with NF-κB/p65 and ERβ cistrome data in colon cancer cell lines HT29 and SW480.METHODS:The TNF-α transcriptome was integrated with p65 and ERβ cistrome data.Protein interaction net-works of TNF-α,NF-κB/p65 and ERβ were constructed in colon cancer cell lines HT29 and SW480 using R.RE-SULTS:TNF-α regulated genes through p65 DNA binding,which were mainly enriched in the NF-κB and mitogen-acti-vated protein kinase(MAPK)pathways.Components of the NF-κB/p65 and MAPK pathways had potential interactions with AP-1 family proteins.ERβ overexpression did not significantly affect TNF-α-mediated gene regulation but may regu-late AP-1 activity through the MAPK and phosphatidylinositol 3-kinase(PI3K)/Akt pathways.Furthermore,ERβ de-creased p65 DNA binding sites in HT29 but increased p65 binding sites in SW480,suggesting cell line-specific regulation of NF-κB by ERβ.CONCLUSION:In colorectal cancer,NF-κB,ERβ and AP-1 have potential interactions:TNF-α can regulate AP-1 through NF-κB,while ERβ overexpression can alter NF-κB-mediated regulation,and the influence of ERβ on NF-κB may be gender-related.

Objective:To explore the therapeutic effect of intra-articular injection of triptolide nanomaterials on rabbit antigen-induced knee arthritis.Methods:Twenty-seven New Zealand white rabbits were randomly divided into 4 groups. After antigen-induced arthritis (AIA) model were induced, the knee joints of triptolide nanomaterials (TPNA) group, triptolide (TP) group and betamethasone (BS) group were injected intra-articularly under ultrasound guidance with triptolide nanomaterials, triptolide and betamethasone respectively, 7 rabbits in each group. And the other 6 rabbits were punctured but not injected with any drugs as the control group. The pathological changes of joint swelling, synovitis and bone erosion were examined. Student's test, repeated measure data of analysis of variance (ANOVA), Mann-Whitney U test and Kruskal- Wallis test were used for statistical analysis. Results:① Before treatment, the knee joint diameters of the TPNA group, TP group, BS group and control group were (2.02±0.08) cm, (2.08±0.06) cm, (2.10±0.06) cm and (2.18±0.07) cm, respectively. After one week of administration, the knee joint diameters of the above groups were (1.85±0.06) cm, (1.89±0.07) cm, (1.93±0.08) cm and (2.15±0.08) cm, respectively. Knee joint swelling was significantly reduced in each treated group after a week of intra-articular injection. With the extension of treatment, the diameter of rabbit knee joints in each experimental group gradually decreased gradually ( F=58.83, P<0.01; F=53.78, P<0.01; F=68.24, P<0.01), and the diameter of rabbit knee joints in the TP group, TPNA group and BS group was significantly smaller than that of the control group ( F=63.83, P<0.01; F=71.94, P<0.01; F=140.79, P<0.01). ② The synovitis score of TP group was lower than that of the control group ( Z=-2.082, P<0.05), which was mainly mild synovitis. While the synovitis scores of TPNA group and BS group were lower than that of TP group ( Z=-2.082, P<0.05; Z=-2.687, P<0.05), most of which were free from synovitis. There was no statistical significant difference between BS group and TPNA group ( Z=-1.000, P>0.05). ③ The pathological scores of bone destruction in the TPNA group, TP group and BS group were all reduced compared with the control group ( Z=-2.505, P<0.05; Z=-2.216, P<0.05; Z=-2.505, P<0.05). There was no statistical significant difference between the TPNA group, TP group and BS group ( χ2=0.588, P>0.05). Conclusion:Intra-articular injection of triptolide nanomaterials can relieve joint swelling, reduce synovitis, and delay bone erosion. Its effect is similiar to glucocorticoid, better than simple triptolide. Triptolide nanomaterials have the potential to be an effective drug for arthritis by intra-articular injection.

ObjectiveTo investigate the clinical significance of highly sensitive nucleic acid detection in precise antiviral therapy for patients with liver cirrhosis and its association with aminotransferase level. MethodsA total of 377 patients with hepatitis B cirrhosis who were hospitalized or attended the outpatient service from May 2013 to April 2019 were enrolled and tested by both domestic HBV DNA detection and highly sensitive Cobas HBV DNA detection. All patients underwent biochemical examination, four blood coagulation tests, routine blood test, and upper abdominal computed tomography or ultrasound. Sensitivity of different HBV DNA detection reagents was compared in liver cirrhosis patients with a low viral load, and the correlation between alanine aminotransferase (ALT) level and viral load was analyzed. The paired t-test was used for comparison of continuous data before and after treatment. The receiver operating characteristic (ROC) curve was used to screen out the optimal predictive values of ALT at different cut-off values of HBV DNA. ResultsAmong the 377 patients with hepatitis B cirrhosis, 215 tested positive and 162 tested negative by domestic HBV DNA, and among these 162 patients, 104 (64.2%) tested positive by Cobas HBV DNA detection, with a mean level of 267.5±42.3 IU/ml. After 24 weeks of antiviral therapy, the 104 patients with hepatitis B cirrhosis had significant improvements in viral replication level, ALT, and Child-Pugh score for liver function; HBV DNA decreased from 267.5±32.2 IU/ml before treatment to 59.6±7.7 IU/ml after treatment (t=3.486, P=0.002), ALT decreased from 871±10.8 U/L before treatment to 36.5±7.6 U/L after treatment (t=3.235, P=0.020), and the Child-Pugh score decreased from 6.5±0.7 before treatment to 5.7±0.5 after treatment (t=2.928, P=0.041). The ROC curve analysis of ALT in predicting HBV DNA decision point showed that an ALT level of 29 IU/L was the most sensitive cut-off value for predicting HBV DNA ＜20 IU/ml, with an area under the ROC curve of 0.904, a sensitivity of 1.0, and a specificity of 0.237. ConclusionPrecise detection helps to guarantee the precise clinical treatment of patients with hepatitis B cirrhosis and improve their treatment outcome and prognosis. An ALT level of 29 IU/L is a sensitive indicator for predicting patients with negative Cobas HBV DNA, so as to achieve individualized precise screening and treatment.

Objective To analyze the clinical manifestations and gene mutations of rare causes of primary adrenal insufficiency (PAI) in childhood.Methods The clinical features,laboratory tests and gene mutation of 13 patients with PAI in our hospital from September 2010 to August 2017 were analyzed retrospectively.Patients with congenital adrenal hyperplasia,X-linked adrenoleukodystrophy with neurological onset or a clear family history,and autoimmune adrenal insufficiency were excluded.Results The median age of 13 cases (12 males,1 female) was 3 years and 10 months.Medical history or clinical manifestations on the first visit included hyperpigmentation,electrolyte imbalance/salt-wasting crisis,gastrointestinal symptoms,and fatigue,etc.All developments of external genitalia were normal.All cases presented with decreased serum cortisol and increased ACTH levels.Some of the cases showed decreased aldosterone level and plasma renin activity,while 17α-hydroxyprogesterone,testosterone,and androstenedione were in the normal range.Part of cases revealed delayed bone age and adrenal atrophy.Three gene mutations were detected in 13 patients,including NR0B 1 gene (9/13),ABCD 1 gene (3/13),and CYP 11A 1 gene (1/13).NR0B1,and ABCD1 gene mutations were pathogenic mutations,consistent with clinical characteristics.CYP11A1 gene mutation was heterozygote,which cannot fully explain the clinical features.Conclusion PAI in childhood presents common clinical manifestations of adrenal insufficiency,e.g.hyperpigmentation and electrolyte imbalance/sah-wasting crisis,but without specificity.Gene mutational analysis is necessary for precise diagnosis and prognosis estimation.NR0B1 and ABCD1 gene mutations were common in childhood with rare causes of PAI.

Background:In patients with diffuse large B?cell lymphoma (DLBCL), central nervous system (CNS) relapse is uncom?mon but is nearly always fatal. This study aimed to determine the risk factors for CNS relapse in DLBCL patients and to evaluate the effcacy of rituximab and intrathecal chemotherapy prophylaxis for CNS relapse reduction. Methods:A total of 511 patients with newly diagnosed DLBCL treated at the Sun Yat?sen University Cancer Center between January 2003 and December 2012 were included in the study. Among these patients, 376 received R?CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment, and 135 received CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment. Intrathe?cal chemotherapy prophylaxis (methotrexate plus cytarabine) was administered to those who were deemed at high risk for CNS relapse. In the entire cohort and in the R?CHOP set in particular, the Kaplan–Meier method coupled with the log?rank test was used for univariate analysis, and the Cox proportional hazards model was used for multivariate analysis. Differences were evaluated using a two?tailed test, andP<0.05 was considered signiifcant. Results:At a median follow?up of 46months, 25 (4.9%) patients experienced CNS relapse. There was a trend of reduced occurrence of CNS relapse in patients treated with rituximab; the 3?year cumulative CNS relapse rates were 7.1% in CHOP group and 2.7% in R?CHOP group (P=0.045). Intrathecal chemotherapy prophylaxis did not confer much beneift in terms of preventing CNS relapse. Bone involvement [hazard ratio (HR)=4.21, 95% conifdence interval (CI) 1.38–12.77], renal involvement (HR=3.85, 95% CI 1.05–14.19), alkaline phosphatase (ALP) >110U/L (HR=3.59, 95% CI 1.25–10.34), serum albumin (ALB) <35g/L (HR=3.63, 95% CI 1.25–10.51), treatment with rituxi?mab (HR=0.34, 95% CI 0.12–0.96), and a time to complete remission≤ 108days (HR=0.22, 95% CI 0.06–0.78) were independent predictive factors for CNS relapse in the entire cohort. Bone involvement (HR=4.44, 95% CI 1.08–18.35), bone marrow involvement (HR=11.70, 95% CI 2.24–60.99), and renal involvement (HR=10.83, 95% CI 2.27–51.65) were independent risk factors for CNS relapse in the R?CHOP set. Conclusions:In the present study, rituximab decreased the CNS relapse rate of DLBCL, whereas intrathecal chemo?therapy prophylaxis alone was not suffcient for preventing CNS relapse. Serum levels of ALB and ALP, and the time to complete remission were new independent predictive factors for CNS relapse in the patients with DLBCL. In the patients received R?CHOP regimen, a trend of increased CNS relapse was found to be associated with extranodal lesions.

ObjectiveTo compare the clinical effect of percutaneous iliosacral screws osteosynthesis (PISO) and open reduction internal reconstruction plate fixation in treating unstable pelvic fractures combined with sacroiliac joint dislocation,and evaluate their safety and practicality.MethodsFrom March 2004 to October 2010,37 patients with vertical unstable pelvic fractures were admitted to our department.Twenty cases were treated with percutaneous sacroiliac screw fixation and 17 cases were performed opened reduction and internal reconstruction plate fixation under C-arm X-ray's guide.The perioperative parameters and postoperative imaging indexes were compared and analyzed.ResultsAll patients were followed up for 6 months to 26 months,with an average of 15 months.There were statistical significances between the PISO group and open reduction internal fixation group in operation time,blood loss,postoperative pain,mean fever time and hospital stay.The two groups showed no significant difference on postoperative X-evaluation of reduction effect.The average healing time was 3.2 months and the difference was not statistically significant between two groups.PISO group had no complications such as infection,bent nails or broken nails.ConclusionThrough compared and analyzed the two groups in treating unstable pelvic fractures,the percutaneous sacroiliac screw fixation has been proved for a kind of ideal minimally invasive surgery method because of locating exactly,less damage and blood loss,milder pain and quicker recovery.But it demands higher operation techniques.Adequate preoperative preparation and postoperative patients' cooperation can reduce complications incidence.The second group of anterior reconstruction plate or T-shape plate to fix vertically unstable pelvic fractures at same time shows a good result of stabilization.

Objective To evaluate protective effects of hypothermic pulmonary protective solution with uli-nastatin on lung function during cardiopulmouary bypass (CPB) in the patients with congenital heart disease(CHD) and pulmonary hypertenion. Method Fifty-four children,who had CHD of left-to-fight shunts with moderate-se-rious pulmonary hypertension, were enrolled. They had been performed with the radical operation under CPB from September 2005 to December 2006 in the Department of Cardiovascular Surgery, Children' s Hospital of Zhejiang University. Moderate-serious pulmonary hypertension was defined as pulmonary-to-systolic pressure ratio > 0.45(Pp/Ps > 0.45). Fifty-four children were randomly divided into three groups. Patients in group A (n = 18)didn't receive pulmonary protective solution, and scrved as control; patients in group B (n = 18) were adminis-tered with pulmonary protective solution without ulinastatin;patients in group C (n = 18) were administered with pulmonary protective solution with ulinastatin. The serum concentrations of MDA and MPO were measured at five different time points:pre-operation, 0 h, 3 h, 6 h and 24 h in the intensive care unit (ICU) (T1～5). Patients'lung functions were monitored at T1 - T4. The time of mechanical ventilation was recorded. Results No one died in this study. The mean time of mechanical ventilation was shorter in the group B and group C than that in the group A. The MDA and MPO levels were lower in group B compared with group A at T4. The MDA level at T3-T5 and the MPO level at T4 was lower in group C than those in group A. There were no significant in MDA and MPO levels between group B and group C at five time point.A-aDO2 was lower in groups B and C than those in group A at T3 and T4, whereas at T4, A-aDO2 was lower in group C than that in group B. Cdyn was higher in group B at T3and group C at T3 - T4 than those in group A. Cdyn was lower in groups C than that in group B at T4.Condusions Lung perfusion with hypothermic protective solution during CPB can all lung injury and promote recovery after operation, especialy with ulinastatin.