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Background: Extensive knowledge of allergic multimorbidities is required to improve the management of allergic diseases with the industrialization of China. However, the demography and allergen distribution patterns of allergic multimorbidities in China remain unclear, despite the increasing prevalence of allergies. Methods: This was a real-world, cross-sectional study of 1273 outpatients diagnosed with one or more allergic diseases in Guangzhou, the most populated city of southern China, with leading industrial and commercial centers, between April 2021 and March 2022. Seven allergic diseases (allergic rhinitis (AR), asthma (AS)/cough variant asthma (CVA), atopic dermatitis (AD)/eczema, food allergy (FA), allergic conjunctivitis (AC), drug allergy (DA), and anaphylaxis) were assessed. Positive rates of sensitization to different allergens were measured using an allergen detection system of the UniCAP (Pharmacia Diagnostics, Sweden) instrument platform to compare the groups of allergic multimorbidities against a single entity. Results: There were 659 (51.8%) males and 614 (48.2%) females aged from 4 months to 74 years included in the analysis. The study participants who were diagnosed with allergic diseases had an average of 1.6 diagnoses. Overall, 46.5% (592 of 1273) of the patients had more than one allergic condition, and allergic rhinitis was the most common type of multimorbidity. Women were more likely to suffer from an allergic disease alone, whereas allergic multimorbidities were more likely to be diagnosed in men (p = 0.005). In addition, allergic multimorbidities were common in all age groups, with an incidence ranging from 37.1% to 57.4%, in which children and adolescents were more frequently diagnosed with allergic multimorbidities than adults (18–60 years old) (all p < 0.05). Allergic multimorbidity was observed throughout the year. A difference in the positive rate of allergens sensitization and total immunoglobulin E (tIgE) levels between different allergic multimorbidities was observed. Conclusions: Allergic multimorbidities were very commonly found in nearly half of all patients with allergies. The proportion of allergic multimorbidities varied with the type of disease, sex, age, and allergen distribution pattern. These findings may help clinicians to develop “One health” strategies for the clinical management of allergic diseases.

BackgroundBacterial infections have long been a significant cause of child mortality worldwide; however, models for predicting the risk of death in children with bacterial infections that combine predictive ability and interpretability are scarce. Here we try to explore a new method to complete the task. MethodsWe use Paediatric Intensive Care Database (PIC) to carry out the research. Data from hospitalized children with positive bacterial culture results was extracted and categorized into three groups: the positive culture group, the gram-positive group, and the gram-negative group, which were divided into 80% training and 20% test sets. Then we extracted the demographic information, vital signs, and laboratory data within 24 hours of admission of the datasets. We use the XGBoost algorithm to select the features and rank their importance，and the Logistic Regression (LR) algorithm for model development based on various numbers of feature. All the models were evaluated by Receiver Operating Characteristic curve (ROC), area under the ROC curve (ROC-AUC), Precision-Recall curve (PR), the area under the PR curve (PR-AUC), and compared with Paediatric Mortality Risk Score III (PRISM III), the paediatric logistic organ dysfunction score-2 (PELOD-2), and the paediatric multiple organ dysfunction scores (P-MODS).ResultIn total, 3695 children with bacterial infection were included, with an average age of 20.17 ± 36.74 months, average paediatric intensive care unit stay of 18.51 ± 28.84 days, and overall mortality rate of 8.39%. The following predictors appeared in the 64 most important predictors of the three datasets: average white blood cell count, maximum value of white blood cell technology, average value of anion gap, minimum value of anion gap, maximum value of type B natriuretic peptide, and maximum value of thrombocytocrit. Finally, we established a LR model for bacterial infected children with 4 features and a LR model for gram-negative bacterial infected children with 10 features, which achieve a 0.7244 and a 0.7848 ROC-AUC score respectively. The ROC-AUC scores of the two models were better than PRISM III、PELOD-2 and P-MODS. ConclusionThis study developed models to predict the risk of death in children with bacterial infections. The final models use fewer features and achieve better mortality prediction performance than traditional scoring models, and the models are easier for paediatricians to understand.

To analyze the clinical characteristics of multiple myeloma(MM) patients with early relapse.A total of 50 MM patients with early relapse (≤12 months) and 50 matched controls with late relapse (12 months) were selected. The time from diagnosis to relapse and related clinical data of the 100 patients were retrospectively analyzed, and the factors associated with early relapse were identified. Kaplan-Meier curve was used to analyze the overall survival (OS) time of the whole cohort. Area under the curve (AUC) was used to evaluate the effect of circulating plasma cells on early recurrence of the patients.The results showed that high-risk cytogenetics (FISH) (P=0.005), and ISS stage III (P=0.008) were associated with early recurrence of the patients. For patients with early relapse, high-risk FISH showed poor survival. Compared with the patients with late relapse, most of the chromosome karyotype of patients with early relapse showed quantitative and structural abnormalities. The expression of circulating plasma cells was significantly increased in patients with early recurrence group (P=0.0318). The response to initial treatment was poor in the early recurrence group (P=0.001), and the prognosis was significantly worse than those in the late recurrence group (median OS: 38 vs 81 months, P=0.002).Early relapse is a marker poor prognostic in MM patients, and such patients should be focused on the improving their prognosis.多发性骨髓瘤早期复发患者临床特征的分析.分析多发性骨髓瘤（MM）早期复发患者的临床特征.纳入50 例早期复发(≤12个月) MM患者，另50 例晚期复发MM (12个月)作为对照组。回顾性分析这100例MM患者从诊断到复发的时间及相关临床资料，并确定与早期复发相关的因素。Kaplan-Meier曲线分析整个队列的总生存(OS)时间。应用曲线下面积（AUC）评估循环浆细胞对早期复发的影响.高危细胞遗传学(FISH) (P=0.005)、ISS分期 III期 （P=0008）与早期复发相关。对于早期疾病复发的患者，高危FISH在单变量分析中显示出较差的生存结果，并且与晚期复发患者相比，早期复发患者的染色体核型多数出现数量和结构上的异常。循环浆细胞在早期复发组患者中的表达显著增高（P＝0.0318）。早期复发组患者对初始治疗的反应较差(P=0.001)，预后也显著差于晚期复发的患者（中位OS为38 vs 81个月，P=0.002）.早期复发是MM患者不良预后的标志，此类患者应重点关注，以改善其预后.

Objectives Clinical data with respect to the impact of meconium on the prognosis of neonatal bacterial meningitis are scarce. Therefore, in this study, we aimed to determine whether meconium-stained amniotic fluid (MSAF) represents a risk factor for poor prognosis of neonatal bacterial meningitis in a confirmed case population. Methods This was a retrospective cohort study of 256 neonates diagnosed with bacterial meningitis hospitalized at one of three hospitals in Shantou, China, between October 2013 and September 2018. Clinical manifestation, laboratory test results and treatment were compared between the two groups, with outcomes dichotomized into ‘good’ or ‘poor’ prognosis. Multivariate analysis and follow-up logistic regression analysis were used to identify predictive factors of a poor outcome. Results Of the 256 neonates with BM, 95 (37.1%) had a good prognosis at discharge and 161 (62.9%) had a poor prognosis. In the poor prognosis group, 131/161 (79.4%) neonates had a permanent neurological sequelae and 19 (11.8%) had ≥2 sequelae. Of note, 11 neonates died. The rate of poor prognosis of BM was significantly higher among neonates with than without MSAF (26.1% vs. 12.6%, respectively; p Conclusion MSAF is significantly associated with poor prognosis of neonatal bacterial meningitis. Therefore, in case of MSAF, more attention should be paid to neonatal bacterial meningitis.

With the increase in pet keeping among families in China, there has been a corresponding increase in the incidence of allergic diseases such as bronchial asthma and allergic rhinoconjunctivitis. Pet allergies pose important social and health problems, making their management in children crucial. There is an increasing trend of sensitization to cat and dog dander among Chinese children. The process underlying allergic sensitization is complex and is associated with an IgE-mediated type I hypersensitivity reaction that involves the upregulation of type 2 T-helper (Th2) cells, resulting in Th2 immunity. Compared with traditional serum-specific IgE (sIgE) and skin tests, molecular diagnosis may be better at predicting the progression of diseases. The association between pet keeping and allergic diseases in children remains controversial. Although the hygiene hypothesis is widely accepted in Chinese children, exposure to pets in early life remains a risk factor for allergies. Pet avoidance and allergy immunotherapy (AIT) are recommended for children with pet allergies. However, pet avoidance is difficult to maintain, and AIT is not widely available in China. There is an imbalance between the increase in allergic diseases and the shortage of prevention and treatment options. We hope that advancements in medicine, diagnosis, and healthcare policies will help resolve this issue.

The mammalian internal circadian clock system has been evolved to adapt to the diurnal changes in the internal and external environment of the organism to regulate diverse physiological functions, such as the sleep-wake cycle and feeding rhythm, thereby coordinating the rhythmic changes of energy demand and nutrition supply in each diurnal cycle. The circadian clock regulates glucose metabolism, lipid metabolism, and hormones secretion in diverse tissues and organs, including the liver, skeletal muscle, pancreas, heart, and vessels. As a special "organ" of the host, the gut microbiota, together with the intestinal microenvironment (tissues, cells, and metabolites) in a co-evolutionary process, constitutes a micro-ecosystem and plays an important role in the process of nutrient digestion and absorption in the intestine of the host. In recent years, accumulating evidence indicates that the compositions, quantities, colonization, and functional activities of the gut microbiota exhibit significant circadian variations, which are closely related to the changes of various physiological functions under the regulation of host circadian clock system. In addition, several studies have shown that the gut microbiota can produce many important metabolites such as the short-chain fatty acids through the degradation of indigestive dietary fibers. A portion of gut microbiota-derived metabolites can regulate the circadian clock system and metabolism of the host. This article mainly discusses the interaction between the host circadian clock system and the gut microbiota, and highlights its influence on energy metabolism of the host, providing a novel clues and thought for the prevention and treatment of metabolic diseases.

The nucleotide-binding domain and leucine-rich repeat-containing family pyrin domain containing 3 (NLRP3) inflammasome is involved in various acute and chronic liver diseases, however, it is not clear whether NLRP3 contributes to d -Galactosamine (D-GalN) plus lipopolysaccharide (LPS)-induced acute liver failure (ALF). This study aims to investigate the role of NLRP3 inflammasome in D-GalN/LPS-induced fatal hepatitis. We found that Nlrp3−/− and WT mice showed similar mortality against a lethal dose of D-GalN/LPS treatment. Serum ALT and AST levels, as well as liver necrosis area and hepatocyte apoptosis, were not significantly different between Nlrp3−/− and WT mice at 6 h after D-GalN/LPS injection. Moreover, the numbers of intrahepatic F4/80+ cells and Ly6G+ cells were comparable in two genotype mice following D-GalN/LPS treatment. Besides, Nlrp3−/− mice had reduced IL-1β levels but similar TNF-α, IL-6, and MCP-1 levels compared with WT mice upon D-GalN/LPS administration. Our findings revealed that NLRP3 ablation does not protect mice from D-GalN/LPS-induced fatal hepatitis and has a marginal effect on intrahepatic inflammatory response upon D-GalN/LPS treatment. This suggests that NLRP3 inflammasome does not appear to be a major contributor to D-GalN/LPS-induced ALF.

Three novel dimeric sesquiterpenoids named sarglanoids A-C (1-3), two undescribed monomeric sesquiterpenoids named sarglanoids D (4) and E (5), and seven known compounds (6-12), were isolated and characterized from Sarcandra glabra. Compound 1 represents the first heterodimeric sesquiterpenoid composed of a eudesmane and an eremophilane moiety. Compound 2 possesses two eremophilane monomers featuring an undescribed dimerization pattern. Compound 3 is a symmetric eudesmane dimer with a rare 1,4-epoxy bridge. The structures of 1-5 were fully identified by spectroscopic methods and single-crystal X-ray diffraction experiments. Compounds 3 and 6 suppressed the LPS-triggered inflammatory responses in RAW 264.7 cells.

Background. There is much evidence that confirms the inextricable link between inflammation and malignancy. Inflammation-related regulators were involved in the progression of kidney renal clear cell carcinoma (KIRC). However, the predictive role of single gene biomarkers is inadequate, and more accurate prognostic models are necessary. We undertook the current research to construct a robust inflammation-related gene signature that could stratify patients with KIRC. Methods. The transcriptome sequencing data along with clinicopathologic information of KIRC were obtained from TCGA. A list of inflammation-related genes was acquired from the Molecular Signatures Database. Using the RNA-seq and survival time data from the TCGA training cohort, an inflammation-related gene signature was built using bioinformatic methods, and its performance in predicting patient prognosis was assessed by Kaplan–Meier and ROC curve analyses. Furthermore, we explored the association of risk score with immune score, stromal score, tumor immune-infiltrating cells (TIICs), immunosuppressive molecules, m6A regulators, and autophagy-related biomarkers. Results. Herein, nine inflammation-related hub genes (ROS1, PLAUR, ACVR2A, KLF6, GABBR1, APLNR, SPHK1, PDPN, and ADORA2B) were determined and used to build a predictive model. All sets, including training set, four testing sets, and the entire TCGA group, were divided into two groups (low and high risk), and Kaplan–Meier curves all showed an adverse prognosis for patients in the high-risk group. ESTIMATE algorithm revealed a higher immune score in the high-risk subgroup. CIBERSORT algorithm illustrated that the high-risk group showed higher-level immune infiltrates. Furthermore, LAG3, TIGIT, and CTLA4 were overexpressed in the high-risk subgroup and positively associated with risk scores. Moreover, except for METTL3 and ALKBH5, the other m6A regulators decreased in the high-risk subgroup. Conclusions. In conclusion, a novel inflammation-related gene signature comprehensively constructed in the current study may help stratify patients with KIRC.

The physiological activity of the 50% ethanolic extract of

BACKGROUND Diarrhea is a major infectious cause of childhood morbidity and mortality worldwide. In clinical trials, Lactobacillus rhamnosus GG ATCC 53013 (LGG) has been used to treat diarrhea. However, recent randomized controlled trials (RCTs) found no evidence of a beneficial effect of LGG treatment. AIM To evaluate the efficacy of LGG in treating acute diarrhea in children. METHODS The EMBASE, MEDLINE, PubMed, Web of Science databases, and the Cochrane Central Register of Controlled Trials were searched up to April 2019 for metaanalyses and RCTs. The Cochrane Review Manager was used to analyze the relevant data. RESULTS Nineteen RCTs met the inclusion criteria and showed that compared with the control group, LGG administration notably reduced the diarrhea duration [mean difference (MD) -24.02 h, 95% confidence interval (CI) (-36.58, -11.45)]. More effective results were detected at a high dose . 1010 CFU per day [MD -22.56 h, 95%CI (-36.41, -8.72)] vs a lower dose. A similar reduction was found in Asian and European patients [MD -24.42 h, 95%CI (-47.01, -1.82); MD -32.02 h, 95%CI (- 49.26, -14.79), respectively]. A reduced duration of diarrhea was confirmed in LGG participants with diarrhea for less than 3 d at enrollment [MD -15.83 h, 95%CI (-20.68, -10.98)]. High-dose LGG effectively reduced the duration of rotavirus-induced diarrhea [MD -31.05 h, 95%CI (-50.31, -11.80)] and the stool number per day [MD -1.08, 95%CI (-1.87, -0.28)]. CONCLUSION High-dose LGG therapy reduces the duration of diarrhea and the stool number per day. Intervention at the early stage is recommended. Future trials are expected to verify the effectiveness of LGG treatment. (Less)

A sequential multistep reaction toward 5-thio- or 5-selenotriazoles has been established by generation of both copper(I) triazolides and sulfenylating or selenylating agents in situ, starting from elemental sulfur or selenium. This reaction features mild conditions, readily available and broad-scope substrates, good functional group compatibility, high efficiency and regioselectivity, easy operation, and ligand-free CuI.

Background No comprehensive analysis is available on the viral etiology and clinical characterization among children with severe acute lower respiratory tract infection (SALRTI) in Southern China. Methods Cohort of 659 hospitalized children (2 months to 14 years) with SALRTI admitted to the Pediatric Intensive Care Unit (PICU) in the Guangzhou from May 2015 to April 2018 was enrolled in this study. Nasopharyngeal aspirate specimens or induced sputum were tested for eight categories respiratory viral targets. The viral distribution and its clinical characters were statistically analyzed. Results Viral pathogen was detected in 326 (49.5%) of children with SALRTI and there were 36 (5.5%) viral coinfections. Overall, the groups of viruses identified were, in descending order of prevalence: Influenza virus (IFV) (n = 94, 14.3%), respiratory syncytial virus (RSV) (n = 75, 11.4%), human rhinovirus (HRV) (n = 56, 8.5%), adenovirus (ADV) (n = 55, 8.3%), parainfluenza (PIV) (n = 47, 7.1%), human coronavirus (HCoV) (n = 15, 2.3%), human metapneumovirus (HMPV) (n = 14, 2.1%) and human bocavirus (HBoV) (n = 11, 1.7%). The positive rate in younger children ( 5 years) (52.5% vs 35.1%, P = 0.001). There were clear seasonal peaks for IFV, RSV, HRV, ADV, PIV, and HMPV. And the individuals with different viral infection varied significantly in terms of clinical profiles. Conclusions Viral infections are present in a consistent proportion of patients admitted to the PICU. IFV, RSV, HRV, and ADV accounted for more than two‐thirds of all viral SALRTI. Our findings could help the prediction, prevention and potential therapeutic approaches of SALRTI in children., Highlight Viral infections are present in a consistent proportion of patients admitted to the Pediatric Intensive Care Unit.Influenza virus, respiratory syncytial virus, human rhinovirus and adenovirus accounted for more than two‐thirds of all viral SALRTI.

Objective To discuss the effect and the corresponding mechanism of transforming growth factor β1 (TGF-β1) in promoting the bronchial epithelia synthesis and the expression of thymic stromal lymphopoietin (TSLP), so seek out a potential therapeutic target for asthma. Methods Human bronchial epithelia cells (HBEc) were cultured in vitro, and then divided into 0h group, 3h group, 6h group, 12h group, 24h group and 48h group to evaluate the effect of TGF-β1 stimulation in different time points; and divided into 0ng/ml group, 0.1ng/ml group, 1ng/ml group and 10ng/ml group to evaluate the effect of TGF-β1 stimulation in different concentrations. SB431542, a TGF-β1 antagonist, was used to block the effect of TGF-β1, HBEc were divided into negative control group, TGF-β1 group (1ng/ml TGF-β1) and TGF-β1+SB431542 group (1ng/ml TGF-β1+10μmol/L SB431542). Western blotting was performed to detect the protein expression level of TSLP, p-Smad3 and Smad3, while qRT-PCR was performed to determine the mRNA transcription level of TSLP. Concentrations of TSLP in HBEc culture supernatants were measured by ELISA. Results As the co-culture time with TGF-β1 prolonged, the expression of TSLP in HBEc increased. The relative expression of TSLP protein was significantly higher in 24h group (0.803±0.022) than in 0h group (0.350±0.032, P

Background: The implementation of allergen immunotherapy (AIT) requires extensive knowledge of allergen distribution in the region to identify high-risk regions for AIT utilization. However, the geographical distribution patterns of the major Dermatophagoides allergens in China remain unclear despite the increasing prevalence of these allergens. Methods: We performed comprehensive database searches of articles demonstrating the distribution patterns of Dermatophagoides-sensitized allergic rhinitis (AR) and allergic asthma (AA) in China, published between 1990 and 2017. Results: We retrieved 163 articles encompassing 114,302 allergen-positive cases to generate the distribution maps. The rate of sensitization to Dermatophagoides pteronyssinus(D. pteronyssinus)and Dermatophagoides farinae (D. farinae) was similar in patients with AR (75.1 vs. 75.2%, p > 0.05) but not in those with AA (78.5 vs. 77.7%, p = 0.041). Patients with AR and AA shared similar regional distribution patterns of both D. pteronyssinus and D. farinae sensitization, which were highest in the southern and central parts of China and lowest in the northern regions, especially in the Northwest. The overall rate of sensitization to D. pteronyssinus and D. farinae was significantly higher in patients with AA (p < 0.001). Additionally, the annual mean temperature and humidity were the 2 major determinants of D. pteronyssinus and D. farinae sensitization in AR and of D. pteronyssinus sensitization in AA, whereas the annual mean temperature was the sole determinant for D. farinae sensitization in AA. Conclusion: These findings may inform clinicians of the strategies for the prevention of Dermatophagoides sensitization and may be of benefit to the future clinical management of allergic diseasesassociated with sensitization to Dermatophagoides mites.

Background Capillary leak syndrome (CLS) is a rare disease characterized by profound vascular leakage and presents as a classic triad of hypotension, hypoalbuminemia and hemoconcentration. Severe CLS is mostly induced by sepsis and generally life-threatening in newborns, especially in premature infants. Continuous renal replacement therapy (CRRT) plays an important role of supportive treatment for severe CLS. Unfortunately, CRRT in preterm infants has rarely been well defined. Case presentation We report the case of a 11-day-old girl with CLS caused by sepsis, who was delivered by spontaneous vaginal delivery (SVD) at gestational age of 25 weeks and 4 days, and a birth weight of 0.89 Kilograms(kg). The infant received powerful management consisting of united antibiotics, mechanical ventilation, intravenous albumin and hydroxyethyl starch infusion, vasoactive agents, small doses of glucocorticoids and other supportive treatments. However, the condition rapidly worsened with systemic edema, hypotension, pulmonary exudation, hypoxemia and anuria in about 40 h. Finally, we made great efforts to perform CRRT for her. Fortunately, the condition improved after 82 h’ CRRT, and the newborn was rescued and gradually recovered. Conclusion CRRT is an effective rescue therapeutic option for severe CLS and can be successfully applied even in extremely-low-birth-weight premature.

Objective: Observe the clinical characteristics of children with SLE, namely, to observe the symptoms and laboratory examinations, such as blood routine, blood lipid, immunoglobulin, complement, autoantibodies, serum 25 (OH) D and other indicators, and to explore the clinical characteristics, the difference and the significance of vitamin D supplements between male and female SLE patients in children respectively. Methods: We enrolled 64 cases of SLE patients in children who were admitted into the department of pediatrics and rheumatology of the third affiliated hospital of sun yat-sen university in guangzhou from May 1, 2011 to February 1, 2019, They were analyzed retrospectively, adopting ?² test for statistical analysis. Results: 64 cases of SLE in children, which included 10 cases of male and 54 cases of female. Clinical manifestations: facial skin rash in 48 patients (75%), fever in 38 cases (59.4%), arthritis in 28 cases (43.8%), oral ulcer in 18 cases (28.1%), serositis in13 cases (20.3%), and the sun allergy in 9 cases (14.1%), the damage of central nervous system in 7 cases (10.9%) . Laboratory examination: 30 cases of leukopenia (46.9%), anemia in 30 cases (46.9%), thrombocytopenia in 12 cases (18.8%), hematuria in 18 cases (28.1%), proteinuria in 33 cases (51.2%), 6 patients with renal impairment (9.4%), antinuclear antibody positive in 63 cases (98.4%), anti-double-stranded DNA (dsDNA) antibody positive in 48 cases (75%), anti SSA antibody positive in 44 cases (68.7%), SSB antibody positive in 33 cases (51.6%), Sm antibody positive in 40 cases (62.5%), nucleosome antibody positive in 28 cases (43.8%) .Among these children, male SLE patients were higher than female children with SLE in the damage of kidney, Sm antibodies and resisting nucleosome antibody positive rates (?²= 4.451, 8.336, 6.803, P

Background: The NOD-like receptor family protein 3 (NLRP3) inflammasome is involved in the progression of liver inflammation. NLRP3 inactivation has been shown to protect mice against multiple types of experimental liver injury. However, it is unclear whether NLRP3 contributes to D-Galactosamine (DGalN) plus lipopolysaccharide (LPS) induced fatal hepatitis. This study aims to examine the function of NLRP3 inflammasome in DGalN/LPS induced acute liver failure.Method: The expression of inflammasomes was detected by quantitative PCR. Wild type (WT) mice and NLRP3 knockout mice were given an intraperitoneal injection of DGalN plus LPS. Liver damage was examined at 6 h post DGalN/LPS administration by histological analysis and serum aminotransferases measurement. Hepatocyte apoptosis and pyroptosis was detected with TUNEL assay, immunohistochemistry (IHC) staining, and western blot. Hepatic macrophages (F4/80+) and neutrophils (Ly6G+) were analyzed by IHC staining. The proinflammatory cytokines levels in serum and liver were examined using cytometric bead array and quantitative PCR. Hepatic IL1β level was further detected by western blot.Result: The hepatic NLRP3 activity was upregulated in WT mice treated with DGalN/LPS. Nlrp3−/− and WT mice showed similar mortality against lethal dose of DGalN/LPS. Serum aminotransferases levels and liver necrosis area of Nlrp3−/− mice did not differ from that in WT mice after DGalN/LPS injection. The numbers of liver TUNEL positive cells and cleaved caspase3 positive hepatocytes were comparable between Nlrp3−/− and WT mice. The hepatic GSDMDNterm peptide production also showed no difference between Nlrp3−/− and WT mice. Mice treated with DGalN/LPS displayed significantly increased numbers of intrahepatic F4/80+ cells and Ly6G+ cells, but the cell numbers in Nlrp3−/− mice livers were similar to those in WT mice. Consistently, serum and hepatic TNFα, IL6, and MCP-1 levels were similar between Nlrp3−/− and WT mice upon DGalN/LPS administration, but serum IL1β and hepatic mature IL1β level in Nlrp3−/− mice was reduced.Conclusions: NLRP3 ablation does not protect mice from DGalN/LPS induced acute liver failure, nor affect hepatocyte apoptosis and pyroptosis. Deficiency of NLRP3 has a limited effect on intrahepatic inflammatory response induced by DGalN/LPS treatment. NLRP3 inflammasome does not appear to be a major contributor to DGalN/LPS induced fatal hepatitis.

Pharmacologically inhibiting nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation results in potent therapeutic effects in a wide variety of preclinical inflammatory disease models. NLRP3 deubiquitination is essential for efficient NLRP3 inflammasome activity, but it remains unclear whether this process can be harnessed for therapeutic benefit. Here, we show that thiolutin (THL), an inhibitor of the JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease, blocks NLRP3 inflammasome activation by canonical, noncanonical, alternative, and transcription-independent pathways at nanomolar concentrations. In addition, THL potently inhibited the activation of multiple NLRP3 mutants linked with cryopyrin-associated periodic syndromes (CAPS). Treatment with THL alleviated NLRP3-related diseases in mouse models of lipopolysaccharide-induced sepsis, monosodium urate-induced peritonitis, experimental autoimmune encephalomyelitis, CAPS, and methionine-choline-deficient diet-induced nonalcoholic fatty liver disease. Mechanistic studies revealed that THL inhibits the BRCC3-containing isopeptidase complex (BRISC)-mediated NLRP3 deubiquitination and activation. In addition, we show that holomycin, a natural methyl derivative of THL, displays an even higher inhibitory activity against NLRP3 inflammasome than THL. Our study validates that posttranslational modification of NLRP3 can be pharmacologically targeted to prevent or treat NLRP3-associated inflammatory diseases. Future clinical development of derivatives of THL may provide new therapies for NLRP3-related diseases.

BRCA1/BRCA2-containing complex subunit 3 (BRCC3) is a lysine 63-specific deubiquitinase involved in multiple biological processes, such as DNA repair and immune responses. However, the regulation mechanism for BRCC3 protein stability is still unknown. Here, we demonstrate that BRCC3 is mainly degraded through the ubiquitin-proteasome pathway. The HECT-type E3 ubiquitin ligase WWP2 modulates BRCC3 ubiquitination and degradation. ABRO1, a subunit of the BRCC36 isopeptidase complex (BRISC), competes with WWP2 to bind to BRCC3, thereby preventing WWP2-mediated BRCC3 ubiquitination and enhancing BRCC3 stability. Functionally, we show that lentivirus-mediated overexpression of WWP2 in murine macrophages inhibits NLRP3 inflammasome activation by decreasing BRCC3 protein level. This study provides the first insights into the regulation of BRCC3 stability and expands our knowledge about the physiological function of WWP2.

To detect substation faults for timely repair, this paper proposes a fault detection method that is based on the time series model and the statistical process control method to analyze the regulation and characteristics of the behavior in the switching process. As the first time, this paper proposes a fault detection model using SARIMA, statistical process control (SPC) methods, and 3σ criterion to analyze the characteristics in substation’s switching process. The employed approaches are both very common tools in the statistics field, however, via effectively combining them with industrial process fault diagnosis, these common statistical tolls play excellent role to achieve rich technical contributions. Finally, for different fault samples, the proposed method improves the rate of detection by at least 9% (and up to 15%) than other methods.

BACKGROUND Intestinal dysbiosis has been shown to be associated with the pathogenesis of alcoholic liver disease (ALD), which includes changes in the microbiota composition and bacterial overgrowth, but an effective microbe-based therapy is lacking. Pediococcus pentosaceus (P. pentosaceus) CGMCC 7049 is a newly isolated strain of probiotic that has been shown to be resistant to ethanol and bile salts. However, further studies are needed to determine whether P. pentosaceus exerts a protective effect on ALD and to elucidate the potential mechanism. AIM To evaluate the protective effect of the probiotic P. pentosaceus on ethanol-induced liver injury in mice. METHODS A new ethanol-resistant strain of P. pentosaceus CGMCC 7049 was isolated from healthy adults in our laboratory. The chronic plus binge model of experimental ALD was established to evaluate the protective effects. Twenty-eight C57BL/6 mice were randomly divided into three groups: The control group received a pair-fed control diet and oral gavage with sterile phosphate buffered saline, the EtOH group received a ten-day Lieber-DeCarli diet containing 5% ethanol and oral gavage with phosphate buffered saline, and the P. pentosaceus group received a 5% ethanol Lieber-DeCarli diet but was treated with P. pentosaceus. One dose of isocaloric maltose dextrin or ethanol was administered by oral gavage on day 11, and the mice were sacrificed nine hours later. Blood and tissue samples (liver and gut) were harvested to evaluate gut barrier function and liver injury-related parameters. Fresh cecal contents were collected, gas chromatography–mass spectrometry was used to measure short-chain fatty acid (SCFA) concentrations, and the microbiota composition was analyzed using 16S rRNA gene sequencing. RESULTS The P. pentosaceus treatment improved ethanol-induced liver injury, with lower alanine aminotransferase, aspartate transaminase and triglyceride levels and decreased neutrophil infiltration. These changes were accompanied by decreased levels of endotoxin and inflammatory cytokines, including interleukin-5, tumor necrosis factor-α, granulocyte colony-stimulating factor, keratinocyte-derived protein chemokine, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. Ethanol feeding resulted in intestinal dysbiosis and gut barrier disruption, increased relative abundance of potentially pathogenic Escherichia and Staphylococcus, and the depletion of SCFA-producing bacteria, such as Prevotella, Faecalibacterium, and Clostridium. In contrast, P. pentosaceus administration increased the microbial diversity, restored the relative abundance of Lactobacillus, Pediococcus, Prevotella, Clostridium and Akkermansia and increased propionic acid and butyric acid production by modifying SCFA-producing bacteria. Furthermore, the levels of the tight junction protein ZO-1, mucin proteins (mucin [MUC]-1, MUC-2 and MUC-4) and the antimicrobial peptide Reg3β were increased after probiotic supplementation. CONCLUSION Based on these results, the new strain of P. pentosaceus alleviated ethanol-induced liver injury by reversing gut microbiota dysbiosis, regulating intestinal SCFA metabolism, improving intestinal barrier function, and reducing circulating levels of endotoxin and proinflammatory cytokines and chemokines. Thus, this strain is a potential probiotic treatment for ALD.

Aberrant epithelial remodeling and/or abnormalities in mucociliary apparatus in airway epithelium contribute to infection and inflammation. It is uncertain if these changes occur in both large and small airways in non-cystic fibrosis bronchiectasis (non-CF bronchiectasis). In this study, we aim to investigate the histopathology and inflammatory profile in the epithelium of bronchi and bronchioles in bronchiectasis.Excised lung tissue sections from 52 patients with non-CF bronchiectasis were stained with specific cellular markers and analyzed by immunohistochemistry and immunofluorescence to assess the epithelial structures, including ciliated cells and goblet cells morphology. Inflammatory cell counts and ciliary proteins expression levels of centrosomal protein 110 (CP110) and dynein heavy chain 5, axonemal (DNAH5) were assessed.Epithelial hyperplasia is found in both bronchi and bronchioles in all specimens, including hyperplasia and/or hypertrophy of goblet cells. The median cilia length is longer in hyperplastic epithelium [bronchi: 8.16 (7.03-9.14) µm, P0.0001; bronchioles: 7.46 (6.41-8.48) µm, P0.0001] as compared to non-hyperplastic epithelium (bronchi: 5.60 µm; bronchioles: 4.89 µm). Hyperplastic epithelium is associated with overexpression of CP110 and decreased intensity of DNAH5 expression in both bronchial and bronchiolar epithelium. Though infiltration of neutrophils is predominant (63.0% in bronchi and 76.7% in bronchioles), eosinophilic infiltration is also present in the mucosa of bronchi (30.8%) and bronchioles (54.8%).Aberrant epithelial remodeling with impaired mucociliary architecture is present in both large and small airways in patients with refractory non-CF bronchiectasis. Future studies should evaluate the interplay between these individual components in driving chronic inflammation and lung damage in patients.

Fulminant myocarditis (FM) is a life-threatening disease in children. With a rapid, progressive course of deterioration, it causes refractory cardiorespiratory failure even with optimal clinical intervention. We present the case of a 9-year-old girl with FM complicated by cardiogenic shock, malignant arrhythmia, and refractory cardiac arrest. She received effective cardiopulmonary resuscitation, therapeutic hypothermia, and other supportive treatments. However, the patient rapidly worsened into pulseless ventricular tachycardia and refractory cardiac arrest. Therefore, we performed extracorporeal membrane oxygenation (ECMO) to establish spontaneous circulation after the failure of standard resuscitation measures. The girl recovered with intact cardiac and neurocognitive functions after continued ECMO treatment for 221 hours. Therefore, ECMO is an effective rescue therapeutics for FM, especially when complicated with refractory cardiac arrest.

Airway remodeling is a hallmark of bronchial asthma. Our group has previously reported that the thymic stromal lymphopoietin (TSLP), an airway epithelial-derived cytokine, has a central role in the pathogenesis of airway remodeling, and that toll-like receptor (TLR) 4 signaling in epithelial cells may trigger T-helper 2 (Th2) immune responses by overexpression of TSLP. However, it is currently unclear whether TLR4 is a target in the treatment of airway remodeling in asthma. The present study established a house dust mite (HDM)-induced chronic asthmatic model in female BALB/c mice and treated the HDM-exposed mice with 3 mg/kg TAK242, as a TLR4 antagonist, 30 min prior to HDM challenge for up to 2 weeks. General structural changes in the airways were subsequently evaluated and the levels of TSLP in the bronchoalveolar lavage fluid (BALF) and interleukin (IL)-4, IL-13 and interferon (IFN)-γ in the blood serum were determined. Results indicated that TAK242 treatment markedly reduced pathological changes in the airways of HDM-induced asthmatic mice, as demonstrated by reductions in airway wall thickening, peribronchial collagen deposition and subepithelial fibrosis. Furthermore, airway hyperresponsiveness to inhaled methacholine and the levels of TSLP in the BALF and IL-4, IL-13 and IFN-γ in the peripheral blood were significantly reduced by TAK242 treatment (P