Nasal Staphylococcus aureus Carriage and Antimicrobial Resistance Profiles Among Community-Dwelling Adults in Jiangsu, China.

INTRODUCTION: Persistent nasal carriage has been associated with Staphylococcus aureus infection. Previous S. aureus studies in Asia have primarily focused on clinical patients, providing limited information on persistent nasal carriage among the general adult population. METHODS: This study examined 143 healthy adults in a community in Jiangsu, China. Nasal swab samples were collected 10 times. The colonization status was identified using SPA typing. We also determined antimicrobial susceptibility, genotype, and genomic characteristics of S. aureus. RESULTS: The prevalence of S. aureus nasal carriage among the community individuals was on average 16.78%. The carriage rates of methicillin-resistant S. aureus and multidrug-resistant S. aureus were 6.29% and 7.69%, respectively. We identified 8.39% persistent carriers, 39.16% intermittent carriers, and 52.45% noncarriers. Furthermore, family members displayed concordance in terms of genotype and genomic characteristics. CONCLUSION: Persistent nasal sampling captured intermittent carriers that were missed during short-term sampling, thus highlighting the necessity for regular community testing. SPA typing can serve as a rapid method for determining S. aureus colonization. The potential for intrafamilial transmission of S. aureus is evident, with persistent carriers being the most probable source of infection.

Therapeutic efficacy of a K5-specific phage and depolymerase against Klebsiella pneumoniae in a mouse model of infection.

Klebsiella pneumoniae has become one of the most intractable gram-negative pathogens infecting humans and animals due to its severe antibiotic resistance. Bacteriophages and protein products derived from them are receiving increasing amounts of attention as potential alternatives to antibiotics. In this study, we isolated and investigated the characteristics of a new lytic phage, P1011, which lyses K5 K. pneumoniae specifically among 26 serotypes. The K5-specific capsular polysaccharide-degrading depolymerase dep1011 was identified and expressed. By establishing murine infection models using bovine strain B16 (capable of supporting phage proliferation) and human strain KP181 (incapable of sustaining phage expansion), we explored the safety and efficacy of phage and dep1011 treatments against K5 K. pneumoniae. Phage P1011 resulted in a 60% survival rate of the mice challenged with K. pneumoniae supporting phage multiplication, concurrently lowering the bacterial burden in their blood, liver, and lungs. Unexpectedly, even when confronted with bacteria impervious to phage multiplication, phage therapy markedly decreased the number of viable organisms. The protective efficacy of the depolymerase was significantly better than that of the phage. The depolymerase achieved 100% survival in both treatment groups regardless of phage propagation compatibility. These findings indicated that P1011 and dep1011 might be used as potential antibacterial agents to control K5 K. pneumoniae infection.

Antimicrobial resistance survey and whole-genome analysis of nosocomial P. Aeruginosa isolated from eastern Province of China in 2016-2021.

BACKGROUND: Pseudomonas aeruginosa is a major Gram-negative pathogen that can exacerbate lung infections in the patients with cystic fibrosis, which can ultimately lead to death. METHODS: From 2016 to 2021, 103 strains of P. aeruginosa were isolated from hospitals and 20 antibiotics were used for antimicrobial susceptibility determination. Using next-generation genome sequencing technology, these strains were sequenced and analyzed in terms of serotypes, ST types, and resistance genes for epidemiological investigation. RESULTS: The age distribution of patients ranged from 10 days to 94 years with a median age of 69 years old. The strains were mainly isolated from sputum (72 strains, 69.9%) and blood (14 strains, 13.6%). The size of these genomes ranged from 6.2 Mb to 7.4 Mb, with a mean value of 6.5 Mb. In addition to eight antibiotics that show inherent resistance to P. aeruginosa, the sensitivity rates for colistin, amikacin, gentamicin, ceftazidime, piperacillin, piperacillin-tazobactam, ciprofloxacin, meropenem, aztreonam, imipenem, cefepime and levofloxacin were 100%, 95.15%, 86.41%, 72.82%, 71.84%, 69.90%, 55.34%, 52.43%, 50.49%, 50.49%, 49.51% and 47.57% respectively, and the carriage rate of MDR strains was 30.69% (31/101). Whole-genome analysis showed that a total of 50 ST types were identified, with ST244 (5/103) and ST1076 (4/103) having a more pronounced distribution advantage. Serotype predictions showed that O6 accounted for 29.13% (30/103), O11 for 23.30% (24/103), O2 for 18.45% (19/103), and O1 for 11.65% (12/103) of the highest proportions. Notably, we found a significantly higher proportion of ExoU in P. aeruginosa strains of serotype O11 than in other cytotoxic exoenzyme positive strains. In addition to this, a total of 47 crpP genes that mediate resistance to fluoroquinolones antibiotics were found distributed on 43 P. aeruginosa strains, and 10 new variants of CrpP were identified, named 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41 and 7.1. CONCLUSIONS: We investigated the antibiotic susceptibility of clinical isolates of P. aeruginosa and genomically enriched the diversity of P. aeruginosa for its prophylactic and therapeutic value.

Epidemiological characteristics and temporal-spatial clustering analysis on human brucellosis in Jiangsu Province, 2006-2021.

The marked increase in the incidence rate of brucellosis is a serious public health concern in Jiangsu Province. However, its temporal and spatial distribution has not been studied in depth. The main purpose of this study is to depict the demographic, temporal and spatial distribution patterns and clustering characteristics of brucellosis cases in Jiangsu Province, China, from 2006 to 2021 to develop and implement effective scientific prevention and control strategies. Data for human brucellosis cases in Jiangsu Province from 2006 to 2021 were obtained from the Nationwide Notifiable Infectious Diseases Reporting Information System (NIDRIS). Spatial autocorrelation analysis and temporal-spatial scan statistics were used to identify potential changes in the spatial and temporal distributions of human brucellosis in Jiangsu Province. During the years 2006-2021, 1347 brucellosis cases were reported in Jiangsu Province, with an average annual incidence rate of 0.1036 per 100,000 individuals. Middle-aged and elderly individuals (aged 40-69 years) were the main infected populations, accounting for 69.72% (939/1347) of all reported cases. The incidence of brucellosis in Jiangsu showed a long-term increasing trend and displayed pronounced seasonal variations, with the peak occurring between April and June annually. The incidence gradually expanded from the northern and southern areas to the central areas between 2006 and 2021. Global spatial autocorrelation analysis demonstrated a positive correlation in the incidence of brucellosis between 2008 and 2012-2021. Temporal-spatial clustering analysis showed that the primary cluster was detected in the northern, highly endemic regions of Jiangsu, and the three secondary clusters were in areas where there had been outbreaks of brucellosis. Human brucellosis remains a serious public health issue in Jiangsu Province. Northern and southern Jiangsu regions, with high rates of brucellosis, may require special plans and measures to monitor and control the disease. Additionally, the capacity to respond to outbreaks in high-incidence areas should be improved to prevent further brucellosis outbreaks.

Early detection of hepatocellular carcinoma via no end-repair enzymatic methylation sequencing of cell-free DNA and pre-trained neural network.

BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is important in order to improve patient prognosis and survival rate. Methylation sequencing combined with neural networks to identify cell-free DNA (cfDNA) carrying aberrant methylation offers an appealing and non-invasive approach for HCC detection. However, some limitations exist in traditional methylation detection technologies and models, which may impede their performance in the read-level detection of HCC. METHODS: We developed a low DNA damage and high-fidelity methylation detection method called No End-repair Enzymatic Methyl-seq (NEEM-seq). We further developed a read-level neural detection model called DeepTrace that can better identify HCC-derived sequencing reads through a pre-trained and fine-tuned neural network. After pre-training on 11 million reads from NEEM-seq, DeepTrace was fine-tuned using 1.2 million HCC-derived reads from tumor tissue DNA after noise reduction, and 2.7 million non-tumor reads from non-tumor cfDNA. We validated the model using data from 130 individuals with cfDNA whole-genome NEEM-seq at around 1.6X depth. RESULTS: NEEM-seq overcomes the drawbacks of traditional enzymatic methylation sequencing methods by avoiding the introduction of unmethylation errors in cfDNA. DeepTrace outperformed other models in identifying HCC-derived reads and detecting HCC individuals. Based on the whole-genome NEEM-seq data of cfDNA, our model showed high accuracy of 96.2%, sensitivity of 93.6%, and specificity of 98.5% in the validation cohort consisting of 62 HCC patients, 48 liver disease patients, and 20 healthy individuals. In the early stage of HCC (BCLC 0/A and TNM I), the sensitivity of DeepTrace was 89.6 and 89.5% respectively, outperforming Alpha Fetoprotein (AFP) which showed much lower sensitivity in both BCLC 0/A (50.5%) and TNM I (44.7%). CONCLUSIONS: By combining high-fidelity methylation data from NEEM-seq with the DeepTrace model, our method has great potential for HCC early detection with high sensitivity and specificity, making it potentially suitable for clinical applications. DeepTrace: https://github.com/Bamrock/DeepTrace.

Research on risk contagion mechanism of big fintech based on the SIRS model.

In recent years, while the relationship between the new financial institutions, represented by financial technology companies, and the traditional financial institutions(banks, securities, insurance, etc.) has been steadily enhanced, a New Relational Network has silently emerged. Along with the rapid expansion of big fintech companies, the possibility of financial risk breeding and spreading in the New Relational Network is also rising. This article analyzes and simulates the risk contagion mechanism of big fintech risks based on the SIRS epidemic model. The study's findings imply that: when the number of big fintech companies infected with risk exceeds the risk threshold, the big fintech risk will spread in the New Relational Network. At this time, the number of big fintech companies infected with risk can be reduced below the threshold by enhancing the risk warning, risk management, risk buffering and blocking capabilities, and timely improving risk prevention and control measures in the post-infection phase. It means that the big fintech risk is controlled. For big fintech risks, proactive interventions are more effective than post-incident response measures. This paper makes the following recommendations for preventing big fintech risks: creating a risk monitoring and early warning system to raise the Big Fintech companies' direct immunization rates; strengthening the big fintech companies' risk management and risk mitigation capabilities; enhancing the internal and external supervision to achieve sustainable development of big fintech companies.

Environmental Impact Assessment for the Use of an Orally Aerosolized Adenovirus Type-5 Vector-Based COVID-19 Vaccine in Randomized Clinical Trials.

BACKGROUND: An orally aerosolized adenovirus type-5 vector-based coronavirus disease 2019 (COVID-19) vaccine (Ad5-nCoV) has recently been authorized for boosting immunization in China. Our study aims to assess the environmental impact of the use of aerosolized Ad5-nCoV. METHODS: We collected air samples from rooms, swabs from the desks on which the vaccine nebulizer was set, mask samples from participants, and blood samples of nurses who administered the inoculation in the clinical trials. The viral load of adenovirus type-5 vector in the samples and the antibody levels against the wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain in serum were detected. RESULTS: Only one (4.00%) air sample collected before initiation of vaccination was positive and most air samples collected during and after vaccination were positive (97.96%, 100%, respectively). All nurses in trial A showed at least 4-fold increase of the neutralizing antibody against SARS-CoV-2 after initiation of the study. In trial B, the proportion of positive mask samples was 72.97% at 30 minutes after vaccination, 8.11% at day 1, and 0% at days 3, 5, and 7. CONCLUSIONS: Vaccination with the orally aerosolized Ad5-nCoV could result in some spillage of the vaccine vector viral particles in the environment and cause human exposure. Clinical Trials Registration. NCT04840992 and NCT05303584.

RP11-40C6.2 Inactivates Hippo Signaling by Attenuating YAP1 Ubiquitylation in Hepatitis B Virus-associated Hepatocellular Carcinoma.

Background and Aims: Chronic hepatitis caused by hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). We investigated the roles of oncogenic HBV infection-associated long noncoding RNAs in HCC. Methods: Bioinformatics analysis of data from the Cancer Genome Atlas (TCGA) was performed to screen potential oncogenic HBV-related lncRNAs. Next, we assessed their expression in clinical samples and investigated their correlation with clinical characteristics. The detailed oncogenic effects were analyzed by performing in vitro and in vivo studies. Results: RP11-40C6.2, an HBV infection-related lncRNA, was identified by analysis of the TCGA-Liver Hepatocellular Carcinoma database. Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of differentially expressed genes revealed a strong association of RP11-40C6.2 with the Hippo signaling pathway. RP11-40C6.2 was overexpressed in HCC patients with HBV infection compared to those without HBV infection. RP11-40C6.2 transcription showed a positive association with HBV-X protein (HBx), but not HBV core protein (HBc) expression, both of which are carcinogenic proteins. Luciferase gene reporter and ChIP assays revealed that YAP1/TAZ/TEADs complex enhanced RP11-40C6.2 transcription by binding to its promoter area. RP11-40C6.2 showed oncogenic characteristics in HCC cell lines and in animal models that were mediated via activation of YAP1. In vitro ubiquitylation assay revealed that RP11-40C6.2 can promote the stabilization of YAP1 by stopping phosphorylation at its s127 residue and further stopping its degradation through binding to 14-3-3. Conclusions: RP11-40C6.2 is an HBV infection-related lncRNA that exerts its oncogenic effects by targeting the Hippo signaling pathway.

Metformin Suppresses Hepatocellular Carcinoma through Regulating Alternative Splicing of LGR4.

Methods: First, the expression of LGR4 in HCC tumor tissues and cell lines was detected by western blotting and immunofluorescence. The ability of cell proliferation, migration, and invasion was detected with CCK8, wound-healing, and transwell assays when overexpressing LGR4 or treating with metformin. The ß-catenin expression was detected by immunofluorescence. In order to investigate novel AS-associated LGR4, we discarded LGR4 isoforms from GSO databases. We used siRNA to knock down the specific isoform to check the cell proliferation, migration, and invasion when treated with metformin. Results: The level of LGR4 expression was higher in HCC cell lines and tumor tissues. The HCC cell proliferation, migration, and invasion were increased when overexpressing LGR4, which could be reduced by metformin treatment. The GEO database (GSE190076) showed that LGR4 had switching properties in HCC cell lines treated with metformin. We used siRNA to knock down the specific isoform, and the result showed that the specific isoform siRNA could promote the inhibition of cell invasion caused by metformin treatment. Conclusions: LGR4 could promote the ability of cell proliferation, migration, and invasion in HCC, which could be reduced by metformin through alternative splicing.

CircMYH9 increases KPNA2 mRNA stability to promote hepatocellular carcinoma progression in an EIF4A3-dependent manner.

Hepatocellular carcinoma (HCC) is the most commonly diagnosed cancer worldwide with a high incidence of recurrence and metastasis; however, the molecular mechanisms underlying HCC development remain to be fully understood. In this study, we identified circMYH9 as an important regulator of HCC. Overexpression of circMYH9 induced, while knockdown of circMYH9 inhibited, the proliferation, migration, and invasion of HCC cells. Mechanistically, circMYH9 bound to eukaryotic translation initiation factor 4A3 (EIF4A3) and increased karyopherin subunit alpha 2 (KPNA2) mRNA stability. circMYH9 knockdown in HCC cells reduced the stability of KPNA2 mRNA. Importantly, circMYH9 regulation of HCC required the activity of KPNA2. In support with this, circMYH9 level was positively correlated with the expression of KPNA2 in HCC patient samples. Taken together, our study was the first to uncover the oncogenic role of circMYH9 in HCC and further elucidated the functional mechanism of circMYH9 by interacting with EIF4A3 to increase KPNA2 mRNA stability. Our findings might provide a novel potential target for the diagnose and treatment of HCC.

Whole-genome analyses of APEC carrying mcr-1 in some coastal areas of China from 2019 to 2020.

OBJECTIVES: Polymyxin is considered as one of the 'last lines of defense' for the treatment of multidrug resistant bacteria. Increased use of polymyxin during recent years poses a risk to public health. The purpose of this study was to investigate the carrying situation of the mcr-1 drug-resistance gene in waterfowl in some coastal areas of China from 2019 to 2020. METHODS: Fifty-seven isolated avian pathogenic Escherichia coli strains were selected from 493 APEC isolates for whole-genome sequencing. The 24 mcr-1-positive APEC strains were tested for conjugation and genome-wide analysis, including sequence type (ST) analysis, serotype analysis, and drug-resistance gene analysis. Numerous mcr-1-positive E. coli were downloaded from the National Center for Biotechnology Information (NCBI) for comparative genomic analysis. RESULTS: Antimicrobial susceptibility test results showed that 57 APEC isolates were highly resistant to gentamicin, cefotaxime, and ofloxacin, and 24 mcr-1-positive APEC isolates were resistant to polymyxin. Fourteen isolates of mcr-1-positive APEC plasmids were successfully conjugated to EC600. Both ST156 and ST10 were found in high proportions in human and avian sources through genome-wide analysis; it is worth noting that these two isolates of APEC were detected to contain the blaNDM-1 and blaNDM-4 genes, respectively. CONCLUSION: In this study, the epidemiological investigation of the mcr-1 gene was carried out on APEC in some coastal areas of China from 2019 to 2020, and our results have enriched the data on the transmission of APEC isolates carrying the mcr-1 gene in waterfowl.

CircASPH Promotes Hepatocellular Carcinoma Progression Through Methylation and Expression of HAO2.

CircRNAs have been reported to be related to hepatocellular carcinoma (HCC) development. Limited studies have revealed the expression profile of circRNAs in tumor and para-tumor normal samples in HCC patients. We found that circASPH was significantly increased in HCC tumor samples and that the level of circASPH was closely related to the overall survival of HCC patients. Mechanistically, circASPH could regulate the methylation of the promoter and expression of hydrocyanic oxidase 2 (HAO2) to promote HCC progression by acting as a sponge for miR-370-3p, and miR-370-3p could target DNMT3b and increase the 5mC level. In summary, our study determined that circASPH could regulate the methylation and expression of HAO2 and it could be considered an important epigenetic regulator in HCC progression.

Combing Immunoinformatics with Pangenome Analysis To Design a Multiepitope Subunit Vaccine against Klebsiella pneumoniae K1, K2, K47, and K64.

Klebsiella pneumoniae is an opportunistic Gram-negative bacterium that has become a leading causative agent of nosocomial infections, mainly infecting patients with immunosuppressive diseases. Capsular (K) serotypes K1, K2, K47, and K64 are commonly associated with higher virulence (hypervirulent Klebsiella pneumoniae), and more threateningly, isolates belonging to the last two K serotypes are also frequently associated with resistance to carbapenem (hypervirulent carbapenem-resistant Klebsiella pneumoniae). The prevalence of these isolates has posed significant threats to human health, and there are no appropriate therapies available against them. Therefore, in this study, a method combining immunoinformatics and pangenome analysis was applied for contriving a multiepitope subunit vaccine against these four threatening serotypes. To obtain cross-protection, 12 predicted conserved antigens were screened from the core genome of 274 complete Klebsiella pneumoniae genomes (KL1, KL2, KL47, and KL64), from which the epitopes of T and B cells were extracted for vaccine construction. In addition, the immunological properties, the interaction with Toll-like receptors, and the stability in a simulative humoral environment were evaluated by immunoinformatics methods, molecular docking, and molecular dynamics simulation. All of these evaluations indicated the potency of this constructed vaccine to be an effective therapeutic agent. Lastly, the cDNA of the designed vaccine was optimized and ligated to pET-28a(+) for expression vector construction. Overall, our research provides a newly cross-protective control strategy against these troublesome pathogens and paves the way for the development of a safe and effective vaccine. IMPORTANCE Klebsiella pneumoniae is an opportunistic Gram-negative bacterium that has become a leading causative agent of nosocomial infections. Among the numerous capsular serotypes, K1, K2, K47, and K64 are commonly associated with higher virulence (hypervirulent K. pneumoniae). More threateningly, the last two serotypes are frequently associated with resistance to carbapenem (hypervirulent carbapenem-resistant K. pneumoniae). However, there is currently no therapeutic agent or vaccine specifically against these isolates. Therefore, development of a vaccine against these pathogens is very essential. In this study, for the first time, a method combining pangenome analysis, reverse vaccinology, and immunoinformatics was applied for contriving a multiepitope subunit vaccine against K. pneumoniae isolates of K1, K2, K47, and K64. Also, the immunological properties of the constructed vaccine were evaluated and its high potency was revealed. Overall, our research will pave the way for the vaccine development against these four threatening capsular serotypes of K. pneumoniae.

Genomic characterization of Streptococcus parasuis, a close relative of Streptococcus suis and also a potential opportunistic zoonotic pathogen.

Streptococcus parasuis (S. parasuis) is a close relative of Streptococcus suis (S. suis), composed of former members of S. suis serotypes 20, 22 and 26. S. parasuis could infect pigs and cows, and recently, human infection cases have been reported, making S. parasuis a potential opportunistic zoonotic pathogen. In this study, we analysed the genomic characteristics of S. parasuis, using pan-genome analysis, and compare some phenotypic determinants such as capsular polysaccharide, integrative conjugative elements, CRISPR-Cas system and pili, and predicted the potential virulence genes by associated analysis of the clinical condition of isolated source animals and genotypes. Furthermore, to discuss the relationship with S. suis, we compared these characteristics of S. parasuis with those of S. suis. We found that the characteristics of S. parasuis are similar to those of S. suis, both of them have "open" pan-genome, their antimicrobial resistance gene profiles are similar and a srtF pilus cluster of S. suis was identified in S. parasuis genome. But S. parasuis still have its unique characteristics, two novel pilus clusters are and three different type CRISPR-Cas system were found. Therefore, this study provides novel insights into the interspecific and intraspecific genetic characteristics of S. parasuis, which can be useful for further study of this opportunistic pathogen, such as serotyping, diagnostics, vaccine development, and study of the pathogenesis mechanism.

Evaluation of a recombinant five-antigen Staphylococcus aureus vaccine: The randomized, single-centre phase 1a/1b clinical trials.

BACKGROUND: Staphylococcus aureus is an important pathogen that causes hospital and community infections. To control Staphylococcus aureus infection and reduce the usage of antibiotics, we evaluated the safety and immunogenicity of a recombinant five-antigen Staphylococcus aureus vaccine (rFSAV) in healthy adults. METHODS: We conducted a randomized, double-blind, placebo-controlled phase 1a study and a randomized, open-label phase 1b study. In phase 1a, we randomly allocated 144 healthy participants in a ratio of 1:1:1:1 to receive the low-(60 µg), middle-(120 µg), and high-dose (240 µg) vaccine or placebo at day 0, 3, 7 and 14. In phase 1b, 144 healthy participants were randomly allocated at a ratio of 1:1:1:1 to receive 0-3-7, 0/0-7, 0/0-3-7, 0/0-7-14 regimens to estimate the optimal strategy. The primary study endpoint was the incidence of solicited adverse events post-vaccination. The immunogenicity endpoints included the level of specific antibodies to five antigens after vaccination, as well as the cellular immune responses and functional antibodies. RESULTS: There were 31 (86%), 30 (83%), and 32 (89%) of 36 participants in the low-, middle-, and high-dose group reported solicited adverse events, respectively, most of the adverse events were mild or moderate. In phase 1b, the dose-adjusted rFSAV (90 µg) showed a better safety profile in the four immune procedures, and no vaccine-related serious adverse events were reported. The antigen-specific binding antibodies started to increase at day 7 and reached the peak around day 14 to 21. The cellular immune responses and functional antibodies also were substantially above background levels. CONCLUSIONS: rFSAV is safe, well tolerated in healthy adults, elicits rapid and robust specific humoral and cellular immune responses with unconventional immunization procedure in phase 1a and 1b. It deserves to be noted and further explored. CLINICAL TRIALS REGISTRATION: NCT02804711 and NCT03966040.

SOCS2 Suppresses Inflammation and Apoptosis during NASH Progression through Limiting NF-κB Activation in Macrophages.

Background: Inflammation and apoptosis play a crucial role in the progression of nonalcoholic steatohepatitis (NASH). Suppressor of cytokine signaling 2 (SOCS2) is one of classic negative regulators of cytokine signaling, which has recently been described as anti-inflammatory mediators. However, the role of SOCS2 in macrophages during NASH progression and the relationship among SOCS2, inflammation, apoptosis and NASH is largely unknown. Herein, we aimed to study the function of SOCS2 in NASH progression. Methods: We detected SOCS2 expression in macrophages in human subjects without steatosis, with simple steatosis and with NASH to confirm the relationship between SOCS2 and NASH. Free fatty acids was used to establish stress environment in RAW 264.7 cell lines stably overexpressing or knockdown SOCS2. In vitro and vivo assays also performed to study the molecular function of SOCS2 in NASH progression. Findings: Our human samples illustrated that SOCS2 was decreased in macrophages during NASH progression and was negatively correlated to NASH level. Meanwhile, In vitro assays showed SOCS2 overexpression in macrophages suppressed inflammation and apoptosis via inhibiting NF-κB signaling pathway, while SOCS2 knock-down in macrophages caused an increased activation of NF-κB, which could be blocked by ammonium 1-pyrrolidinedithiocarbamate (PDTC). In addition, SOCS2 in macrophages also suppressed inflammation via limiting the activation of inflammasomes. Consistent with these, our BMT model also confirmed the SOCS2 function in macrophages during NASH. Interpretation: Our data strongly indicate that SOCS2 plays a role in inhibiting inflammation and apoptosis via NF-κB and inflammasome signaling pathway in macrophages during NASH. Further studies are required to explore the potential preventive and therapeutic strategies of SOCS2 for this common liver disease.

Evaluation of the immunogenicity and protective ability of a pili subunit, SBP2', of Streptococcus suis serotype 2.

Streptococcus suis is an important zoonotic pathogen that leads to huge economic losses in the swine industry. Because of the enormous genetic and phenotypic diversity within S. suis, it is necessary to develop effective vaccines to control this zoonotic pathogen. SBP2' is a major pili subunit in S. suis that belongs to an srtBCD pili cluster and has already been reported to be associated with the pathogenesis of this bacterium. In this study, we aimed to evaluate the immunogenicity and protective ability of SBP2'. The rSBP2' protein was expressed by an Escherichia coli expression system and emulsified with Montanide ISA 201 adjuvant to prepare the subunit vaccine. Through active immune assays, the results showed that rSBP2' exhibited good immunogenicity and could protect mice from a lethal dose challenge. Additionally, the qRT-PCR data showed that the transcription levels of cytokines associated with systemic symptoms caused by S. suis were decreased, indicating that immunization with rSBP2' could protect the host from cytokine storms caused by S. suis. Furthermore, the passive immune assay showed that the humoral immunity induced by rSBP2' played an important role against S. suis infection. Taken together, SBP2' could provide proper immune protection against S. suis challenge and could be a candidate for S. suis subunit vaccine. The results of this study could provide new ideas for the development of effective vaccines against S. suis.

Novel insight from the first lung transplant of a COVID-19 patient.

BACKGROUND: To reveal detailed histopathological changes, virus distributions, immunologic properties and multi-omic features caused by SARS-CoV-2 in the explanted lungs from the world's first successful lung transplantation of a COVID-19 patient. MATERIALS AND METHODS: A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID-19-associated pulmonary fibrosis. RESULTS: The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+ CD4- T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL-1ß and IL-6 were in the area of mild fibrosis. Multi-omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation. CONCLUSIONS: Our results provide novel insight that the significant neutrophil/ CD3+ CD4- T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID-19 patient and may contribute to a better understanding of COVID-19 pathogenesis.

Circulating circRNA predicting the occurrence of hepatocellular carcinoma in patients with HBV infection.

A microarray-based high-throughput screening of human circulating circular RNA (circRNA) was applied with five patients newly diagnosed with hepatocellular carcinoma (HCC), five patients with HBV-positive chronic hepatitis (CH) and five healthy controls (NC) enrolled. The plasma of HCC patients after hepatectomy was also collected. After multiple staged validation, we obtained five circRNAs as candidate. Based on the stratified risk score analysis, three increased circRNAs including circ_0009582, circ_0037120 and circ_0140117 were confirmed as candidate circulating fingerprints for distinguishing HCC from CH or NC group. With the combination of AFP, higher sensitivity and specificity were further guaranteed, suggesting that circ_0009582, circ_0037120 and circ_0140117 may serve as potential biomarkers for predicting the occurrence of HCC in patients with HBV infection.