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OBJECTIVE Previous studies have shown Interleukin (IL)-17A as an important contributor to the development of severe asthma, which is mainly characterized by neutrophilic inflammation and less response to corticosteroids. Consequently, the IL-17A-neutrophil axis could be a potential therapeutic target. Previously, we constructed a recombinant Mycobacterium smegmatis (rMS) expressing fusion protein Ag85A-IL-17A, and confirmed it could induce production of IL-17A autoantibody in vivo. This study uses a murine model of neutrophilic asthma to further investigate the effects of rMS on airway inflammation. METHODS DO11.10 mice were divided into four groups: phosphate buffered saline (PBS), asthma, rMS and MS. This murine model of neutrophilic asthma was established with ovalbumin (OVA) challenge, whereby PBS, rMS and MS were administered intranasally. Anti-inflammatory effects on inflammatory cell infiltration and expression of inflammatory mediators in bronchoalveolar lavage fluid (BALF) were evaluated, along with histopathological changes in lung tissues. RESULTS A sustained high-titer IL-17A autoantibody was detected in sera of the rMS group. Compared to the asthma group, the number of neutrophils, IL-17A, CXCL-1 levels and MPO activity in the rMS group were all significantly reduced (p < 0.01). Histological analysis showed rMS remarkably suppressed inflammatory infiltration around bronchia. The inflammation score and the mucus score in the rMS group were both significantly lower than those in the asthma group (p < 0.001). CONCLUSION rMS ameliorated airway inflammation in mice with neutrophilic asthma caused by inducing IL-17A autoantibody and regulating the IL-17A-neutrophil axis, thus offering a possible novel treatment for neutrophilic asthma.

Hospital-acquired infections with Pseudomonas aeruginosa have become a great challenge in caring for critically ill and immunocompromised patients. The cause of high mortality is the presence of multi-drug resistant (MDR) strains, which confers a pressing need for vaccines. Although vaccines against P. aeruginosa have been in development for more than several decades, there is no vaccine for patients at present. In this study, we purified genomic DNA of P. aeruginosa from sera of patients affected, constructed genome-wide library with random recombinants, and screened candidate protein antigens by evaluating their protective effects in vivo. After 13-round of screening, 115 reactive recombinants were obtained, among which 13 antigens showed strong immunoreactivity (more than 10% reaction to PcrV, a well-characterized V-antigen of P. aeruginosa). These 13 antigens were: PpiA, PtsP, OprP, CAZ10_34235, HmuU_2, PcaK, CarAd, RecG, YjiR_5, LigD, KinB, RtcA, and PscF. In vivo studies showed that vaccination with PscF protected against lethal P. aeruginosa challenge, and decreased lung inflammation and injury. A genomic library of P. aeruginosa could be constructed in this way for the first time, which could not only screen candidate antigens but also in a high-throughput way. PscF was considered as an ideal promising vaccine candidate for combating P. aeruginosa infection and was supported for further evaluation of its safety and efficacy.

Recent studies have reported an increasing incidence of ischemic stroke, particularly in younger age groups. Dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) are the most common stem cells acquired from the teeth of adults, even elderly people. However, there are no detailed reports on whether DPSCs or PDLSCs are suitable for the treatment of ischemic stroke. In this study, the in vitro differentiation of DPSCs and PDLSCs into neuron-like cells was evaluated. Then, we established a rat model of cerebral ischemia. DPSCs or PDLSCs were administered to animals, and the therapeutic effects of these two types of cells were investigated. The results showed that PDLSCs had a higher differentiation rate than DPSCs. Immunofluorescence studies showed that the expression of the neuronal differentiation marker Thy-1 was higher in PDLSCs than in DPSCs, and other gene markers of neuronal differentiation showed corresponding trends, which were confirmed by western blot analysis. In this process, the Notch and Wnt signaling pathways were inhibited and activated, respectively. Finally, rats with transient occlusion of the right middle cerebral artery were used as a model to assess the therapeutic effect of PDLSCs and DPSCs on ischemia. The results showed that rats in the PDLSC-treated group emitted significantly greater red fluorescence signal than the DPSC-treated group. PDLSC transplantation promoted the recovery of neurological function more effectively than DPSC transplantation. Hence, PDLSCs represent an autogenous source of adult mesenchymal stem cells with desirable biological properties and may be an ideal candidate for clinical applications.

Acinetobacter baumannii (A. baumannii) is an opportunistic pathogen that causes serious infections in the lungs, blood, and brain in critically ill hospital patients, resulting in considerable mortality rates every year. Due to the rapid appearance of multi-drug resistance or even pan-drug resistance isolates, it is becoming more and more difficult to cure A. baumannii infection by traditional antibiotic treatment, alternative strategies are urgently required to combat A. baumannii infection. In this study, we developed a DNA vaccine encoding two antigens from A. baumannii, OmpA and Pal, and the immunogenicity and protective efficacy was further evaluated. The results showed that the DNA vaccine exhibited significant immune protective efficacy against acute A. baumannii infection in a mouse pneumonia model, and cross protective efficacy was observed when immunized mice were challenged with clinical strains of A. baumannii. DNA vaccine immunization induced high level of humoral response and a mixed Th1/Th2/Th17 cellular response, which protect against lethal bacterial challenges by decreased bacterial loads and pathology in the lungs, and reduced level of inflammatory cytokines expression and inflammatory cell infiltration in BALF. These results demonstrated that it is possible to prevent A. baumannii infection by DNA vaccine and both OmpA and Pal could be serve as promising candidate antigens.

Cross-regional governance of government often faces various problems, which often brings great loss to the society The global outbreak of the novel coronavirus pneumonia (NCP) in early 2020 has not only caused serious economic and social losses to various countries but also put the current public health event governance system to a severe test The cross-regional character and spillover effects of public health outbreak governance often make it difficult to coordinate cross-regional governance In this context, this paper adopts a regional evolutionary game analysis framework and studies the cross-regional governance of public health emergencies by constructing a symmetric game of peripheral regions and an asymmetric game of core-peripheral regions The marginal contribution of this paper is to attempt to construct a symmetric game model for peripheral regions and an asymmetric game model for core and peripheral regions using an evolutionary game approach to study the behavioral strategies of multiple regions in the governance of public health emergencies, and it is found that when the regional spillover effects and governance costs are small or the economic and social damages caused by public health emergencies are large, all regions will choose to conduct coordinated governance Otherwise, there will be regions that choose to "free-ride " This "free-rider" mentality has led to the failure in achieving good cross-regional collaborative governance of public health emergencies, resulting in a lack of efficiency in the overall governance of public health in society However, when the spillover effect of regional governance exceeds a certain critical value, the result of the regional governance game is also the socially optimal result, when public health emergencies are effectively governed At the same time, the relevant findings and analytical framework of this paper will provide a policy reference for the cross-regional governance of the current new crown epidemic [ABSTRACT FROM AUTHOR] Copyright of Mathematical Problems in Engineering is the property of Hindawi Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

Ischemia or hemorrhagic stroke is one of the leading causes of death and permanent disability in the worldwide population. As a consequence of the potential increasing in stroke, stem cell therapy is currently an area of intense focus. However, there are less data available regarding the promotion of healing efficacy after stroke. The present study aimed to investigate whether the cytokine interleukin-17A (IL-17A) could have a role in promoting the neuronal differentiation of mesenchymal stem cells (MSCs) and to investigate the associated molecular mechanism. Firstly, different concentration of IL-17A at range from 5-40 ng/mL was applied to stimulate bone marrow MSCs (BMSCs) during the course of neurogenic differentiation. Then reverse transcription-PCR, histological analyses and immunofluorescence assays were used to determine the optimum concentration of IL-17A in promoting the neuronal differentiation of BMSCs, which was 20 ng/mL. Mechanistically, Wnt signaling pathway was activated and Notch signaling pathway was suppressed. In addition, there were antergic effect of these two signaling pathways modulating the neurogenic differentiation of BMSCs induced by IL-17A. The present study demonstrated the potential role of IL-17A-based BMSCs strategy for promoting neuronal differentiation in vitro. However, the treatment efficacy could be considerably confirmed in animals with ischemia stroke. Therefore, a more sophisticated strategy that addresses the complicated treatment associated with stroke is needed.

Various methods have been used to induce the neuronal differentiation of marrow mesenchymal stem cells (MSCs). However, the limited induction efficiency of cells in vitro has restricted their use. Therefore, identifying a simple and efficient treatment method is necessary. Dendrobium officinale is an important traditional Chinese medicine, and its main component, polysaccharides, has many pharmacological activities. However, the effects of D. officinale polysaccharide (DOP) on the neuronal differentiation of bone marrow mesenchymal stem cells (BMSCs) and treatment of ischaemic stroke remain unknown. We found that DOP promoted the neuronal differentiation of BMSCs by increasing the expression levels of neural markers, and the optimal concentration of DOP was 25 μg/mL. Additionally, the Notch signalling pathway was inhibited during the neuronal differentiation of BMSCs induced by DOP, and this effect was strengthened using an inhibitor of this pathway. The Wnt signalling pathway was activated during the differentiation of BMSCs, and inhibition of the Wnt signalling pathway downregulated the expression of neuronal genes. Furthermore, the transplantation of neuron-like cells induced by DOP improved neuronal recovery, as the brain infarct volume, neurologic severity scores and levels of inflammatory factors were all significantly reduced in vivo. In conclusion, DOP is an effective inducer of the neuronal differentiation of BMSCs and treatment option for ischaemic stroke.

Background In this case report, giant calculus in the urethral diverticulum was found through ureteroscopy investigation, the pneumatic lithotripsy combined with ultrasound lithotripsy (PLCUL) was successfully performed to break down this rare and giant urethral calculus in the diverticulum without open surgery. Case presentation A 82-year-old male presented to the urology department, complaining of frequent urination and dysuria. One giant, dark brown stone (6.5 × 6 × 5.5 cm) was revealed in the diverticulum of the anterior urethra using combination of local ultrasound, pelvic Computer Tomography (CT) and Magnetic Resonance Imaging (MRI). The stone was then successfully broken down via the PLCUL, and the emptied anterior urethral diverticulum was left untreated. In the 18 months’ follow-up, no new calculus was found in urethral tract, anterior diverticula became gradually smaller, eventually disappeared. Conclusion In the treatment of giant calculus in the urethral diverticulum, this case report provides an effective method of lithotripsy in the clinical trials.

Pseudomonas aeruginosa (PA) is a major cause of nosocomial infections, which remain an unsolved problem in the clinic despite conventional antibiotic treatment. A PA vaccine could be both an effective and economical strategy to address this issue. Many studies have shown that PcrV, a structural protein of the type 3 secretion system (T3SS) from PA, is an ideal target for immune prevention and therapy. However, difficulties in the production of high-quality PcrV likely hinder its further application in the vaccine industry. Thus, we hypothesized that an optimized PcrV derivative with a rational design could be produced. In this study, the full-length PcrV was divided into four domains with the guidance of its structure, and the Nter domain (Met1-Lys127) and H12 domain (Leu251 - Ile294) were found to be immunodominant. Subsequently, Nter and H12 were combined with a flexible linker to generate an artificial PcrV derivative (PcrVNH). PcrVNH was successfully produced in E. coli and behaved as a homogenous monomer. Moreover, immunization with PcrVNH elicited a multifactorial immune response and conferred broad protection in an acute PA pneumonia model and was equally effective to full-length PcrV. In addition, passive immunization with anti-PcrVNH antibodies alone also showed significant protection, at least based on inhibition of the T3SS and mediation of opsonophagocytic killing activities. These results provide an additional example for the rational design of antigens and suggest that PcrVNH is a promising vaccine candidate for the control of PA infection.

Interleukin-17F (IL-17F) is an important member of IL-17 cytokine family, which plays important roles in host defense against microbial infections. Streptococcus pneumoniae is a common pathogen associated with several invasive and noninvasive pneumococcal diseases, and mucosal immune response plays crucial roles in defenses against pneumococcal infection. Thus, intranasal inoculation may be an alternative approach against pneumococci. In this study, BALB/c mice were intranasally inoculated with recombinant IL-17F (rIL-17F) prior to S. pneumoniae (American Type Culture Collection 6303, serotype 3) infection. As compared with the control group, numbers of total leukocyte, neutrophil, and macrophage in lungs were significantly increased in mice inoculated with rIL-17F. The levels of macrophage inflammatory protein 1α (MIP-1α), MIP-2β, and interferon γ were significantly increased in bronchoalveolar lavage fluid and culture supernatant of splenocytes from mice inoculated with rIL-17F. rIL-17F inoculation also significantly elevated β-defensin-2 expression in lung tissues. Furthermore, compared with S. pneumoniae infection group, rIL-17F inoculation prior to infection significantly reduced S. pneumoniae colonization in lungs. These findings demonstrated that rIL-17F intranasal inoculation strengthened host defense against pneumococci, which may be developed to prevent pneumococcal infection.

Asthma is a chronic inflammatory disorder, previous studies have shown that IL-17A contributes to the development of asthma, and there is a positive correlation between the level of IL-17A and the severity of disease. Here, we constructed recombinant Mycobacterium smegmatis expressing fusion protein Ag85A-IL-17A (rMS-Ag85a-IL-17a) and evaluated whether it could attenuate allergic airway inflammation, and further investigated the underlying mechanism. In this work, the murine model of asthma was established with ovalbumin, and mice were intranasally vaccinated with rMS-Ag85a-IL-17a. Autoantibody of IL-17A in sera was detected, and the airway inflammatory cells infiltration, the local cytokines and chemokines production and the histopathological changes of lung tissue were investigated. We found that the administration of rMS-Ag85a-IL-17a induced the autoantibody of IL-17A in sera. The vaccination of rMS-Ag85a-IL-17a remarkably reduced the infiltration of inflammatory cells and the secretion of mucus in lung tissue and significantly decreased the numbers of the total cells, eosinophils and neutrophils in BALF. Th1 cells count in spleen, Th1 cytokine levels in BALF and supernatant of splenocytes and mediastinal lymph nodes, and T-bet mRNA in lung tissue were significantly increased with rMS-Ag85a-IL-17a administration. Meanwhile, rMS-Ag85a-IL-17a vaccination markedly decreased Th2 cells count, Th2 cytokine and Th17 cytokine levels in BALF and supernatant of splenocytes and mediastinal lymph nodes, and chemokines mRNA expression in lung tissue. These data confirmed that recombinant Mycobacterium smegmatis in vivo could induce autoantibody of IL-17A, which attenuated asthmatic airway inflammation.

Histone acetyltransferases regulate transcription, but little is known about the role of these enzymes in developmental processes. Gcn5 (encoded by Gcn5l2) and Pcaf, mouse histone acetyltransferases, share similar sequences and enzymatic activities1. Both interact with p300 and CBP (encoded by Ep300 and Crebbp, respectively), two other histone acetyltransferases that integrate multiple signalling pathways1. Pcaf is thought to participate in many of the cellular processes regulated by p300/CBP (refs 2–8), but the functions of Gcn5 are unknown in mammalian cells. Here we show that the gene Pcaf is dispensable in mice. In contrast, Gcn5l2-null embryos die during embryogenesis. These embryos develop normally to 7.5 days post coitum (d.p.c.), but their growth is severely retarded by 8.5 d.p.c. and they fail to form dorsal mesoderm lineages, including chordamesoderm and paraxial mesoderm. Differentiation of extra-embryonic and cardiac mesoderm seems to be unaffected. Loss of the dorsal mesoderm lineages is due to a high incidence of apoptosis in the Gcn5l2 mutants that begins before the onset of morphological abnormality. Embryos null for both Gcn5l2 and Pcaf show even more severe defects, indicating that these histone acetyltransferases have overlapping functions during embryogenesis. Our studies are the first to demonstrate that specific acetyltransferases are required for cell survival and mesoderm formation during mammalian development.