Enantioselective Synthesis of C2-Quaternary Indolin-3-ones by Pt-Catalyzed Alkynylation of 2-Aryl-3H-indol-3-one with Alkynylsilanes.

An efficient method for the synthesis of five-membered chiral propargylic amines from 2-aryl-3H-indol-3-one and alkynylsilanes has been developed. The reaction proceeded under the catalytic system of PtCl4, oxazoline-based ligand L11, Zn(CF3COO)2, and AcOH in DCE at 95 °C via in situ desilylation of TMS-alkynes. This methodology also highlights a new protocol for the in situ desilylation of alkynylsilanes. The reaction showed a broad substrate scope with good yields and enantioselectivity.

Advanced lung cancer inflammation index combined with geriatric nutritional risk index predict all-cause mortality in heart failure patients.

BACKGROUND: This study was undertaken to explore the predictive value of the advanced lung cancer inflammation index (ALI) combined with the geriatric nutritional risk index (GNRI) for all-cause mortality in patients with heart failure (HF). METHODS AND RESULTS: We enrolled 1123 patients with HF admitted to our cardiology department from January 2017 to October 2021. Patients were divided into four groups, according to the median ALI and GNRI. From the analysis of the relationship between the ALI and GNRI, we concluded that there was a mild positive linear correlation (r = 0.348, p < 0.001) and no interaction (p = 0.140) between the ALI and GNRI. Kaplan‒Meier analysis showed that the cumulative incidence of all-cause mortality in patients with HF was highest in Group 1 (log-rank χ2 126.244, p < 0.001). Multivariate Cox proportional hazards analysis revealed that ALI and GNRI were independent predictors of all-cause mortality in HF patients (ALI: HR 0.407, 95% CI 0.296-0.560, p < 0.001; GNRI: HR 0.967, 95% CI 0.954-0.980, p < 0.001). The area under the curve (AUC) for ALI combined with GNRI was 0.711 (p < 0.001), according to the time-dependent ROC curve. CONCLUSION: ALI and GNRI were independent predictors of all-cause mortality in HF patients. Patients with HF had the highest risk of all-cause mortality when the ALI was < 24.60 and the GNRI was < 94.41. ALI combined with the GNRI has good predictive value for the prognosis of HF patients.

Chiral Phosphoric Acid-Catalyzed Enantioselective Aza-Friedel-Crafts Addition of Naphthols with Isatin-Derived Ketimines.

The enantioselective Friedel-Crafts addition of naphthols with isatin-derived ketimines was developed with H8-BINOL-derived chiral biaryl phosphoric acid. A wide range of isatin-derived ketimines and naphthols were successfully applied and gave a series of chiral 3-amino-2-oxindoles in excellent yields with high optical purities.

Meta-analysis of whether influenza vaccination attenuates symptom severity in vaccinated influenza patients.

BACKGROUND: Influenza vaccination has been associated with decreased risk of influenza-related infections. However, associations between influenza vaccination and the severity of influenza cases have not been systematically summarized. We conducted a meta-analysis to evaluate whether influenza vaccination could attenuate symptom severity in vaccinated influenza patients. METHODS: A systematic literature search was performed using the PubMed, Web of Science, EMBASE, and Scopus databases. A quantitative synthesis of the data was conducted using a fixed/random effects model in the meta-analysis. RESULTS: A total of seven studies, involving 6342 vaccinated and 7036 non-vaccinated patients were included. Compared with non-vaccinated, vaccinated patients were significantly less likely to develop a fever (OR = 0.66, 95% CI: 0.43-0.89), be admitted to the ICU (OR = 0.79, 95% CI: 0.64-0.97), suffer mortality (OR = 0.55, 95% CI: 0.34-0.89), stay in the ICU (WMD = -1.37, 95% CI: -2.15 to -0.60) or stay in the hospital (WMD = -0.32, 95% CI: -0.61 to -0.04). CONCLUSION: Those benefits that could be highlighted in the communication material to enhance the uptake of influenza vaccination among both the public health nurses and the community as a whole.

Haemophilus parasuis infection in 3D4/21 cells induces autophagy through the AMPK pathway.

Haemophilus parasuis (H. parasuis) is a common commensal in the upper respiratory tract of pigs, but causes Glässer's disease in stress conditions. To date, many studies focused on the immune evasion and virulence of H. parasuis; very few have focused on the role autophagy played in H. parasuis infection, particularly in porcine alveolar macrophages (PAMs). In this study, a PAM cell line, 3D4/21 cells were used to study the role of autophagy in H. parasuis infection. 3D4/21 cells tandemly expressing GFP, mCherry, and LC3 were infected with H. parasuis serovar 5 (Hps5). Western blot analysis and confocal and transmission electron microscopy showed that H. parasuis infection effectively induces autophagy. Using Hps strains of varying virulence (Hps4, Hps5, and Hps7) and UV-inactivated Hps5, we demonstrated that autophagy is associated with the internalisation of living virulent strains into cells. In 3D4/21 cells pretreated with rapamycin and 3-MA then infected by Hps4, Hps5, and Hps7, we demonstrated that autophagy affects invasion of H. parasuis in cells. AMPK signal results showed that Hps5 infection can upregulate the phosphorylation level of AMPK, which is consistent with the autophagy development. 3D4/21 cells pretreated with AICAR or Compound C then infected by Hps5 revealed that the autophagy induced by Hps5 infection is associated with the AMPK pathway. Our study contributes to the theoretical basis for the study of H. parasuis pathogenesis and development of novel drugs target for prevention Glässer's disease.

Up-regulated lncRNA XIST contributes to progression of cervical cancer via regulating miR-140-5p and ORC1.

BACKGROUND: The study purpose was to make investigation into the influence of XIST on cervical cancer progression and what's more its potential mechanism. METHODS: The cervical cancer data sets (lncRNA, miRNA, and mRNA) obtained from TCGA were analyzed with the "mixOmics" R package. Then, the expression of XIST, miR-140-5p, and ORC1 were detected using qRT-PCR and western blot in both tissues and cervical cancer cell lines (Hela and C33A) to verify the bioinformatics analyses results. CCK-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) assays, cell cycle assay and cell apoptosis assay were practiced. Besides, immunohistochemistry staining was operated for the detection of the Ki-67, E-cadherin and vimentin expression in cervical cancer tissues and the apoptosis-related proteins expression (c-caspase3, Bcl-2, total PARP and cleaved PARP) was verified through western blot. And in vivo experiments were implemented. RESULTS: MiR-140-5p was down-regulated but XIST and ORC1 were up-regulated in cervical cancer tissues and cell lines. Knocking down of the XIST or ORC1 memorably suppressed cell proliferation, blocked cell cycle, decreased the expression of Bcl-2 while increased the apoptosis rate and the expression of c-caspase3 and cleaved PARP in HeLa and C33A cells. Besides, the results of immunohistochemistry staining showed knocking down the expression of XIST improved the expression levels of E-cadherin and decreased Ki-67 and vimentin expression. And overexpression of miR-140-5p also could inhibit the progression and reverse the influence of XIST and ORC1 in HeLa and C33A cells. CONCLUSION: Our study indicated the effects of XIST/miR-140-5p/ORC1 axis on the progression of cervical cancer which will shed new light on epigenetic diagnostics and therapeutics in cervical cancer.

Management of Cesarean Scar Pregnancy: A Case Series.

OBJECTIVE: To survey effective treatment strategies for cesarean scar pregnancy (CSP). METHODS: The clinical data of 78 patients diagnosed with CSP from January 2010 to December 2013 were reviewed. RESULTS: Among these patients, 17 patients were first treated at our hospital; of them, 2 were misdiagnosed. The other 61 patients were referred from other hospitals; of them, 21 were initially misdiagnosed. There were 9 patients who were treated with laparotomy, 50 patients with curettage after uterine artery embolization (UAE) with or without local methotrexate (MTX) infusion, 10 patients with dilatation and curettage, 6 patients with transvaginal sonographic guided local intragestational MTX injection, and 3 patients with systemic MTX injection. All patients finally recovered. Patients with excessive vaginal hemorrhage underwent either emergency UAE treatment or laparotomy. These two treatments had similar success rates (81.82% vs. 100%, χ2 =0.289, P>0.05). CONCLUSIONS: The accurate diagnosis of CSP is important. Curettage after UAE with or without local MTX infusion is a safe and effective method.

Sulforaphane Inhibits Oxidative Stress and May Exert Anti-Pyroptotic Effects by Modulating NRF2/NLRP3 Signaling Pathway in Mycobacterium tuberculosis-Infected Macrophages.

Sulforaphane (SFN) is a natural isothiocyanate derived from cruciferous vegetables such as broccoli, Brussels sprouts, and cabbage. SFN plays a crucial role in maintaining redox homeostasis by interacting with the active cysteine residues of Keap1, leading to the dissociation and activation of NRF2 in various diseases. In this study, our objective was to investigate the impact of SFN on oxidative stress and pyroptosis in Mycobacterium tuberculosis (Mtb)-infected macrophages. Our findings demonstrated that Mtb infection significantly increased the production of iNOS and ROS, indicating the induction of oxidative stress in macrophages. However, treatment with SFN effectively suppressed the expression of iNOS and COX-2 and reduced MDA and ROS levels, while enhancing GSH content as well as upregulating NRF2, HO-1, and NQO-1 expression in Mtb-infected RAW264.7 macrophages and primary peritoneal macrophages from WT mice. These results suggest that SFN mitigates oxidative stress by activating the NRF2 signaling pathway in Mtb-infected macrophages. Furthermore, excessive ROS production activates the NLRP3 signaling pathway, thereby promoting pyroptosis onset. Further investigations revealed that SFN effectively suppressed the expression of NLRP3, Caspase-1, and GSDMD, IL-1ß, and IL-18 levels, as well as the production of LDH, suggesting that it may exhibit anti-pyroptotic effects through activation of the NRF2 signaling pathway and reductions in ROS production during Mtb infection. Moreover, we observed that SFN also inhibited the expression of NLRP3, ASC, Caspase1, and IL-1ß along with LDH production in Mtb-infected primary peritoneal macrophages from NFR2-/- mice. This indicates that SFN can directly suppress NLRP3 activation and possibly inhibit pyroptosis initiation in an NRF2-independent manner. In summary, our findings demonstrate that SFN exerts its inhibitory effects on oxidative stress by activating the NRF2 signaling pathway in Mtb-infected macrophages, while it may simultaneously exert anti-pyroptotic properties through both NRF2-dependent and independent mechanisms targeting the NLRP3 signaling pathway.

Treatment with Cordyceps sinensis enriches Treg population in peripheral lymph nodes and delays type I diabetes development in NOD mice.

Cordyceps sinensis is a widely used Chinese traditional herb with a long history. In China C. sinensis is usually applied in the treatment of respiratory diseases, however, the efficacy of C. sinensis still lacks experimental evidence. Type I diabetes is a multi-factor related autoimmune disease caused by cellular-mediated destruction of insulin-producing pancreatic beta cells in the islets in human. We tested C. sinensis for its ability to work as an immune modulator in NOD mice, an animal model which mimicks the progression of type I diabetes in humans and found that treatment with C. sinensis extract could slow down disease development in NOD mice. Further research also suggested that treatment with C. sinensis extract increased the frequency of Treg cells and IFN-gama producing Th1 cells in peripheral lymph nodes. However, C. sinensis has no effect on the natural Treg cell differentiation in thymus.

Type 2 congenital generalized lipodystrophy with a heterozygous missense NOTCH2 mutation.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease with a prevalence of less than one in ten million. To our knowledge, ~500 cases, including 95% of BSCL2, have been reported in the literatures, but no types of CGL with NOTCH2 gene mutation has been described.

Anti-inflammatory activities of Qingfei oral liquid and its influence on respiratory microbiota in mice with ovalbumin-induced asthma.

Dysbiosis of respiratory microbiota is closely related to the pathophysiological processes of asthma, including airway inflammation. Previous studies have shown that Qingfei oral liquid (QF) can alleviate airway inflammation and airway hyper-responsiveness in respiratory syncytial virus-infected asthmatic mice, but its effect on the respiratory microbiota is unknown. We therefore aimed to observe the effects of QF on airway inflammation and respiratory microbiota in ovalbumin (OVA)-induced asthmatic mice. We also explored the potential mechanism of QF in reducing airway inflammation by regulating respiratory microbiota. Hematoxylin and eosin as well as periodic acid-Schiff staining were performed to observe the effects of QF on lung pathology in asthmatic mice. Cytokine levels in bronchoalveolar lavage fluid (BALF) specimens were also measured. Changes in respiratory microbiota were analyzed using 16S rRNA gene sequencing, followed by taxonomical analysis. In order to verify the metagenomic function prediction results, the expression of key proteins related to the MAPK and NOD-like receptor signaling pathways in the lung tissues were detected by immunohistochemistry. The current study found that QF had a significant anti-inflammatory effect in the airways of asthmatic mice. This is mainly attributed to a reduction in lung pathology changes and regulating cytokine levels in BALF. Analysis of the respiratory microbiota in asthmatic mice showed that the abundance of Proteobacteria at the phylum level and Pseudomonas at the genus level increased significantly and QF could significantly regulate the dysbiosis of respiratory microbiota in asthmatic mice. Metagenomic functional prediction showed that QF can downregulate the MAPK and Nod-like receptor signaling pathways. Immunohistochemical results showed that QF could downregulate the expression of p-JNK, p-P38, NLRP3, Caspase-1, and IL-1ß, which are all key proteins in the signaling pathway of lung tissue. Our study therefore concluded that QF may reduce airway inflammation in asthmatic mice by regulating respiratory microbiota, and to the possibly downregulate MAPK and Nod-like receptor signaling pathways as its underlying mechanism.

The spatial-temporal distribution and etiological characteristics of hand-foot-and-mouth disease before and after EV­A71 vaccination in Kunming, China, 2017-2020.

After vaccination with enterovirus 71 (EV-A71), the prevalence of hand-foot-and-mouth disease (HFMD) remained high, and the spatial-temporal distribution of enteroviruses changed. Therefore, it is essential to define the temporal features, spatial distributions, and epidemiological and etiological characteristics of HFMD in Kunming. Between 2017 and 2020, a total of 36,540 children were diagnosed with HFMD in Kunming, including 32,754 children with enterovirus-positive clinical samples. Demographic, geographical, epidemiological and etiological data of the cases were acquired and analyzed. Other enteroviruses replaced EV-A71, and the incidence of EV-A71 decreased dramatically, whereas coxsackievirus A6 (CV-A6) and coxsackievirus A16 (CV-A16) had substantial outbreaks in 2018 and 2019, respectively. The major and minor peaks all extended for 2-4 months compared to before vaccination with the EV-A71 vaccine. From 2019 to 2020, CV-A6, as the predominant serotype, showed only a single peak. Although a high incidence of HFMD was observed in Guandu, Chenggong and Xishan, the annual incidence of different enterovirus serotypes was different in different regions. In 2017, other enteroviruses were most prevalent in Shilin. In 2018, CV-A16 and CV-A6 were most prevalent in Luquan and Shilin, respectively. In 2019, CV-A16 was most prevalent in Jinning. In 2020, CV-A6 and coxsackievirus A10 (CV-A10) were most prevalent in Luquan and Shilin, respectively. Meanwhile, the epidemic cycle of CV-A6 and CV-A16 was only 1 year, and CV-A10 and other enteroviruses were potential risk pathogens. The spatial and temporal distribution of HFMD varies at different scales, and the incidence of HFMD associated with different pathogens has obvious regional differences and seasonal trends. Therefore, research on multivalent combined vaccines is urgently needed, and proper preventive and protective measures could effectively control the incidence of HFMD-like diseases.

Respiratory Microbiota Profiles Associated With the Progression From Airway Inflammation to Remodeling in Mice With OVA-Induced Asthma.

BACKGROUND: The dysbiosis of respiratory microbiota plays an important role in asthma development. However, there is limited information on the changes in the respiratory microbiota and how these affect the host during the progression from acute allergic inflammation to airway remodeling in asthma. OBJECTIVE: An ovalbumin (OVA)-induced mouse model of chronic asthma was established to explore the dynamic changes in the respiratory microbiota in the different stages of asthma and their association with chronic asthma progression. METHODS: Hematoxylin and eosin (H&E), periodic acid-schiff (PAS), and Masson staining were performed to observe the pathological changes in the lung tissues of asthmatic mice. The respiratory microbiota was analyzed using 16S rRNA gene sequencing followed by taxonomical analysis. The cytokine levels in bronchoalveolar lavage fluid (BALF) specimens were measured. The matrix metallopeptidase 9 (MMP-9) and vascular endothelial growth factor (VEGF-A) expression levels in lung tissues were measured to detect airway remodeling in OVA-challenged mice. RESULTS: Acute allergic inflammation was the major manifestation at weeks 1 and 2 after OVA atomization stimulation, whereas at week 6 after the stimulation, airway remodeling was the most prominent observation. In the acute inflammatory stage, Pseudomonas was more abundant, whereas Staphylococcus and Cupriavidus were more abundant at the airway remodeling stage. The microbial compositions of the upper and lower respiratory tracts were similar. However, the dominant respiratory microbiota in the acute inflammatory and airway remodeling phases were different. Metagenomic functional prediction showed that the pathways significantly upregulated in the acute inflammatory phase and airway remodeling phase were different. The cytokine levels in BALF and the expression patterns of proteins associated with airway remodeling in the lung tissue were consistent with the metagenomic function results. CONCLUSION: The dynamic changes in respiratory microbiota are closely associated with the progression of chronic asthma. Metagenomic functional prediction indicated the changes associated with acute allergic inflammation and airway remodeling.

The epidemiological characteristics of enterovirus infection before and after the use of enterovirus 71 inactivated vaccine in Kunming, China.

Enterovirus A71 (EV-A71) inactivated vaccines have been widely inoculated among children in Kunming City after it was approved. However, there was a large-scale outbreak of Enteroviruses (EVs) infection in Kunming, 2018. The epidemiological characteristics of HFMD and EVs were analysed during 2008-2018, which are before and three years after EV-A71 vaccine starting to use. The changes in infection spectrum were also investigated, especially for severe HFMD in 2018. The incidence of EV-A71 decreased dramatically after the EV-A71 vaccine starting use. The proportion of non-CV-A16/EV-A71 EVs positive patients raised to 77.17-85.82%, while, EV-A71 and CV-A16 only accounted for 3.41-7.24% and 6.94-19.42% in 2017 and 2018, respectively. CV-A6 was the most important causative agent in all clinical symptoms (severe HFMD, HFMD, Herpangina and fever), accounting from 42.13% to 62.33%. EV-A71 only account for 0.36-2.05%. In severe HFMD, CV-A6 (62.33%), CV-A10 (11.64%), and CV-A16 (10.96%) were the major causative agent in 2018. EV-A71 inactivated vaccine has a good protective effect against EV-A71 and induced EVs infection spectrum changefully. EV-A71 vaccine has no or insignificant cross-protection effect on CV-A6, CV-A10, and CV-A16. Herein, developing 4-valent combined vaccines is urgently needed.

Evaluation of carbopol as an adjuvant on the effectiveness of progressive atrophic rhinitis vaccine.

The Gram-negative pathogen toxigenic P. multocida causes progressive atrophic rhinitis (PAR) in swine throughout the world. Although some vaccines are being developed against PAR, their efficacy has not been evaluated using carbopol. In our study, a mixture of killed B. bronchiseptica and P. multocida bacteria, combined with recombinant proteins containing the C- and N-termini of PMT, was emulsified using two different adjuvants (ISA-15A and carbopol 971). The efficacy of these two vaccines was evaluated in a mouse model. Balb/C mice were immunized twice at a 14-day interval. Two weeks after the secondary immunization, blood samples were collected and the mice were challenged with toxigenic P. multocida. Thirty-five days later, the mice were euthanized, blood and tissue samples were collected. Compared with mice inoculated with vaccine emulsified with ISA-15A, higher titers of SN (1:64) and significantly increased levels of TNF-α, IL-6 and IL-17A were observed in mice inoculated with vaccine emulsified with the carbopol 971P. Especially, mice immunized with vaccine emulsified with the carbopol 971P had no detectable pathological changes in snouts or organs after challenge. The results demonstrated that carbopol adjuvanted vaccine provides good protection against PAR and P. multocida infection which can induce robust humoral and cell-mediated responses. We conclude that the carbopol adjuvanted vaccine is a good candidate for PAR prevention.

A novel variant in MITF in a child from Yunnan-Guizhou Plateau with autosomal dominant inheritance of nonsyndromic hearing loss: A case report.

Deafness and hearing loss may have functional, economic, social and emotional impacts on humans, including the ability of an individual to communicate with others, feelings of isolation and frustration, and health sector costs. The World Health Organization reported that there are 32 million children worldwide with hearing loss. In order to investigate genetic mutations in children of 26 nationalities with hearing loss in Yunnan, Sanger sequencing was employed to screen for mutations in four of the most common pathological genes, including gap junction protein ß2 and 3, solute carrier family 26 member 4 and mitochondrial DNA. Whole exome sequencing was used to detect the mutation in the proband of a family in which these four genes were normal. Subsequently, the mutation was identified by Sanger sequencing. The present study reports a novel mutation, c.718C>G; p. (Arg240Gly) in the melanogenesis associated transcription factor gene, in Han people with hearing loss. The results of the present study may provide parents and children an accurate diagnosis, which may allow physicians to how to rehabilitate children's hearing.