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We evaluated and compared humoral immune responses after inactivated coronavirus disease 2019 (COVID-19) vaccination among naïve individuals, asymptomatically infected individuals, and recovered patients with varying severity. In this multicenter, prospective cohort study, blood samples from 666 participants were collected before and after 2 doses of inactivated COVID-19 vaccination. Among 392 severe acute respiratory syndrome coronavirus 2-naïve individuals, the seroconversion rate increased significantly from 51.8% (median antispike protein pan-immunoglobulins [S-Igs] titer: 0.8 U/ml) after the first dose to 96% (median S-Igs titer: 79.5 U/ml) after the second dose. Thirty-two percent of naïve individuals had detectable neutralizing antibodies (NAbs) against the original strain but all of them lost neutralizing activity against the Omicron variant. In 274 individuals with natural infection, humoral immunity was significantly improved after a single vaccine dose, with median S-Igs titers of 596.7, 1176, 1086.5, and 1828 U/ml for asymptomatic infections, mild cases, moderate cases, and severe/critical cases, respectively. NAb titers also improved significantly. However, the second dose did not substantially increase antibody levels. Although a booster dose is needed for those without infection, our findings indicate that recovered patients should receive only a single dose of the vaccine, regardless of the clinical severity, until there is sufficient evidence to confirm the benefits of a second dose.

Background The memory immune response is crucial for preventing reinfection or reducing disease severity. However, the robustness and functionality of the humoral and T-cell response to SARS-CoV-2 remains unknown 12 months after initial infection. The aim of this study is to investigate the durability and functionality of the humoral and T-cell response to the original SARS-CoV-2 strain and variants in recovered patients 12 months after infection. Methods In this longitudinal cohort study, we recruited participants who had recovered from COVID-19 and who were discharged from the Wuhan Research Center for Communicable Disease Diagnosis and Treatment at the Chinese Academy of Medical Sciences, Wuhan, China, between Jan 7 and May 29, 2020. Patients received a follow-up visit between Dec 16, 2020, and Jan 27, 2021. We evaluated the presence of IgM, IgA, and IgG antibodies against the SARS-CoV-2 nucleoprotein, Spike protein, and the receptor-binding domain 12 months after initial infection, using ELISA. Neutralising antibodies against the original SARS-CoV-2 strain, and the D614G, beta (B.1.351), and delta (B.1.617.2) variants were analysed using a microneutralisation assay in a subset of plasma samples. We analysed the magnitude and breadth of the SARS-CoV-2-specific memory T-cell responses using the interferon γ (IFNγ) enzyme-linked immune absorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) assay. The antibody response and T-cell response (ie, IFN-γ, interleukin-2 [IL-2], and tumour necrosis factor α [TNFα]) were analysed by age and disease severity. Antibody titres were also analysed according to sequelae symptoms. Findings We enrolled 1096 patients, including 289 (26·4%) patients with moderate initial disease, 734 (67·0%) with severe initial disease, and 73 (6·7%) with critical initial disease. Paired plasma samples were collected from 141 patients during the follow-up visits for the microneutralisation assay. PBMCs were collected from 92 of 141 individuals at the 12-month follow-up visit, of which 80 were analysed by ELISpot and 92 by ICS assay to detect the SARS-CoV-2-specific memory T-cell responses. N-IgG (899 [82·0%]), S-IgG (1043 [95·2%]), RBD-IgG (1032 [94·2%]), and neutralising (115 [81·6%] of 141) antibodies were detectable 12 months after initial infection in most individuals. Neutralising antibodies remained stable 6 and 12 months after initial infection in most individuals younger than 60 years. Multifunctional T-cell responses were detected for all SARS-CoV-2 viral proteins tested. There was no difference in the magnitude of T-cell responses or cytokine profiles in individuals with different symptom severity. Moreover, we evaluated both antibody and T-cell responses to the D614G, beta, and delta viral strains. The degree of reduced in-vitro neutralising antibody responses to the D614G and delta variants, but not to the beta variant, was associated with the neutralising antibody titres after SARS-CoV-2 infection. We also found poor neutralising antibody responses to the beta variant; 83 (72·2%) of 115 patients showed no response at all. Moreover, the neutralising antibody titre reduction of the recovered patient plasma against the delta variant was similar to that of the D614G variant and lower than that of the beta variant. By contrast, T-cell responses were cross-reactive to the beta variant in most individuals. Importantly, T-cell responses could be detected in all individuals who had lost the neutralising antibody response to SARS-CoV-2 12 months after the initial infection. Interpretation SARS-CoV-2-specific neutralising antibody and T-cell responses were retained 12 months after initial infection. Neutralising antibodies to the D614G, beta, and delta viral strains were reduced compared with those for the original strain, and were diminished in general. Memory T-cell responses to the original strain were not disrupted by new variants. This study suggests that cross-reactive SARS-CoV-2-specific T-cell responses could be particularly important in the protection against severe disease caused by variants of concern whereas neutralising antibody responses seem to reduce over time.

Background Gastric cancer was still one of the commonly diagnosed cancer types and the third-most common cause of cancer-related death in the world. Gentiopicroside, which is extracted from the Gentianella acuta, is commonly used in both traditional treatment and modern clinical care; therefore, its anticancer effects have been attracted more attention. However, the systematic analysis of action mechanism of Gentiopicroside on gastric cancer (GC) has not yet been carried out. Aim A network pharmacology-based strategy combined with molecular docking studies and in vitro validation was employed to investigate potential targets and molecular mechanism of Gentiopicroside against GC. Materials and Methods Potential targets of Gentiopicroside, as well as related genes of GC, were acquired from public databases. Potential targets, and signaling pathways were determined through bioinformatic analysis, including protein–protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, molecular docking and cell experiments were performed to further verify the above findings. Results Our findings revealed that the anticancer activity of Gentiopicroside potentially involves 53 putative identified target genes. In addition, GO, KEGG, and network analyses revealed that these targets were associated with cell proliferation, metabolic process, and other physiological processes. Furthermore, we have proved that critical compound affected the expression of CCND1, CCNE1, p-AKT and p-P38 at protein levels. These findings provide an overview of the anticancer action of Gentiopicroside from a network perspective; meanwhile, it might also set an example for future studies of other materials used in traditional Chinese medicine (TCM). Conclusion This study comprehensively illuminated the potential targets and molecular mechanism of Gentiopicroside against GC. It also provided a promising approach to uncover the scientific basis and therapeutic mechanism of TCM treating for disease.

Background. With the widespread use and abuse of antimicrobial drugs, the problem of bacterial resistance is becoming increasingly prominent. The clinical detection rate of drug-resistant bacteria is increasing year by year, so there is an urgent need to develop new antimicrobial drugs. Qixingjian Decoction (QXJT) is a formula commonly used in Chinese medicine for the treatment of sepsis caused by acute purulent infections of the face, hands, and feet. There are many compounds with antimicrobial effects that are available, but little is known about their mode of action. In this study, we mainly evaluated the antimicrobial activity of QXJT and explored its synergistic interaction with oxacillin (OX) and the mechanism of its antimicrobial activity. Methods. The antimicrobial activity of QXJT against methicillin-resistant Staphylococcus aureus (MRSA) was determined by the microdilution method, the broth macrodilution method, and the time-kill curve method. The main compounds in QXJT were analyzed by ultra-performance liquid chromatography. The synergistic interaction of QXJT and oxacillin (OX) was determined by checkerboard assay, and the antimicrobial mechanism of QXJT, OX, and QXJT + OX was evaluated by transmission electron microscopy (TEM) technique. The expression of MRSA superantigen virulence factors (sea, seb, and tst), and drug resistance gene (mecA) was detected to provide a new strategy for new antibiotic drugs. Results. QXJT exhibited antimicrobial activity against both clinical isolates of MRSA, MICs ranging from 18.75 to 37.5 mg/mL. Active substances such as Scutellarein, Scutellarin, Apigenin, and Wogonin 7-O-glucuronide were detected in the phytochemical analysis that may be associated with the antimicrobial activity of QXJT. The synergistic effect of QXJT and OX was determined by checkerboard assay (FICI = 0.5), and TEM images showed that QXJT could cause the disruption of MRSA cell wall, and QXJT + OX could produce greater disruption of MRSA cell wall, elucidating the synergistic effect of the two together on cell wall disruption by microscopic mechanisms. Our study shows that the combination of QXJT and OX can inhibit the expression of MRSA virulence factor, reduce the virulence of MRSA, and have no significant effect on the expression of MRSA resistance gene mecA. Conclusion. The results of this study provide scientific experimental data for the traditional application of QXJT and initially explore the mechanism of action of QXJT combined with OX.

With the widespread use and abuse of antimicrobial drugs, the problem of bacterial resistance is becoming increasingly prominent. The clinical detection rate of drug-resistant bacteria is increasing year by year, so there is an urgent need to develop new antimicrobial drugs. Qixingjian Decoction (QXJT) is a formula commonly used in Chinese medicine for the treatment of sepsis caused by acute purulent infections of the face, hands, and feet. There are many compounds with antimicrobial effects that are available, but little is known about their mode of action. In this study, we mainly evaluated the antimicrobial activity of QXJT and explored its synergistic interaction with oxacillin (OX) and the mechanism of its antimicrobial activity.The antimicrobial activity of QXJT against methicillin-resistantQXJT exhibited antimicrobial activity against both clinical isolates of MRSA, MICs ranging from 18.75 to 37.5 mg/mL. Active substances such asThe results of this study provide scientific experimental data for the traditional application of QXJT and initially explore the mechanism of action of QXJT combined with OX.

Background Distant metastasis has been the main failure pattern for locoregionally advanced rectal cancer (LARC) patients, and intensified neoadjuvant chemotherapy has become a popular research topic. The present study aimed to compare the survival outcomes, acute toxicities and surgical complications in LARC patients who received preoperative chemoradiotherapy with triweekly oxaliplatin and capecitabine (triweekly XELOX) or capecitabine. Methods: Between 2007 and 2017, patients with clinically staged II-III rectal cancer who were treated with preoperative chemoradiotherapy using either triweekly XELOX (oxaliplatin 130 mg/m2 plus capecitabine 825 mg/m2) or capecitabine were included. Variables potentially influencing chemotherapy treatment selection were used to generate propensity scores (PS). The association between chemotherapy regimens and survival endpoints, including distant metastasis-free survival (DMFS), overall survival (OS) and disease-free survival (DFS), were evaluated and adjusted with PS. The acute toxicities and surgical complications were also compared. Results A total of 810 patients were included in the analysis; 277 (34.2%) patients received triweekly XELOX, and 533 (65.8%) received capecitabine. The pathological complete response (pCR) rates were 20.2 and 19.9% (P = 0.912) for the groups treated with triweekly XELOX and capecitabine, respectively. The 5-year DMFS, OS and DFS with triweekly XELOX versus capecitabine were 75.6% vs. 77.6% (P = 0.555), 79.2% vs. 83.3% (P = 0.101), and 69.9% vs. 73.7% (P = 0.283), respectively. Triweekly XELOX was not associated with an increased risk of severe toxicity during chemoradiotherapy, but it increased the risk of postoperative complications compared to capecitabine. After PS adjustment, the differences between the two groups remained insignificant in pCR rate, survival outcomes, and acute toxicities, and the difference in surgical complications disappeared. Conclusions Triweekly XELOX or capecitabine concurrent with neoadjuvant radiotherapy leads to similar long-term survival outcomes, acute toxicities and surgical complications in LARC patients.

Fractional exhaled nitric oxide (FeNO) has been developed as a useful marker for eosinophilic airway inflammation and is widely used in clinical practice due to its convenience and noninvasiveness. There are two NO analyzers commonly used in China: the Sunvou-CA2122 Analyzer (NOS) and the NIOX VERO Analyzer (NOV). However, the relationships between the two devices have not yet been reported. The aim of our study was to determine the correlation and differences in the FeNO levels measured by the two devices. FeNO levels were measured by both NOS and NOV in 107 adult patients with asthma. The asthma control test (ACT) score and lung function were also evaluated. This study was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn). NOS yielded generally higher FeNO values than NOV [median (range): 87.0 (16 ∼ 276) vs 58.0 (9 ∼ 228); p rs = 0.878, p NOS and logFeNONOV (95% CI: –0.45 ∼ 0.14). The conversion equation was calculated as follows: logFeNONOS= 0.027 + 0.904× logFeNONOV. This was the first report to compare FeNO levels measured by NOS and NOV, showing a strongly positive correlation and a low degree of consistency between the two devices. Further prospective studies are required to verify our conclusions and determine the validity of the equation.

A large amount of waste activated sludge (WAS) and food waste (FW) are produced every year in China. Anaerobic co-digestion is considered to be an effective way to solve this problem. This study applied FW/WAS mixture as co-substrate to create different digestive environment, aiming to understand the mechanism of Fe

The lung is constantly exposed to environmental particulates such as aeroallergens, pollutants, or microorganisms and is protected by a poised immune response. Innate lymphoid cells (ILCs) are a population of immune cells found in a variety of tissue sites, particularly barrier surfaces such as the lung and the intestine. ILCs play a crucial role in the innate immune system, and they are involved in the maintenance of mucosal homeostasis, inflammation regulation, tissue remodeling, and pathogen clearance. In recent years, group 3 innate lymphoid cells (ILC3s) have emerged as key mediators of mucosal protection and repair during infection, mainly through IL-17 and IL-22 production. Although research on ILC3s has become focused on the intestinal immunity, the biology and function of pulmonary ILC3s in the pathogenesis of respiratory infections and in the development of chronic pulmonary inflammatory diseases remain elusive. In this review, we will mainly discuss how pulmonary ILC3s act on protection against pathogen challenge and pulmonary inflammation, as well as the underlying mechanisms.

A large amount of waste activated sludge (WAS) and food waste (FW) are produced every year in China. Anaerobic co-digestion is considered to be an effective way to solve this problem. This study applied FW/WAS mixture as co-substrate to create different digestive environment, aiming to understand the mechanism of Fe3O4 particles in promoting AD performance. The results showed that the addition of Fe3O4 presented various performances when facing different digestive acidification stress brought by different mixing ratios of WAS and FW. Methanogenic pathways and microbial communities varied with substrates’ properties. For group A (WAS mono-digestion), the acetoclastic methanogens dominated, 20 mg/g VS (according to the iron element) Fe3O4 could promote methane production, while 200 mg/g VS Fe3O4 would inhibit microbial activity. The promoted methane production by Fe3O4 was attributable to the promotion of sludge hydrolysis. For group B (WAS: FW = 1:0.5, based on VS addition, similarly hereinafter), Fe3O4 triggered direct interspecific electron transfer (DIET) between bacteria and methanogens. For group C (WAS: FW = 1:1), the hydrogenotrophic methanogens dominated, bacteria excreted more non-conductive polysaccharides in EPS to resist unfavorable environment, thereby it prevented their contact with Fe3O4 particles. So, it was difficult for Fe3O4 to trigger DIET and promote the digestive performance of batch experiments in such condition.

To the Editor,We read with great interest the recent study by Zayed et al. reporting dupilumab safety and efficacy in uncontrolled asthma [1]. They reported that the addition of dupilumab reduced r...

Background Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists are novel agents for asthma but with controversial efficacies in clinical trials. Therefore, we conducted a meta-analysis to determine the roles of CRTH2 antagonists in asthma. Methods We searched in major databases for RCTs comparing CRTH2 antagonists with placebo in asthma. Fixed- or random-effects model was performed to calculate mean differences (MD), risk ratio (RR) or risk difference (RD) and 95% confidence interval (CI). Results A total of 14 trails with 4671 participants were included in our final analysis. Instead of add-on treatment of CRTH2 antagonists to corticosteroids, CRTH2 antagonist monotherapy significantly improved pre-bronchodilator FEV1 (MD = 0.09, 95% CI 0.04 to 0.15, P = 0.0005), FEV1% predicted (MD = 3.65, 95% CI 1.15 to 6.14, P = 0.004), and AQLQ (MD = 0.25, 95% CI 0.09 to 0.41, P = 0.002), and reduced asthma exacerbations (RR = 0.45, 95% CI 0.23 to 0.85, P = 0.01). Rescue use of SABA was significantly decreased in both CRTH2 antagonist monotherapy (MD = − 0.04, 95% CI -0.05 to − 0.03, P

Figure S1. Beggâ s test for publication bias on pre-bronchodilator FEV1 (L). Figure S2. Meta-regression plot of mean difference for pre-bronchodilator FEV1 (L) predicted by treatment duration. Figure S3. Meta-regression plot of mean difference for pre-bronchodilator FEV1 (L) predicted by asthma severity. Figure S4. Meta-regression plot of mean difference for pre-bronchodilator FEV1 (L) predicted by concomitant treatment. Figure S5. The effect of CRTH2 antagonists used as monotherapy or add-on therapy versus placebo on pre-bronchodilator FEV1% predicted. Figure S6. The effect of CRTH2 antagonists used as monotherapy or add-on therapy versus placebo on post-bronchodilator FEV1 (L). Figure S7. The effect of CRTH2 antagonists used as monotherapy or add-on therapy versus placebo on FVC. Figure S8. The effect of CRTH2 antagonists used as monotherapy or add-on therapy versus placebo on severe adverse events. Figure S9. The effect of CRTH2 antagonists used as monotherapy or add-on therapy versus placebo on treatment related adverse events. Figure S10. The effect of CRTH2 antagonists used as monotherapy or add-on therapy versus placebo on adverse events leading to treatment withdrawal. Figure S11. Beggâ s test for publication bias on adverse event. Figure S12. Meta-regression plot of risk ratio for adverse events predicted by treatment duration. Figure S13. Meta-regression plot of risk ratio for adverse events predicted by concomitant treatment. Figure S14. Meta-regression plot of risk ratio for adverse events predicted by asthma severity. (DOCX 10650 kb)

The transforming growth factor-β (TGF-β) signaling pathway exhibits an important role in cancer invasion and metastasis. Excessive expression of TGF-β activates Smad4, leading to the upregulation of downstream metastasis-associated genes. Thus, the inhibition of the TGF-β/Smad4 signaling pathway may be a novel strategy for treatment of cancer metastasis. Baicalein, a flavonoid derived from the root of Scutellaria baicalensis, has been reported to exert strong anti-tumor activity towards various types of cancer. In the present study the effect of baicalein on migration and invasion of cancer cells was evaluated using wound-healing and Transwell assays. In order to investigate the possible molecular mechanisms of the anti-metastatic effects of baicalein, quantitative polymerase chain reaction (qPCR) and western blot analyses were performed to examine the effect on the expression of TGF‑β, Smad4, N-cadherin, vimentin, ZEB1 and ZEB2. It was determined that baicalein inhibited the migration and invasion of AGS cells by suppressing the TGF-β/Smad4 signaling pathway. In addition, baicalein treatment reduced the expression of the metastasis-associated N-cadherin, vimentin, ZEB1 and ZEB2, downstream target genes of the TGF‑β/Smad4 signaling pathway. Collectively, these results suggest that inhibition of the metastasis of cancer cells via inactivation of TGF-β/Smad4 signaling is one of the mechanisms by which baicalein may treat cancer.

Non-hemolytic enterotoxin (NHE), a tri-partite, proteinaceous toxin encoded by contiguous nheA, nheB and nheC genes of Bacillus cereus sensu lato (B. cereus s.l.), is considered to be associated with the foodborne diarrheic syndrome. However, B. cereus s.l. includes a number of closely related strains, and the occurrence of NHE among them, and other members of Bacillus is unclear. Consequently, we aimed to determine the distribution and evolution of NHE within Bacillus by confirming the presence of the nheA, B and C sequences and variation within them using published data, and to analyze the genomic and genetic diversity. The phylogenetic tree of NHE proteins (NheA, NheB and NheC) from 81 different B. cereus s.l. strains was constructed. And on the genetic determinants of the NHE toxin did not bring any obvious link between the nheABC genes sequence of a strain and its virulence in the diarrhoeal pathogenesis. Analysis of the genomic diversity of the nheA, B and C loci revealed that their upstream regions were more conserved than the downstream sequences. Multilocus sequence typing schemes (MLST) based on seven concatenated housekeeping genes and nheA, B and C genes of the 75 strains were developed. The neighbor joining phylogenetic tree based on seven housekeeping genes together with nheA, B and C genes was similiar to published Bacillus phylogenetic trees. And on the genetic determinants of the NHE toxin did not bring any obvious link between the nheABC genes sequence of a strain and its virulence in the diarrhoeal pathogenesis.The results indicate that nheA, B and C genes do not affect the diversity of housekeeping genes, and this specific NHE protein does not participate in the diarrheic syndrome. Electronic supplementary material The online version of this article (doi:10.1007/s00203-017-1350-9) contains supplementary material, which is available to authorized users.

A new variable speed control moment gyro (VSCMG) steering law is proposed in order to achieve higher torque precision. The dynamics of VSCMGs is established, and two work modes are then designed according to command torque: control momentum gyro (CMG)/reaction wheel (RW) hybrid mode for the large torque case and RW single mode for the small. When working in the CMG/RW hybrid mode, the steering law deals with the gimbal dead-zone nonlinearity through compensation by RW sub-mode. This is in contrast to the conventional CMG singularity avoidance and wheel speed equalization, as well as the proof of definitely hyperbolic singular property of the CMG sub-mode. When working in the RW single mode, the motion of gimbals will be locked. Both the transition from CMG/RW hybrid mode to RW single mode and the reverse are studied. During the transition, wheel speed equalization and singularity avoidance of both the CMG and RW sub-modes are considered. A steering law for the RWs with locked gimbals is presented. It is shown by simulations that the VSCMGs with this new steering law could reach a better torque precision than the normal CMGs in the case of both large and small torques.