TREG cells and CXCR3+ circulating TFH cells concordantly shape the neutralizing antibody responses in individuals who have recovered from mild COVID-19.

Regulatory T (TREG) cells are involved in the antiviral immune response in patients with COVID-19; however, whether TREG cells are involved in the neutralizing antibody (nAb) response remains unclear. Here, we found that individuals who recovered from mild but not severe COVID-19 had significantly greater frequencies of TREG cells and lower frequencies of CXCR3+ circulating TFH (cTFH) cells than healthy controls. Furthermore, TREG and CXCR3+ cTFH cells were negatively and positively correlated with the nAb responses, respectively, and TREG cells was inversely associated with CXCR3+ cTFH cells in individuals who recovered from mild COVID-19 but not in those with severe disease. Mechanistically, TREG cells inhibited memory B-cell differentiation and antibody production by limiting the activation and proliferation of cTFH cells, especially CXCR3+ cTFH cells, and functional molecule expression. This study provides novel insight showing that mild COVID-19 elicits a concerted nAb responses which are shaped by both TREG and TFH cells.

SARS-CoV-2 spike-reactive naïve B cells and pre-existing memory B cells contribute to antibody responses in unexposed individuals after vaccination.

Introduction: Since December 2019, the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has presented considerable public health challenges. Multiple vaccines have been used to induce neutralizing antibodies (nAbs) and memory B-cell responses against the viral spike (S) glycoprotein, and many essential epitopes have been defined. Previous reports have identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-reactive naïve B cells and preexisting memory B cells in unexposed individuals. However, the role of these spike-reactive B cells in vaccine-induced immunity remains unknown. Methods: To elucidate the characteristics of preexisting SARS-CoV-2 S-reactive B cells as well as their maturation after antigen encounter, we assessed the relationship of spike-reactive B cells before and after vaccination in unexposed human individuals. We further characterized the sequence identity, targeting domain, broad-spectrum binding activity and neutralizing activity of these SARS-CoV-2 S-reactive B cells by isolating monoclonal antibodies (mAbs) from these B cells. Results: The frequencies of both spike-reactive naïve B cells and preexisting memory B cells before vaccination correlated with the frequencies of spike-reactive memory B cells after vaccination. Isolated mAbs from spike-reactive naïve B cells before vaccination had fewer somatic hypermutations (SHMs) than mAbs isolated from spike-reactive memory B cells before and after vaccination, but bound SARS-CoV-2 spike in vitro. Intriguingly, these germline-like mAbs possessed broad binding profiles for SARS-CoV-2 and its variants, although with low or no neutralizing capacity. According to tracking of the evolution of IGHV4-4/IGKV3-20 lineage antibodies from a single donor, the lineage underwent SHMs and developed increased binding activity after vaccination. Discussion: Our findings suggest that spike-reactive naïve B cells can be expanded and matured by vaccination and cocontribute to vaccine-elicited antibody responses with preexisting memory B cells. Selectively and precisely targeting spike-reactive B cells by rational antigen design may provide a novel strategy for next-generation SARS-CoV-2 vaccine development.

SARS-CoV-2 spike-specific TFH cells exhibit unique responses in infected and vaccinated individuals.

Long-term humoral immunity to SARS-CoV-2 is essential for preventing reinfection. The production of neutralizing antibody (nAb) and B cell differentiation are tightly regulated by T follicular help (TFH) cells. However, the longevity and functional role of TFH cell subsets in COVID-19 convalescents and vaccine recipients remain poorly defined. Here, we show that SARS-CoV-2 infection and inactivated vaccine elicited both spike-specific CXCR3+ TFH cell and CXCR3- TFH cell responses, which showed distinct response patterns. Spike-specific CXCR3+ TFH cells exhibit a dominant and more durable response than CXCR3- TFH cells that positively correlated with antibody responses. A third booster dose preferentially expands the spike-specific CXCR3+ TFH cell subset induced by two doses of inactivated vaccine, contributing to antibody maturation and potency. Functionally, spike-specific CXCR3+ TFH cells have a greater ability to induce spike-specific antibody secreting cells (ASCs) differentiation compared to spike-specific CXCR3- TFH cells. In conclusion, the persistent and functional role of spike-specific CXCR3+ TFH cells following SARS-CoV-2 infection and vaccination may play an important role in antibody maintenance and recall response, thereby conferring long-term protection. The findings from this study will inform the development of SARS-CoV-2 vaccines aiming to induce long-term protective immune memory.

Effect of Dietary Casein Phosphopeptide Addition on the Egg Production Performance, Egg Quality, and Eggshell Ultrastructure of Late Laying Hens.

(1) Objective: This study aimed to assess the effects of dietary casein phosphopeptide (CPP) supplementation on the egg production performance of late laying hens and the resulting egg quality and eggshell ultrastructure. (2) Methods: A total of 800 laying hens aged 58 weeks were randomly assigned into 5 groups with 8 replicates of 20 hens each. The hens were fed a basal diet supplemented with 0 (control, T1), 0.5 (T2), 1.0 (T3), 1.5 (T4), and 2.0 (T5) g/kg CPP for 9 weeks. (3) Results: Dietary CPP supplementation was found to be beneficial for improving eggshell quality. The spoiled egg rate of the experimental groups was lower than that of the control group (linear and quadratic effect, p < 0.05). The yolk color in the T2, T3, and T4 groups was higher than that in the T1 group (quadratic effect, p < 0.05). The shell thickness in the T4 group was higher than that in the T1 and T2 groups (linear effect, p < 0.05). The shell color in the experimental groups was higher than that in the control group (linear and quadratic effect, p < 0.05). The effective thickness in the T3-T5 groups (linear and quadratic, p < 0.05) and the number of papillary nodes in the T2 and T3 groups were higher than those in the T1 group (quadratic, p < 0.05). The calcium content in the T2 and T3 groups was higher than that in the T1 group (quadratic effect, p < 0.05). The iron content in the T2 and T3 groups was higher than that in the T1 group (p < 0.05). (4) Conclusion: In summary, 0.5-1.0 g/kg CPP supplementation reduced the spoiled egg rate, enhanced the yolk and eggshell colors, increased the thickness of the effective layer, and the calcium and iron contents in the eggshell.

Relationship between common telomere length-related genetic variations, telomere length, and risk of antituberculosis drug-induced hepatotoxicity in Chinese Han population: As assessed for causality using the updated Roussel Uclaf Causality Assessment Method.

Antituberculosis drug-induced hepatotoxicity (ATDH) is a significant threat to tuberculosis control, and two recent studies indicated that leukocyte telomere length (LTL) might be a potential biomarker for ATDH. This study aimed to investigate the relationship between common telomere length-related genetic variations, LTL, and risk of ATDH in Eastern Chinese antituberculosis treatment patients. A 1:4 matched case-control study was conducted among 79 ATDH cases assessed for causality using the updated RUCAM and 316 controls. LTL was determined by quantitative real-time PCR, and nine SNPs involved in telomere biology reported by previous GWAS were assessed. Conditional logistic regression model was used to estimate the association between genotypes and risk of ATDH with odds ratios (ORs) and 95% confidence intervals (CIs). The average RUCAM score of cases was 7.1. The average LTL in cases was significantly shorter than that in controls (median = 1.239 vs. 1.481, P = 0.032). Differences in the distribution of LTL were statistically significant among three genotypes of SNP rs2736098 (CC vs. CT vs. TT, median = 1.544 vs. 1.356 vs. 1.337, P = 0.026) and rs2853677 (AA vs. AG vs. GG, median = 1.511 vs. 1.544 vs. 1.159, P = 0.005) in TERT. SNP rs7675998 in NAF1 was statistically associated with the risk of ATDH under the dominant model (adjusted OR = 1.725, 95% CI: 1.021-2.913, P = 0.042). This is the first study to investigate the relationship of LTL, common telomere length-related variations, and risk of ATDH. SNP rs2736098 and rs2853677 in TERT were significantly associated with LTL, and SNP rs7675998 in NAF1 may be associated with ATDH in Chinese population.

The relationship between relative telomere length and anti-tuberculosis drug-induced hepatitis : A case-control study.

AIM: Anti-tuberculosis drug-induced hepatitis (AT-DIH) is a common and serious adverse drug reaction of tuberculosis treatment. Evidence demonstrated that many factors could affect the occurrence of AT-DIH, such as ageing, smoking, alcohol, oxidative stress, etc., while these factors could also promote telomere shortening. Therefore, relative telomere length (RTL) is indirectly related to the occurrence of AT-DIH. The present study aimed to explore and validate this relationship in Chinese tuberculosis patients. METHODS: A 1:4 matched case-control study was undertaken using 202 AT-DIH cases and 808 controls. Logistic regression models were used to estimate the association between RTL and AT-DIH with odds ratios (ORs) and 95% confidence intervals (CIs). The area under receiver operating characteristic curve (AUC) was calculated to estimate the discriminative performance for distinguishing AT-DIH cases from controls. RESULTS: The average RTL in AT-DIH cases was significantly shorter than that in controls (1.24 vs. 1.46, P=0.002). Patients with longer RTL were at a reduced risk of AT-DIH (OR=0.79, 95% CI: 0.66-0.94, P=0.009), and a dose-response relationship also existed between RTL and lower AT-DIH risk (P for trend=0.012). Under the optimal RTL cut-off value of 1.22, the corresponding AUCs were 0.57 (95% CI: 0.53-0.62, P=0.001) in the univariate model and 0.62 (95% CI: 0.57-0.66, P<0.001) in the multivariate model. CONCLUSION: This study showed that the shorter the RTL, the higher the risk of AT-DIH during an anti-tuberculosis treatment. The short RTL could potentially serve as a risk factor or a predictive test of the hepatotoxic risk associated with anti-tuberculosis treatments.

The role of the genetic variant FECH rs11660001 in the occurrence of anti-tuberculosis drug-induced liver injury.

WHAT IS KNOWN AND OBJECTIVE: The pathogenic mechanism of anti-tuberculosis drug-induced liver injury (AT-DILI) is still largely unknown. Recent studies have indicated that rifampicin and isoniazid cotreatment causes the accumulation of endogenous protoporphyrin IX in the liver through the haem biosynthesis pathway. Alanine synthase 1 (ALAS1) and ferrochelatase (FECH) are the rate-limiting enzymes in the production of haem. The present study aimed to investigate the genetic contribution of the ALAS1 and FECH genes to the risk of AT-DILI in an Eastern Chinese Han population. METHODS: A 1:4 matched case-control study was conducted, and eight SNPs in the ALAS1 and FECH genes were detected and assessed. A multivariate conditional logistic regression model was used to estimate the association between genotypes and the risk of AT-DILI by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking and drinking history as covariates. RESULTS AND DISCUSSION: Overall, 202 AT-DILI cases and 808 controls were included in this study. The female patients carrying polymorphisms of rs11660001 in FECH had an increased risk of AT-DILI under the dominant and additive models (OR = 1.831, 95% CI: 1.014-3.307, p = 0.045; OR = 1.673, 95% CI: 1.015-2.760, p = 0.044, respectively). The peak aspartate transaminase level was significantly higher in female patients carrying the GA+AA genotype of rs11660001 than in those with the GG genotype during anti-TB treatment (p = 0.032). WHAT IS NEW AND CONCLUSION: Based on this 1:4 individual matched case-control study, SNP rs11660001 in the FECH gene may be associated with susceptibility to AT-DILI in Chinese female anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.

Heme oxygenase-1 and hemopexin gene polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity in China.

Objective: To assess whether the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) might be influenced by heme oxygenase-1 (HMOX1) and hemopexin (HPX) gene polymorphisms. Methods: A dynamic anti-tuberculosis treatment cohort was constructed, and the 1:4 matched nested case-control study was analysed. Eight single-nucleotide polymorphisms (SNPs) of the two genes were selected for genotyping and Bonferroni correction was performed to correct for multiple comparison. Results: Overall, 7.8% of patients developed ATDH. SNP rs1807714 in the HMOX1 gene had decreased effects on the risk of moderate and severe hepatotoxicity under the dominant and additive models, and hepatocellular injury under the additive model. SNP rs2682099 in the HPX gene had increased effects on the risk of moderate and severe hepatotoxicity under the recessive model. However, these associations disappeared after Bonferroni correction. Conclusion:HMOX1 and HPX gene polymorphisms might not be associated with susceptibility to ATDH in the Chinese population.

Monoclonal antibodies constructed from COVID-19 convalescent memory B cells exhibit potent binding activity to MERS-CoV spike S2 subunit and other human coronaviruses.

Introduction: The Middle East respiratory syndrome coronavirus (MERS-CoV) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are two highly contagious coronaviruses causing MERS and COVID-19, respectively, without an effective antiviral drug and a long-lasting vaccine. Approaches for diagnosis, therapeutics, prevention, etc., particularly for SARS-CoV-2 that is continually spreading and evolving, are urgently needed. Our previous study discovered that >60% of sera from convalescent COVID-19 individuals, but <8% from general population, showed binding activity against the MERS-CoV spike protein, indicating that SARS-CoV-2 infection boosted antibodies cross-reactive with MERS-CoV. Methods: To generate antibodies specific to both SARS-CoV-2 and MERS-CoV, here we screened 60 COVID-19 convalescent sera against MERS-CoV spike extracellular domain and S1 and S2 subunits. We constructed and characterized monoclonal antibodies (mAbs) from COVID-19 convalescent memory B cells and examined their binding and neutralizing activities against human coronaviruses. Results and Discussion: Of 60 convalescent serum samples, 34 showed binding activity against MERS-CoV S2, with endpoint titers positively correlated with the titers to SARS-CoV-2 S2. By sorting single memory B cells from COVID-19 convalescents, we constructed 38 mAbs and found that 11 mAbs showed binding activity with MERS-CoV S2, of which 9 mAbs showed potent cross-reactivity with all or a proportion of spike proteins of alphacoronaviruses (229E and NL63) and betacoronaviruses (SARS-CoV-1, SARS-CoV-2, OC43, and HKU1). Moreover, 5 mAbs also showed weak neutralization efficiency against MERS-CoV spike pseudovirus. Epitope analysis revealed that 3 and 8 mAbs bound to linear and conformational epitopes in MERS-CoV S2, respectively. In summary, we have constructed a panel of antibodies with broad-spectrum reactivity against all seven human coronaviruses, thus facilitating the development of diagnosis methods and vaccine design for multiple coronaviruses.

A validation study of the UGT1A4 rs2011404 variant and the risk of anti-tuberculosis drug-induced hepatotoxicity in an Eastern Chinese Han population.

WHAT IS KNOWN AND OBJECTIVE: Anti-tuberculosis (anti-TB) drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. A recent study found that the rs2011404 variant of uridine 5'-diphospho-glucuronosyl-transferase 1A4 (UGT1A4) is a marker of susceptibility to ATDH. The present study aimed to validate this relationship in an Eastern Chinese Han anti-TB treatment population. METHODS: A 1:4 matched case-control study was conducted among anti-TB treatment patients in four regions of Jiangsu. ATDH was diagnosed based on the criteria from the Chinese Society of Hepatology and the updated Roussel Uclaf Causality Assessment Method. A conditional logistic regression model was used to estimate the association between rs2011404 genotypes and the risk of ATDH using odds ratios (ORs) with 95% confidence intervals (95% CIs) and smoking, drinking, hepatoprotectant use and liver diseases as covariates. RESULTS AND DISCUSSION: A total of 202 ATDH cases and 808 controls were matched according to age, sex and treatment history. After correcting for potential confounding factors, conditional logistic regression analysis indicated no significant differences in genotypes between the two groups (CC vs. TC: OR = 0.933, 95% CI: 0.457-1.905, p = 0.849). Subgroup analysis suggested that patients carrying the CC genotype at rs2011404 in UGT1A4 were at a reduced risk of moderate or severe liver injury (OR = 0.293, 95% CI: 0.093-0.921, p = 0.036). WHAT IS NEW AND CONCLUSION: Based on a 1:4 individual matched case-control study, possessing the CC genotype at rs2011404 of the UGT1A4 gene reduces the risk of moderate or severe liver injury in Eastern Chinese Han patients receiving anti-TB treatment. Further research is warranted to explain the role of the UGT1A4 gene and its contribution to individual differences in susceptibility to ATDH.

Development Trend of Infectious Disease Hospitals in China 2002-2018: A Longitudinal Analysis of National Survey Data.

BACKGROUND: Infectious disease hospitals (IDHs) play very important roles in the battle against the infectious disease. The present study aims to systematically analyze the development trends and possible problems of IDHs in China. METHODS: Most of the data came from the China Health Statistics Yearbook 2003-2019. Joinpoint Regression Model was used to analyze the development trends of IDHs between 2002 and 2018. RESULTS: From 2002 to 2018, the number of IDHs in China increased from 126 to 167, with an average annual percent change (AAPC) of 1.82%. The ratio of nurses to beds increased from 0.38 to 0.46 with the AAPC of 0.88%, and average business housing area per bed increased with an AAPC of 1.97%. The percentage of liabilities to total assets increased year by year and the percentage of medical business costs to total expenditure decreased. The segmented trend of daily visits per physician from 2014 to 2018 was stable, and the segmented trend of daily inpatients per physician from 2012 to 2018 decreased significantly. In 2017, the rates of surgical inpatients leaving the hospital without the doctor's advice and surgical inpatients mortality were higher than 2016. CONCLUSION: Although the development of IDHs was generally good in China, the scale of IDHs was generally small, the ability to respond to major emergencies was weak, the problem of irrational resource allocation was still prominent, and the operation of IDHs was facing a dilemma.

Spike-specific circulating T follicular helper cell and cross-neutralizing antibody responses in COVID-19-convalescent individuals.

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-3 and individuals with COVID-19 have symptoms that can be asymptomatic, mild, moderate or severe4,5. In the early phase of infection, T- and B-cell counts are substantially decreased6,7; however, IgM8-11 and IgG12-14 are detectable within 14 d after symptom onset. In COVID-19-convalescent individuals, spike-specific neutralizing antibodies are variable3,15,16. No specific drug or vaccine is available for COVID-19 at the time of writing; however, patients benefit from treatment with serum from COVID-19-convalescent individuals17,18. Nevertheless, antibody responses and cross-reactivity with other coronaviruses in COVID-19-convalescent individuals are largely unknown. Here, we show that the majority of COVID-19-convalescent individuals maintained SARS-CoV-2 spike S1- and S2-specific antibodies with neutralizing activity against the SARS-CoV-2 pseudotyped virus, and that some of the antibodies cross-neutralized SARS-CoV, Middle East respiratory syndrome coronavirus or both pseudotyped viruses. Convalescent individuals who experienced severe COVID-19 showed higher neutralizing antibody titres, a faster increase in lymphocyte counts and a higher frequency of CXCR3+ T follicular help (TFH) cells compared with COVID-19-convalescent individuals who experienced non-severe disease. Circulating TFH cells were spike specific and functional, and the frequencies of CXCR3+ TFH cells were positively associated with neutralizing antibody titres in COVID-19-convalescent individuals. No individuals had detectable autoantibodies. These findings provide insights into neutralizing antibody responses in COVID-19-convalescent individuals and facilitate the treatment and vaccine development for SARS-CoV-2 infection.

NR1I2 genetic polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity: A systematic review and meta-analysis.

Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. Conflicting results have been obtained regarding the associations of nuclear receptor subfamily 1 group I member 2 (NR1I2) gene polymorphisms on susceptibility to ATDH. Therefore, we aimed to evaluate the associations using a systematic review/meta-analysis approach. PubMed, Medline, Cochrane Library, Web of Science and SinoMed databases were searched for all eligible studies from inception to June 10, 2020. Pooled adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were employed to evaluate the strength of the association between the NR1I2 polymorphisms and the risk of ATDH. Subgroup analysis was performed by region of origin, and meta-regression were performed to detect potential sources of heterogeneity. A total of five case-control studies involving 572 cases and 1867 controls were identified. Fourteen SNPs in the NR1I2 gene have been reported, and the most heavily studied SNPs were rs3814055 and rs7643645. The pooled estimates did not exhibit any significant associations between SNPs rs3814055 and rs7643645 and the risk of ATDH (rs3814055: dominant model, OR = 1.00, 95% CI: 0.82-1.22, P = 1.00; recessive model, OR = 1.17, 95% CI: 0.76-1.78, P = .48; rs7643645: dominant model, OR = 1.04, 95% CI: 0.64-1.68, P = .89; recessive model, OR = 0.98, 95% CI: 0.65-1.49, P = .93). Subgroup analysis obtained similar negative results in Chinese patients, and the diagnostic criteria of ATDH may be the source of heterogeneity. Based on the meta-analysis described in this report, we did not observe any association between NR1I2 gene polymorphisms and ATDH susceptibility. However, this conclusion should be interpreted with caution due to the low number of studies and the relatively small sample size.

Diterpenoids as potential anti-inflammatory agents from Ajuga pantantha.

A phytochemical survey to obtain bioactive natural products from Ajuga pantantha afforded five new neo-clerodane diterpenoids (1-5). The structures were established by analysis of their NMR spectroscopic data, and electronic circular dichroism calculations were applied to define their absolute configurations. Compounds 2 and 5 were found to have the property of inhibiting NO production (IC50 values < 40 µM). Molecular docking and Western blotting were used to study the mechanism of anti-inflammatory action. Furthermore, compound 5 with the highest activity was tested for its in vivo anti-inflammatory effects using a zebrafish model.

Association between NR1I2 polymorphisms and susceptibility to anti-tuberculosis drug-induced hepatotoxicity in an Eastern Chinese Han population: A case-control study.

OBJECTIVE: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction, and its pathogenic mechanism is still largely unknown. Pregnane X receptor (PXR, encoded by the NR1I2 gene) is a ligand-dependent transcription factor, and rifampicin is a human PXR-specific activator. Rifampicin and isoniazid co-therapy targets porphyrin biosynthesis via PXR and results in hepatic protoporphyrin IX accumulation and subsequent liver injury. The present study aimed to investigate the associations between genetic polymorphisms in NR1I2 and ATDH in an Eastern Chinese Han population. METHODS: A 1:4 matched case-control study was conducted using 146 ATDH cases and 584 controls. Seven single nucleotide polymorphisms (SNPs) were detected and analysed. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATDH by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking history and drinking history as covariates. RESULTS: Patients carrying the GG genotype of rs7643645 were at a higher risk of ATDH than those carrying the AA genotype (OR = 1.864, 95% CI: 1.106-3.141, P = .020), and significant differences were also found under the recessive model (P = .029) and additive model (P = .021). Patients with a polymorphism at rs2276707 were at a reduced risk of ATDH under the recessive model (OR = 0.600, 95% CI: 0.364-0.988, P = .045). Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the additive model (rs7643645, OR = 1.429, 95% CI: 1.027-1.988, P = .034) and recessive model (rs2276707, OR = 0.478, 95% CI: 0.253-0.902, P = .023). Functional annotation using ENCODE data also indicated that rs2276707 and rs7643645 were located in the histone modification regions targeting enhancers or promoter (H3K4Me1, H3K4Me3 and H3K27Ac). CONCLUSIONS: Based on this case-control study, SNPs rs7643645 and rs2276707 in NR1I2 may contribute to susceptibility to ATDH in Eastern Chinese Han anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.

Association of ABO blood group and antituberculosis drug-induced liver injury: A case-control study from a Chinese Han population.

WHAT IS KNOWN AND OBJECTIVE: Antituberculosis drug-induced liver injury (ATLI) is a serious adverse drug reaction, and its pathogenic mechanism is still largely unknown. Rifampin (RIF) has been reported to cause haemolysis due to the production of drug-dependent antibodies, and haemolysis results in an increased level of free haem, which affects the function of hepatocytes. Blood group determinants can act as specific receptor sites for drug-antibody complexes, causing erythrocyte destruction in the presence of RIF. RIF-induced immune haemolysis may be a potential mechanism for ATLI. Thus, the study aimed to explore the role of ABO blood group systems in Chinese ATLI patients. METHODS: A 1:4 matched case-control study was conducted among 146 ATLI cases and 584 controls. Multivariable conditional logistic regression and Cox proportional regression were used to estimate the association between ABO blood group and risk of ATLI by odds ratio (OR), hazards ratio (HR) and 95% confidence intervals (CIs), and liver disease history and taking hepatoprotectant were used as covariates. RESULTS AND DISCUSSION: Patients in the A, B, AB and non-O blood groups had a significantly higher risk of ATLI than those in the O blood group (OR = 1.832, 95% CI: 1.126-2.983, P = .015; OR = 1.751, 95% CI: 1.044-2.937, P = .034; OR = 2.059, 95% CI: 1.077-3.938, P = .029; OR = 1.822, 95% CI: 1.173-2.831, P = .007, respectively). After considering the time of ALTI occurrence, similar results were found in the A, B, AB and non-O blood groups (HR = 1.676, 95% CI: 1.072-2.620, P = .024; HR = 1.620, 95% CI: 1.016-2.584, P = .043; HR = 2.010, 95% CI: 1.130-3.576, P = .018; HR = 1.701, 95% CI: 1.138-2.542, P = .010, respectively). Furthermore, subgroup analysis also detected a significant association between ABO blood group and ATLI in patients taking RIF (P < .05). However, no significant difference was observed in patients not taking RIF (P > .05). WHAT IS NEW AND CONCLUSION: The present study is the first to evaluate the role of ABO blood group systems in Chinese ATLI cases. Based on the present matched case-control study, the ABO blood group may be associated with susceptibility to ATLI in the Chinese antituberculosis population, especially in patients with blood groups A, B and AB who are taking RIF.

Anti-inflammatory neo-Clerodane Diterpenoids from Ajuga pantantha.

Eight new neo-clerodane diterpenoids (1-8) were acquired from the aerial parts of Ajuga pantantha. Spectroscopic data analysis permitted the definition of their structures, and experimental and calculated electronic circular dichroism data were used to define their absolute configurations. Compounds 2 and 4-8 were found to have NO inhibitory effects with IC50 values of 20.2, 45.5, 34.0, 27.0, 45.0, and 25.8 µM, respectively. The more potent compounds 2, 6, and 8 were analyzed to establish their anti-inflammatory mechanism, including regulation of the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins as well as their binding interactions with the two proteins.

Circulating CXCR3+ Tfh cells positively correlate with neutralizing antibody responses in HCV-infected patients.

Circulating T follicular helper (cTfh) cells have been identified as counterparts of germinal center Tfh (GC Tfh) cells in humans and can support T-dependent B cell maturation and antibody production in vitro. However, the role of cTfh cells in neutralizing antibody (nAb) responses in HCV infection remains unclear. Here, we characterized the phenotype and function of cTfh cells and demonstrated the associations of cTfh cells and their subsets with nAb responses in HCV infection. A total of 38 HCV-infected individuals and 28 healthy controls were enrolled from a pool of injection drug users. The frequency and function of blood Tfh cells were analyzed by flow cytometry. The titers and breadths of serum nAbs were measured using HCV pseudo-particle neutralization assays. Herein, we report several key observations. First, HCV infection skewed cTfh toward CXCR3+ cTfh cell differentiation. Second, the frequency of CXCR3+ cTfh cells positively correlated with HCV nAb titers and breadths. Third, CXCR3+ cTfh cells showed higher expression of Tfh-associated molecules (PD-1, ICOS, IL-21, Bcl-6) compared with CXCR3- cTfh cells from individuals with HCV infection. Coculture of cTfh cells and autologous memory B cells in vitro indicated that CXCR3+ cTfh cells show a superior ability to support HCV E2-specific B cell expansion compared with CXCR3- cTfh cells from individuals with HCV infection. HCV infection skews cTfh cells toward CXCR3-biased Tfh cell differentiation, which positively correlates with the magnitude and breadth of the HCV nAb response. It is our hope that these findings will provide insights for the rational design of a nAb-based HCV vaccine.