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Marginal zone B cells (MZB) mount a rapid antibody response, potently activate naïve T cells, and are enriched in autoreactive B cells. MZBs express high levels of CD1d, the restriction element for invariant natural killer T cells (iNKT). Here, we examined the effect of iNKT cells on MZB cell activation and numbers in vitro and in vivo in normal and autoimmune mice. Results show that iNKT cells activate MZBs, but restrict their numbers in vitro and in vivo in normal BALB/c and C57/BL6 mice. iNKT cells do so by increasing the activation-induced cell death and curtailing proliferation of MZB cells, whereas they promote the proliferation of follicular B cells. Sorted iNKT cells can directly execute this function, without help from other immune cells. Such MZB regulation by iNKTs is mediated, at least in part, via CD1d on B cells in a contact-dependent manner, whereas iNKT-induced proliferation of follicular B cells occurs in a contact- and CD1d-independent manner. Finally, we show that iNKT cells reduce 'autoreactive' MZB cells in an anti-DNA transgenic model, and limit MZB cell numbers in autoimmune-prone (NZB×NZW)F1 and non-obese diabetic mice, suggesting a potentially new mechanism whereby iNKT cells might regulate pathologic autoimmunity. Differential regulation of follicular B cells versus potentially autoreactive MZBs by iNKT cells has important implications for autoimmune diseases as well as for conditions that require a rapid innate B cell response.

Recent outbreaks of coronavirus disease 2019 (COVID-19) has led a global pandemic cross the world. Most countries took two main interventions: suppression like immediate lockdown cities at epicenter or mitigation that slows down but not stopping epidemic for reducing peak healthcare demand. Both strategies have their apparent merits and limitations; it becomes extremely hard to conduct one intervention as the most feasible way to all countries. Targeting at this problem, this paper conducted a feasibility study by defining a mathematical model named SEMCR, it extended traditional SEIR (Susceptible-Exposed-Infectious-Recovered) model by adding two key features: a direct connection between Exposed and Recovered populations, and separating infections into mild and critical cases. It defined parameters to classify two stages of COVID-19 control: active contain by isolation of cases and contacts, passive contain by suppression or mitigation. The model was fitted and evaluated with public dataset containing daily number of confirmed active cases including Wuhan and London during January 2020 and March 2020. The simulated results showed that 1) Immediate suppression taken in Wuhan significantly reduced the total exposed and infectious populations, but it has to be consistently maintained at least 90 days (by the middle of April 2020). Without taking this intervention, we predict the number of infections would have been 73 folders higher by the middle of April 2020. Its success requires efficient government initiatives and effective collaborative governance for mobilizing of corporate resources to provide essential goods. This mode may be not suitable to other countries without efficient collaborative governance and sufficient health resources. 2) In London, it is possible to take a hybrid intervention of suppression and mitigation for every 2 or 3 weeks over a longer period to balance the total infections and economic loss. While the total infectious populations in this scenario would be possibly 2 times than the one taking suppression, economic loss and recovery of London would be less affected. 3) Both in Wuhan and London cases, one important issue of fitting practical data was that there were a portion (probably 62.9% in Wuhan) of self-recovered populations that were asymptomatic or mild symptomatic. This finding has been recently confirmed by other studies that the seroprevalence in Wuhan varied between 3.2% and 3.8% in different sub-regions. It highlights that the epidemic is far from coming to an end by means of herd immunity. Early release of intervention intensity potentially increased a risk of the second outbreak.

[This corrects the article DOI: 10.1371/journal.pone.0179565.].

Southern Chinese Medicine (SCM) is an important sect of Traditional Chinese Medicine (TCM) with its own special cultural style. Species identification is essential for TCM quality control because authentic herbs are possibly substituted with adulterants that would threaten the health of the public or even cause death. Here, we provided the first local reference DNA barcode library based on the second internal transcribed spacer (ITS2) for the molecular identification of SCM. A total of 1512 specimens of southern herbs representing 359 species were collected under the instructions and identification of taxonomic experts. Genomic DNA was extracted, and the PCR reaction proceeded according to standard procedures. After Sanger sequencing, sequence assembling and annotation, a reliable ITS2 barcode library with 1276 sequences from 309 species of Southern herbs was constructed. The PCR efficiency of the whole samples was 84.39%. Characteristics of the ITS2 barcode were analyzed, including sequence lengths and GC contents in different taxa. Neighbor-joining trees based on Kimura 2-Parameter (K2P) genetic distances showed a 67.56% successful rate of species identification with ITS2 barcode. In addition, 96.57% of species could be successfully identified at the genus level by the BLAST method. Eleven plant species were discovered to be cryptic. In addition, we found that there is an incorrect sequence existing in the public database, making a reliable local DNA barcode reference more meaningful. ITS2 barcodes exhibit advantages in TCM identification. This DNA barcode reference library could be used in Southern Chinese Medicine quality control, thus contributing to protecting public health.

The mammalian target of rapamycin (mTOR), present in mTOR complex 1 (mTORC1) and mTORC2, is a serine/threonine kinase that integrates nutrients, growth factors, and cellular energy status to control protein synthesis, cell growth, survival and metabolism. However, it remains elusive whether mTOR plays a developmental stage-specific role in tissue development and whether mTOR can function independent of its complexes and kinase activity. In this study, by inducible genetic manipulation approach, we investigated the role of mTOR and its dependence on mTOR complexes and kinase activity in mitochondrial fitness of early, progenitor stage (lineage-negative; Lin-) versus later, lineage-committed stage (lineage-positive; Lin+) of hematopoietic cells. We found that oxidative phosphorylation (OXPHOS), ATP production and mitochondrial DNA synthesis were decreased in mTOR-/- Lin- cells but increased in mTOR-/- Lin+ cells, suggesting that mTOR plays a developmental stage-specific role in OXPHOS, ATP production and mitochondrial DNA synthesis. In contrast to mTOR deletion, simultaneous deletion of Raptor, a key component of mTORC1, and Rictor, a key component of mTORC2, led to increased mitochondrial DNA in Lin- cells and decreased mitochondrial DNA and ATP production in Lin+ cells, suggesting that mTOR regulates mitochondrial DNA synthesis in Lin- and Lin+ cells and ATP production in Lin+ cells independent of mTORC1 and mTORC2. Similar to mTOR deletion, deletion of Raptor alone attenuated glycolysis and increased mitochondrial mass and mitochondrial membrane potential in Lin- cells and increased mitochondrial mass and OXPHOS in Lin+ cells, whereas deletion of Rictor alone had no effect on these mitochondrial parameters in Lin- and Lin+ cells, suggesting that mTOR regulates glycolysis and mitochondrial membrane potential in Lin- cells, OXPHOS in Lin+ cells, and mitochondrial mass in both Lin- and Lin+ cells dependent on mTORC1, but not mTORC2. Either Raptor deficiency or Rictor deficiency recapitulated mTOR deletion in decreasing OXPHOS in Lin- cells and glycolysis in Lin+ cells, suggesting that mTOR regulates OXPHOS in Lin- cells and glycolysis in Lin+ cells dependent on both mTORC1 and mTORC2. Finally, mice harboring a mTOR kinase dead D2338A knock-in mutant showed decreased glycolysis in Lin+ cells, as seen in mTOR-/- Lin+ cells, but no change in glycolysis in Lin- cells, in contrast to the decreased glycolysis in mTOR-/- Lin- cells, suggesting that mTOR regulates glycolysis in Lin+ cells dependent on its kinase activity, whereas mTOR regulates glycolysis in Lin- cells independent of its kinase activity.

The "hygiene hypothesis" is a theory try to explain the dramatic increases in the prevalence of autoimmune and allergic diseases over the past two to three decades in developed countries. According to this theory, reduced exposure to parasites and microorganisms in childhood is the main cause for the increased incidences of both T helper 1 (Th1)-mediated autoimmunity and Th2-mediated allergy. In this study, we investigated the impact of Schistosoma japonicum infection on the allergic airway inflammation induced by repeated intracheal inoculations of house dust mites (HDM), which is a Th17 and neutrophils dominant murine asthma model, mimicking severe asthma. We found that S. japonicum infection downregulated airway hyperresponsiveness. The infiltrating cells, Th17 and Th2 effector cytokines in the bronchoalveolar lavage (BAL) fluids and lungs were significantly reduced in the infected mice. Our findings indicated that S. japonicum infection was able to effectively inhibit host's allergic airway inflammation, which may be related to the upregulated Treg cells upon infection. To our knowledge, it is the first study to reveal the impact of S. japonicum infection on house dust mite induced severe asthma. More in depth investigation is need to elucidate the underlying mechanisms.

Cancers from lung and esophagus are the leading causes of cancer-related deaths in China and share many similarities in terms of histological type, risk factors and genetic variants. Recent genome-wide association studies (GWAS) in Chinese esophageal cancer patients have demonstrated six high-risk candidate single nucleotide polymorphisms (SNPs). Thus, the present study aimed to determine the risk of these SNPs predisposing to lung cancer in Chinese population.A total of 1170 lung cancer patients and 1530 normal subjects were enrolled in this study from high-incidence areas for esophageal cancer in Henan, northern China. Five milliliters of blood were collected from all subjects for genotyping. Genotyping of 20 high-risk SNP loci identified from genome-wide association studies (GWAS) on esophageal, lung and gastric cancers was performed using TaqMan allelic discrimination assays. Polymorphisms were examined for deviation from Hardy-Weinberg equilibrium (HWE) using Х2 test. Bonferroni correction was performed to correct the statistical significance of 20 SNPs with the risk of lung cancer. The Pearson's Х2 test was used to compare the distributions of gender, TNM stage, histopathological type, smoking and family history by lung susceptibility genotypes. Kaplan-Meier and Cox regression analyses were carried out to evaluate the associations between genetic variants and overall survival.Four of the 20 SNPs identified as high-risk SNPs in Chinese esophageal cancer showed increased risk for Chinese lung cancer, which included rs3769823 (OR = 1.26; 95% CI = 1.107-1.509; P = 0.02), rs10931936 (OR = 1.283; 95% CI = 1.100-1.495; P = 0.04), rs2244438 (OR = 1.294; 95% CI = 1.098-1.525; P = 0.04) and rs13016963 (OR = 1.268; 95% CI = 1.089-1.447; P = 0.04). All these SNPs were located at 2q33 region harboringgenes of CASP8, ALS2CR12 and TRAK2. However, none of these susceptibility SNPs was observed to be significantly associated with gender, TNM stage, histopathological type, smoking, family history and overall survival.The present study identified four high-risk SNPs at 2q33 locus for Chinese lung cancer and demonstrated the shared susceptibility loci at 2q33 region for Chinese lung and esophageal cancers.

Nuclear factor erythroid-2-related factor 2 (NFE2L2) is a transcription factor associated with resistance to chemotherapy and increased tumor growth. NRF2 is repressed by the inhibitor Keap1. The Keap1-NRF2 pathway is dysfunctional in multiple tumor types. Among Uighur women, the incidence of cervical squamous cell carcinoma (CSCC) and cervical intraepithelial neoplasia (CIN) was associated with elevated nuclear expression of NRF2 and decreased cytoplasmic expression of Keap1. Up-regulation of nuclear NRF2 was significantly associated with reduced cytoplasmic Keap1 expression. NRF2 positivity and Keap1 negativity were frequently associated with more advanced tumors (i.e., higher histological grade, lymph node involvement, and higher tumor stages) (p

To study retrospectively the efficacy of decortication in patients with different stages of ADPKD and to determine which stage for decortication is more appropriate.We analyzed 137 patients with ADPKD from 2001 to 2010. All patients were divided into three stages. A total of 70 patients underwent decortication, and we studied intraoperative indicators and postoperative indicators at 1 and 3 years follow-up.In 70 patients who underwent decortication, significant differences were observed in operative duration and bleeding volume between patients with stage I and II ADPKD (P 0.05). The total complication occurrence rate was significantly different between them (P < 0.05). The serum creatinine (Scr) levels in patients with stage I ADPKD were within normal limits 1 and 3 years postoperatively and did not differ significantly (P > 0.05). Scr levels were significantly decreased in patients with stage II ADPKD in the 1st postoperative year (P < 0.05), but these were not significant differences in the 3rd postoperative year (P > 0.05). In the 1st postoperative year, VAS value, blood pressure and renal volume significantly differed (P < 0.05). However, no significant differences were observed 3 years later (P > 0.05).Decortication in patients with stage I ADPKD can alleviate back pain symptoms and decrease blood pressure within 1 year, but the long-term efficacy is not ideal. Scr levels can be maintained within normal limits, suggesting that decortication does not lead to deterioration of renal function. For patients with stage II ADPKD, decortication can significantly improve renal function over the short term. However, after 3 years, renal function returns to the preoperative level, and surgical difficulties and complications also increase.

CK19-2G2, a new fragment of cytokeratin 19, is a potential tumor marker for diagnosing lung cancer. The preoperative level of serum CK19-2G2 has been demonstrated to be associated with tumor metastasis and survival of breast cancer patients. This study investigated the postoperative dynamic changes in serum CK19-2G2 levels and its clinical significance in lung cancer patients.Preoperative serum CK19-2G2 levels were measured in 630 lung cancer patients and were compared with individuals with benign pulmonary diseases (n = 134) and healthy volunteers (n = 263). In 352 cases, the patients underwent surgery. In these patients, in addition to preoperative assays, serum CK19-2G2 was also monitored at 1 week and 1 month after the operation.The preoperative baseline levels of serum CK19-2G2 was significantly higher in lung cancer patients than patients with benign diseases and healthy controls (P

AIMS:The asymptomatic nature of early-stage esophageal squamous cell carcinoma (ESCC) results in late presentation and consequent dismal prognosis This study characterized 14-3-3σ protein expression in the multi-stage development of ESCC and determined its correlation with clinical features and prognosis. MATERIALS AND METHODS:Western blot was used to examine 14-3-3σ protein expression in normal esophageal epithelium (NEE), low grade intraepithelial neoplasia (LGIN), high grade intraepithelial neoplasia (HGIN), ESCC of TNM I to IV stage and various esophageal epithelial cell lines with different biological behavior. Immunohistochemistry was used to estimate 14-3-3σ protein in 110 biopsy samples of NEE, LGIN or HGIN and in 168 ESCC samples all of whom had follow-up data. Support vector machine (SVM) was used to develop a classifier for prognosis. RESULTS:14-3-3σ decreased progressively from NEE to LGIN, to HGIN, and to ESCC. Chemoresistant sub-lines of EC9706/PTX and EC9706/CDDP showed high expression of 14-3-3σ protein compared with non-chemoresistant ESCC cell lines and immortalized NEC. Furthermore, the downregulation of 14-3-3σ correlated significantly with histological grade (P = 0.000) and worse prognosis (P = 0.004). Multivariate Cox regression analysis indicated that 14-3-3σ protein (P = 0.016) and T stage (P = 0.000) were independent prognostic factors for ESCC. The SVM ESCC classifier comprising sex, age, T stage, histological grade, lymph node metastasis, clinical stage and 14-3-3σ, distinguished significantly lower- and higher-risk ESCC patients (91.67% vs. 3.62%, P = 0.000). CONCLUSIONS:Downregulation of 14-3-3σ arises early in the development of ESCC and predicts poor survival, suggesting that 14-3-3σ may be a biomarker for early detection of high-risk subjects and diagnosis of ESCC. Our seven-feature SVM classifier for ESCC prognosis may help to inform clinical decisions and tailor individual therapy.

BACKGROUND: One major impediment to improving the management of breast cancer is the current lack of tumor marker with sufficient sensitivity and specificity. A growing body of evidence implicates the diagnostic potential of circulating miRNAs in cancer detection. MiR-155 plays an important role in the pathogenesis of breast cancer. However, the level of circulating miR-155 and its clinical relevance are not well established. The objective of the current study was to learn more about serum miR-155 in patients with breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: Using quantitative reverse transcription polymerase chain reaction (RT-qPCR), we demonstrated that serum miR-155 had significant increased levels in breast cancer patients (n = 103) compared with healthy subjects (n = 55) (p

UDP-galactopyranose mutase (UGM) is a flavoenzyme that catalyzes the conversion of UDP-galactopyranose to UDP-galactofuranose, the precursor of galactofuranose (Galf). Galf is found in several pathogenic organisms, including the parasite Trypanosoma cruzi, the causative agent of Chagas' disease. Galf) is important for virulence and is not present in humans, making its biosynthetic pathway an attractive target for the development of new drugs against T. cruzi. Although UGMs catalyze a non-redox reaction, the flavin must be in the reduced state for activity and the exact role of the flavin in this reaction is controversial. The kinetic and chemical mechanism of TcUGM was probed using steady state kinetics, trapping of reaction intermediates, rapid reaction kinetics, and fluorescence anisotropy. It was shown for the first time that NADPH is an effective redox partner of TcUGM. The substrate, UDP-galactopyranose, protects the enzyme from reacting with molecular oxygen allowing TcUGM to turnover ∼1000 times for every NADPH oxidized. Spectral changes consistent with a flavin iminium ion, without the formation of a flavin semiquinone, were observed under rapid reaction conditions. These data support the proposal of the flavin acting as a nucleophile. In support of this role, a flavin-galactose adduct was isolated and characterized. A detailed kinetic and chemical mechanism for the unique non-redox reaction of UGM is presented.

Normal function of human leukocyte antigen class I (HLA-I) and antigen processing machinery (APM) proteins is required for T cell-mediated anti-tumor or antiviral immunity, whereas the tumor survival indicates a failure of the host in immune surveillance associated with the dysfunction in antigen presentation, mainly due to the deregulation in HLA-I and APM expression or function. The posttranscriptional regulation of HLA-I and APM expression may associate with epigenetic modifications in cancer development which was not described so far. Here we showed that the development of cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (CSCC) in Uighur women was accompanied with the partial or total loss of protein expression of HLA-I, ß2-m and APM components, including the transporter associated with antigen processing (TAP1/2), low molecular mass protein (LMP2, LMP7), endoplasmic reticulum aminopeptidase 1(ERAP1), chaperone molecules include calreticulin (CLR), calnexin (CNX) and ERp57, and this was proved again by analysis of transcription of the same genes in addition to three genes HLA-A, B and C coding for HLA-I. By bisulfite sequencing approach, we identified target CpG islands methylated at the gene promoter region of TAP1, TAP2, LMP7, tapasin and ERp57 in cervical carcinoma cells. Further analysis of CpG site specific methylation of these genes in cases of CSCC and CIN demonstrated an inverse correlation of altered CpG island methylation of TAP1, LMP7, and ERp57 with changes in protein expression. Moreover, promoter methylation of these genes was significantly higher in cases positive for human papillomavirus 16 (HPV 16) than negative ones. Our results suggested that epigenetic modifications are responsible for the aberrant expression of certain HLA-I and APM genes, and may help to understand unrevealed mechanisms of tumor escape from immune surveillance in cervical carcinogenesis.

Marginal zone B cells (MZB) mount a rapid antibody response, potently activate naïve T cells, and are enriched in autoreactive B cells. MZBs express high levels of CD1d, the restriction element for invariant natural killer T cells (iNKT). Here, we examined the effect of iNKT cells on MZB cell activation and numbers in vitro and in vivo in normal and autoimmune mice. Results show that iNKT cells activate MZBs, but restrict their numbers in vitro and in vivo in normal BALB/c and C57/BL6 mice. iNKT cells do so by increasing the activation-induced cell death and curtailing proliferation of MZB cells, whereas they promote the proliferation of follicular B cells. Sorted iNKT cells can directly execute this function, without help from other immune cells. Such MZB regulation by iNKTs is mediated, at least in part, via CD1d on B cells in a contact-dependent manner, whereas iNKT-induced proliferation of follicular B cells occurs in a contact- and CD1d-independent manner. Finally, we show that iNKT cells reduce 'autoreactive' MZB cells in an anti-DNA transgenic model, and limit MZB cell numbers in autoimmune-prone (NZB×NZW)F1 and non-obese diabetic mice, suggesting a potentially new mechanism whereby iNKT cells might regulate pathologic autoimmunity. Differential regulation of follicular B cells versus potentially autoreactive MZBs by iNKT cells has important implications for autoimmune diseases as well as for conditions that require a rapid innate B cell response.

BACKGROUND: The safety of the immune complexes composed of yeast-derived hepatitis B surface antigen (HBsAg) and antibodies (abbreviated as YIC) among healthy adults and chronic hepatitis B patients has been proved in phase I and phase IIa trial. A larger number of patients for study of dosage and efficacy are therefore needed. METHODS AND PRINCIPAL FINDINGS: Two hundred forty two HBeAg-positive chronic hepatitis B patients were immunized with six injections of either 30 microg YIC, 60 microg of YIC or alum adjuvant as placebo at four-week intervals under code. HBV markers and HBV DNA were monitored during immunization and 24 weeks after the completion of immunization. The primary endpoint was defined as loss of HBeAg, or presence of anti-HBe antibody or suppression of HBV DNA, while the secondary endpoint was both HBeAg seroconversion and suppression of HBV DNA. Statistical significance was not reached in primary endpoints four weeks after the end of treatment among three groups, however, at the end of follow-up, HBeAg sero-conversion rate was 21.8% (17/78) and 9% (7/78) in the 60 microg YIC and placebo groups respectively (p = 0.03), with 95% confidence intervals at 1.5% to 24.1%. Using generalized estimating equations (GEEs) model, a significant difference of group effects was found between 60 microg YIC and the placebo groups in terms of the primary endpoint. Eleven serious adverse events occurred, which were 5.1%, 3.6%, and 5.0% in the placebo, 30 microg YIC and 60 microg YIC groups respectively (p>0.05). CONCLUSIONS: Though statistical differences in the preset primary and secondary endpoints among the three groups were not reached, a late and promising HBeAg seroconversion effect was shown in the 60 microg YIC immunized regimen. By increasing the number of patients and injections, the therapeutic efficacy of YIC in chronic hepatitis B patients will be further evaluated. TRIAL REGISTRATION: ChiCTR.org ChiCTR-TRC-00000022.

UDP-galactopyranose mutase (UGM) is a flavoenzyme that catalyzes the conversion of UDP-galactopyranose to UDPgalactofuranose, the precursor of galactofuranose (Galf ). Galf is found in several pathogenic organisms, including the parasite Trypanosoma cruzi, the causative agent of Chagas' disease. Galf is important for virulence and is not present in humans, making its biosynthetic pathway an attractive target for the development of new drugs against T. cruzi. Although UGMs catalyze a non-redox reaction, the flavin must be in the reduced state for activity and the exact role of the flavin in this reaction is controversial. The kinetic and chemical mechanism of TcUGM was probed using steady state kinetics, trapping of reaction intermediates, rapid reaction kinetics, and fluorescence anisotropy. It was shown for the first time that NADPH is an effective redox partner of TcUGM. The substrate, UDP-galactopyranose, protects the enzyme from reacting with molecular oxygen allowing TcUGM to turnover ,1000 times for every NADPH oxidized. Spectral changes consistent with a flavin iminium ion, without the formation of a flavin semiquinone, were observed under rapid reaction conditions. These data support the proposal of the flavin acting as a nucleophile. In support of this role, a flavin-galactose adduct was isolated and characterized. A detailed kinetic and chemical mechanism for the unique non-redox reaction of UGM is presented. [ABSTRACT FROM AUTHOR]