Toxoplasma gondii is an intracellular protozoan that affects most species of endothermic animals including humans with a great infection rate. The vertical transmission of T. gondii causes abortion, constituting a serious threat to humans and leading to great losses in livestock production. Distinct from population structure of T. gondii in North America and Europe, Chinese 1 (ToxoDB #9) is a dominant genotype prevalent in China. Among the isolates of Chinese 1, the Wh3 and Wh6 have different virulence and pathogenicity in mice. However, little has been known about their difference at the genomic level. Thus the next-generation sequencing (NGS) approach was used to discover the association of the phenotypical variations with the genome sequencing data and the expression and polymorphisms of the key effectors.

Humoural immunity is crucial for the pathogenesis of ulcerative colitis (UC), but the precise perturbation of B cell immunity is poorly understood. This study is aimed at evaluating the numbers of different subsets of circulating memory B cells, plasmablasts, and the levels of serum immunoglobulin in UC patients. Total of 23 patients with active UC and 14 healthy controls (HC) were examined for the numbers of different subsets of circulating memory B cells and plasmablasts before and after treatment with mesalazine for 8-12 weeks by flow cytometry. Disease activity was evaluated by the Mayo clinic score. The levels of serum immunoglobulin, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured in individual subjects. In comparison with that in HC, significantly reduced numbers of IgG(+) IgD(-) CD27(+) CD19(+) memory B cells, increased numbers of CD20(-) CD19(+) plasmablast subsets, and higher serum IgG levels were detected in UC patients. The concentrations of serum IgG, the numbers of CD138(+) CD38(+) CD20(-) CD19(+), and IgG(+) CD38(+) CD20(-) CD19(+) plasmablasts were negatively associated with the numbers of IgG(+) IgD(-) CD27(+) CD19(+) memory B cells. Furthermore, the values of Mayo clinic score, CRP, or ESR in UC patients were negatively correlated with the numbers of IgG(+) IgD(-) CD27(+) CD19(+) memory B cells, while positively correlated with the serum IgG levels and the numbers of plasmablast subsets. Following treatment with mesalazine, the numbers of circulating IgG(+) IgD(-) CD27(+) CD19(+) memory B cells were significantly increased, while the numbers of CD138(+) CD38(+) CD20(-) CD19(+) and IgG(+) CD38(+) CD20(-) CD19(+) plasmablasts were reduced in UC patients. These decreased IgG(+) IgD(-) CD27(+) CD19(+) memory B cells and increased plasmablasts may be involved in the pathogenic process of UC.

Although the chemopreventive effects of aspirin have been extensively investigated, the roles of many cell components, such as long non-coding RNAs, in these effects are still not completely understood.

Hepatitis B virus (HBV) X protein (HBx), a trans-regulator, is frequently expressed in truncated form without carboxyl-terminus in hepatocellular carcinoma (HCC), but its functional mechanisms are not fully defined. In this report, we investigated frequency of this natural HBx mutant in HCCs and its functional significance. In 102 HBV-infected patients with HCC, C-terminal truncation of HBx, in contrast to full-length HBx, were more prevalent in tumors (70.6%) rather than adjacent non-tumorous tissues (29.4%) (p = 0.0032). Furthermore, two naturally-occurring HBx variants (HBxΔ31), which have 31 amino acids (aa) deleted (codons 123-125/124-126) at C-terminus were identified in tumors and found that the presence of HBxΔ31 significantly correlated with intrahepatic metastasis. We also show that over-expression of HBxΔ31 enhanced hepatoma cell invasion in vitro and metastasis in vivo compared to full-length HBx. Interestingly, HBxΔ31 exerts this function via down-regulating Maspin, RhoGDIα and CAPZB, a set of putative metastasis-suppressors in HCC, in part, by enhancing the binding of transcriptional repressor, myc-associated zinc finger protein (MAZ) to the promoters through physical association with MAZ. Notably, these HBxΔ31-repressed proteins were also significantly lower expression in a subset of HCC tissues with C-terminal HBx truncation than the adjacent non-tumorous tissues, highlighting the clinical significance of this novel HBxΔ31-driven metastatic molecular cascade. Our data suggest that C-terminal truncation of HBx, particularly breakpoints at 124aa, plays a role in enhancing hepatoma cell invasion and metastasis by deregulating a set of metastasis-suppressors partially through MAZ, thus uncovering a novel mechanism for the progression of HBV-associated hepatocarcinogenesis.

Henoch-Schoenlein purpura is the one of most common types of systemic vasculitis that involves impaired renal function and Henoch-Schoenlein purpura nephritis (HSPN). The diagnosis of this condition is largely based on immunohistologic detection of immunoglobulin A1-containing immune complex in the glomerular deposits of mesangium. Despite clinical advances, the etiopathogenesis of HSPN is still largely unknown.

Plasma soluble Receptor for Advanced Glycation End-products (sRAGE) is a strong marker of vascular outcomes although evidence on the direction of association is mixed. Compared to whites, blacks have lower levels of sRAGE. We hypothesized that genetic determinants of sRAGE would help clarify the causal role of sRAGE and the black-white difference in sRAGE levels. We conducted a genome-wide analysis of sRAGE in whites and blacks from the Atherosclerosis Risk in Communities Study. Median plasma sRAGE levels were lower in blacks than whites (728 vs. 1067 pg/ml; P<0.0001). The T (vs. C) allele of rs2070600, a missense variant in AGER, the gene encoding RAGE, was associated with approximately 50% lower sRAGE levels in both whites (N = 1,737; P = 7.26x10-16; minor allele frequency (MAF) = 0.04) and blacks (N = 581; P = 0.02; MAF = 0.01). In blacks, the T (vs. C) allele of rs2071288, intronic to AGER, was associated with 43% lower sRAGE levels (P = 2.22x10-8; MAF = 0.10) and was nearly absent in whites. These AGER SNPs explained 21.5% and 26% of the variation in sRAGE in blacks and whites, respectively, but did not explain the black-white difference in sRAGE. These SNPs were not significantly associated with incident death, coronary heart disease, diabetes, heart failure, or chronic kidney disease in whites (N = 8,130-9,017) or blacks (N = 2,293-2,871) (median follow up ~20 years). We identified strong genetic determinants of sRAGE that did not explain the large black-white difference in sRAGE levels or clearly influence risk of clinical outcomes, suggesting that sRAGE may not be a causal factor in development of these outcomes.

Cholangiocarcinoma (CCA) is a highly aggressive and fatal tumor. CCA occurs in the epithelial cells of bile ducts. Due to increasing incidences, CCA accounts for 3% of all gastrointestinal malignancies. In addition to comprehensive treatments for cancer, such as surgery, chemotherapy, and radiotherapy, during the past few years, cellular immunotherapy has played an increasingly important role. As a result of our research, we have discovered the γδ T cell-based immunotherapy for CCA.

Developing a facile and environmentally friendly approach to the synthesis of nanostructured Ni(OH)2 electrodes for high-performance supercapacitor applications is a great challenge. In this work, we report an extremely simple route to prepare a Ni(OH)2 nanopetals network by immersing Ni nanofoam in water. A binder-free composite electrode, consisting of Ni(OH)2 nanopetals network, Ni nanofoam interlayer and Ni-based metallic glass matrix (Ni(OH)2/Ni-NF/MG) with sandwich structure and good flexibility, was designed and finally achieved. Microstructure and morphology of the Ni(OH)2 nanopetals were characterized. It is found that the Ni(OH)2 nanopetals interweave with each other and grow vertically on the surface of Ni nanofoam to form an "ion reservoir", which facilitates the ion diffusion in the electrode reaction. Electrochemical measurements show that the Ni(OH)2/Ni-NF/MG electrode, after immersion in water for seven days, reveals a high volumetric capacitance of 966.4 F/cm3 at a current density of 0.5 A/cm3. The electrode immersed for five days exhibits an excellent cycling stability (83.7% of the initial capacity after 3000 cycles at a current density of 1 A/cm3). Furthermore, symmetric supercapacitor (SC) devices were assembled using ribbons immersed for seven days and showed a maximum volumetric energy density of ca. 32.7 mWh/cm3 at a power density of 0.8 W/cm3, and of 13.7 mWh/cm3 when the power density was increased to 2 W/cm3. The fully charged SC devices could light up a red LED. The work provides a new idea for the synthesis of nanostructured Ni(OH)2 by a simple approach and ultra-low cost, which largely extends the prospect of commercial application in flexible or wearable devices.

RNA editing, as an essential co-/post-transcriptional RNA modification type, plays critical roles in many biological processes and involves with a variety of human diseases. Although several databases have been developed to collect RNA editing data in both model and non-model animals, there still lacks a resource integrating associations between editome and human disease. In this study, we present Editome-Disease Knowledgebase (EDK; http://bigd.big.ac.cn/edk), an integrated knowledgebase of RNA editome-disease associations manually curated from published literatures. In the current version, EDK incorporates 61 diseases associated with 248 experimentally validated abnormal editing events located in 32 mRNAs, 16 miRNAs, 1 lncRNA and 11 viruses, and 44 aberrant activities involved with 6 editing enzymes, which together are curated from more than 200 publications. In addition, to facilitate standardization of editome-disease knowledge integration, we propose a data curation model in EDK, factoring an abundance of relevant information to fully capture the context of editome-disease associations. Taken together, EDK is a comprehensive collection of editome-disease associations and bears the great utility in aid of better understanding the RNA editing machinery and complex molecular mechanisms associated with human diseases.

Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mTORC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sin1, an essential component of mTORC2, in T lineage cells results in severely impaired thymocyte development at the CD4-CD8- double negative (DN) stages but not at the CD4+CD8+ double positive (DP) or later stages. Notably, Sin1-deficient DN thymocytes show markedly reduced proliferation and glycolysis. Importantly, we discover that the M2 isoform of pyruvate kinase (PKM2) is a novel and crucial Sin1 effector in promoting DN thymocyte development and metabolism. At the molecular level, we show that Sin1-mTORC2 controls PKM2 expression through an AKT-dependent PPAR-γ nuclear translocation. Together, our study unravels a novel mTORC2-PPAR-γ-PKM2 pathway in immune-metabolic regulation of early thymocyte development.

The aim of this study was to investigate changes in regional homogeneity (ReHo) and the functional connectivity of the entorhinal cortex (EC) in vascular mild cognitive impairment (VaMCI) and to evaluate the relationships between such changes and neuropsychological measures in VaMCI individuals. In all, 31 patients with VaMCI and 32 normal controls (NCs) underwent rs-fMRI. Differences in whole-brain ReHo and seed-based bilateral EC functional connectivity (EC-FC) were determined. Pearson's correlation was used to evaluate the relationships between regions with significant group differences and different neuropsychological measures. Vascular mild cognitive impairment (VaMCI) patients had lower scores in Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) and higher ones in Activity of Daily Living (ADL) (p < 0.05). Vascular mild cognitive impairment (VaMCI) individuals had significantly lower ReHo in the left cerebellum and right lentiform nucleus than NCs (P < 0.05, TFCE FWE correction). Vascular mild cognitive impairment (VaMCI) subjects showed significant decreases in the FC of the right EC in the right inferior frontal gyrus, right middle frontal gyrus, bilateral pre-central gyrus, and right post-central/superior parietal lobules (P < 0.05, TFCE FWE correction). Significant positive correlations were found between ReHo and MoCA scores for the right lentiform nucleus (r = 0.37, P < 0.05). The right post-central/superior parietal lobules showed a significant positive correlation between right EC-FC and MoCA scores (r = 0.37, P < 0.05). Patterns in ReHo and EC-FC changes in VaMCI patients and their correlations with neuropsychological measures may be a pathophysiological foundation of cognitive impairment, which may aid the early diagnosis of VaMCI.

Epidemiological studies have provided compelling evidence of associations between ambient temperature and cardiovascular disease. However, evidence of effects of daily temperature variability on cardiovascular disease is scarce and mixed. We aimed to examine short-term associations between temperature variability and hospital admissions for cause-specific cardiovascular disease in urban China.

Human mesenchymal stem cell (MSC)-based tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene delivery is regarded as an effective treatment for glioblastoma (GBM). However, adverse-free target site homing of the delivery vehicles to the tumor microsatellite nests is challenging, leading to erroneously sustained released of this suicide protein into the normal brain parenchyma; therefore, limiting off-target cytotoxicity and controlled expression of the suicide inductor is a prerequisite for the safe use of therapeutic stem cells.

Purpose.ERF3, having been found expressing differently in liver tissues in our previous work, including eRF3a and eRF3b, which are structural homologs named GSPT1 and GSPT2 Recent studies have indicated that eRF3b involved in the development and proliferation of HepG2 cell, and eRF3a may be associated with tumor susceptibility. Based on this, we tested the effects of GSPT1 and GSPT2 single-nucleotide polymorphisms for all major Hepatitis B virus (HBV) outcomes and lamivudine (LAM) treatment in Han Chinese. Method. A total of 1649 samples were enrolled, and peripheral blood samples were collected in the present study. The single-nucleotide polymorphisms in the GSPT1 and GSPT2 region were genotyped using MALDI-TOF MS. Results. Our study demonstrated there was no obvious relevance of either GSPT1-rs33635 or GSPT2-rs974285 polymorphisms with HBV susceptibility, spontaneous recovery, and development of HBV-related diseases. However, we showed for the first time to our knowledge that GSPT1-rs33635C was a predictor for LAM therapy (viral response: odds ratio (OR) = 2.436, P=0.022; biochemical response: OR = 3.328, P=1.73 × 10-4). Conclusions. These findings might provide potential implications for therapeutic guidance.

mPGES-1 is a terminal rate-limiting enzyme responsible for inflammation-induced PGE2 production. The inhibition of mPGES-1 has been considered as a safe and effective target for the treatment of inflammation and cancer. However, a specific, efficient, and simple method for high-throughput screening of mPGES-1 inhibitors is still lacking. In this study, we developed a fluorescence imaging strategy to monitor the expression of mPGES-1 via CRISPR/Cas9 knock-in system. Immunofluorescence colocalisation, Sanger sequencing, RNAi, and IL-1β treatment all confirmed the successful construction of mPGES-1 reporter cells. The fluorescence signal intensity of the reporter cells treated with four conventional mPGES-1 inhibitors was considerably attenuated via flow cytometry and fluorescent microplate reader, demonstrating that the reporter cells can be used as an efficient and convenient means for screening and optimising mPGES-1 inhibitors. Moreover, it provides a new technical support for the development of targeted small molecule compounds for anti-inflammatory and tumour therapy.

Nanoparticles (NPs) offer new solutions for the diagnosis and treatment of tumors. However, the anti-tumor effect has not been greatly improved. Tumors are easily spread through the lymphatic system while the traditional NPs (~100 nm) can hardly reach lymph nodes for the treatment of metastasis. In addition, the NPs with fixed particle size cannot achieve efficient "penetration" and long-term "retention" simultaneously. Herein, we established "transformable" micelles modified with azide/alkyne groups for click chemical reaction. Not surprisingly, the small micelles (~25 nm) could effectively target lymph nodes, limiting the growth of the metastases associated with their size-regulated abilities to extravasate from the vasculature. Tumor lymph node metastasis dropped by 66.7%. After reaching primary tumors, cycloaddition reaction occurred between groups on micelles, resulting in the formation of aggregates. The strategy resulted in improved retention of the micelles in 4 T1 cells both in vitro and in vivo owing to the decreasing of nanoparticle exocytosis and minimizing the backflow to the bloodstream. Enhanced cytotoxicity on 4 T1 cells and improved antitumor efficacy were also observed. S-PTX (+) exhibited 76.23% tumor suppression, and tumor mass at the end of the treatment also showed the best tumor inhibitory effect. In conclusion, this drug delivery system provides a strategy for effective treatment of the primary tumor and lymphatic metastasis.

Hepatitis B virus (HBV) infection and its sequelae are now recognized as serious problems globally. Our aime is to screen hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) and identify the characteristics of proteins involved.

Circulating tumor cells (CTCs), which have stem cell-like characteristics, might play a crucial role in cancer metastasis. CD44 has been identified as gastric cancer (GC) stem cell (CSC) marker. Here, the prognostic significance of CD44-positive CTCs in GC patients was investigated. CTCs were detected in 27 of 45 GC patients. The presence of CTCs was significantly associated with lymph node metastasis, distant metastasis, and recurrence (P = 0.007, P = 0.035, and P = 0.035, resp.). Nineteen of the 27 CTC-positive patients had CD44-positive CTCs. These patients were more likely to develop metastasis and recurrence than patients with CD44-negative CTCs. CD44-positive CTC counts were higher in recurrent patients than in the nonrecurrent ones (means 4.8 and 1.9, resp.; P = 0.010). Furthermore, 13 of 19 patients with CD44-positive CTCs developed recurrent disease, and the mean time to recurrence was shorter than that in patients with CD44-negative CTCs (10.54 ± 5.55 and 19.13 ± 9.72 months, resp.; P = 0.04). COX proportional hazards model indicated that the presence of CD44-positive CTCs and TNM stage were independent predictors of recurrence for GC (P = 0.030 and 0.008). So identifying the stem cell-like CTC subset may provide more clinically useful prognostic information than only detecting CTCs.

Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2) is a multi-functional protein that plays critical role in processes including transcription, transcription-coupled DNA repair, pre-mRNA splicing, homologous recombination and mRNA export. Microarray analysis on gene expression in XAB2 knockdown cells reveals that many genes with significant change in expression function in mitotic cell cycle regulation. Fluorescence-activated cell scanner analysis confirmed XAB2 depletion led to cell arrest in G2/M phase, mostly at prophase or prometaphase. Live cell imaging further disclosed that XAB2 knockdown induced severe mitotic defects including chromosome misalignment and defects in segregation, leading to mitotic arrest, mitotic catastrophe and subsequent cell death. Among top genes down-regulated by XAB2 depletion is mitotic motor protein centrosome-associated protein E (CENPE). Knockdown CENPE showed similar phenotypes to loss of XAB2, but CENPE knockdown followed by XAB2 depletion did not further enhance cell cycle arrest. Luciferase assay on CENPE promoter showed that overexpression of XAB2 increased luciferase activity, whereas XAB2 depletion resulted in striking reduction of luciferase activity. Further mapping revealed a region in CENPE promoter that is required for the transcriptional regulation by XAB2. Moreover, ChIP assay showed that XAB2 interacted with CENPE promoter. Together, these results support a novel function of XAB2 in mitotic cell cycle regulation, which is partially mediated by transcription regulation on CENPE.

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.