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Scale insects are hemimetabolous, showing "incomplete" metamorphosis and no true pupal stage. Ericerus pela, commonly known as the white wax scale insect (hereafter, WWS), is a wax-producing insect found in Asia and Europe. WWS displays dramatic sexual dimorphism, with notably different metamorphic fates in males and females. Males develop into winged adults, while females are neotenic and maintain a nymph-like appearance, which are flightless and remain stationary. Here, we report the de novo assembly of the WWS genome with a size of 638.30 Mbp (69.68 Mbp for scaffold N50) by PacBio sequencing and Hi-C. These data allowed us to perform a robust phylogenetic analysis comprising 24,923 gene orthogroups from 16 representative insect genomes. This analysis indicated that holometabola evolved from insects with incomplete metamorphosis in the Late Carboniferous, about 50 million years earlier than previously thought. To study the distinct developmental fates of males and females, we analysed the methylome landscape in either sex. Surprisingly, WWS displayed high methylation levels (4.42% for males) when compared to other insects. We observed differential methylation patterns in males and females for genes involved in steroid and sesquiterpenoid production as well as genes acting in fatty acid metabolism pathways. We measured titre profiles for ecdysone, the principal insect steroid hormone, and juvenile hormone (a sesquiterpenoid) in both males and females, which suggested that these hormones are the primary drivers of sexually dimorphic development. Our results provide a comprehensive genomic and epigenomic resource of scale insects that provide new insights into the evolution of metamorphosis and sexual dimorphism in insects.

Fluoroquinolone (FQ)-resistant Campylobacter jejuni is a serious problem worldwide that limits effective treatment of infections. The traditional detection method depends on bacterial isolation and MIC testing, or traditional PCR, which is time-consuming and hard to identify the FQ-resistant C. jejuni in a high abundance wild-type background. This study aimed to develop a rapid and accurate ddPCR assay to detect FQ-resistant C. jejuni mutants based on the crucial resistance mutation C257T (Thr-86-Ile) in

The true bug, Aspongopus chinensis Dallas, 1851 (Hemiptera: Dinidoridae), is a fascinating insect with prolonged diapause and medicinal properties but also a notorious pest. However, because of the lack of genomic resources, an in-depth understanding of its biological characteristics is lacking. Here, we report the first genome assembly of A. chinensis anchored to 10 pseudochromosomes, which was achieved by combining PacBio long reads and Hi-C sequencing data. This chromosome-level genome assembly was 1.55 Gb in size with a scaffold N50 of 156 Mb. The benchmarking universal single-copy ortholog (BUSCO) analysis of the assembly captured 96.6% of the BUSCO genes. A total of 686,888,052 bp of repeat sequences, 18,511 protein-coding genes, and 1,749 noncoding RNAs were annotated. By comparing the A. chinensis genome with that of 8 homologous insects and 2 model organisms, 213 rapidly evolving gene families were identified, including 83 expanded and 130 contracted gene families. The functional enrichment of Gene Ontology and KEGG pathways showed that the significantly expanded gene families were primarily involved in metabolism, immunity, detoxification, and DNA/RNA replication associated with stress responses. The data reported here shed light on the ecological adaptation of A. chinensis and further expanded our understanding of true bug evolution in general.

The development of thermostable vaccines can relieve the bottleneck of existing vaccines caused by thermal instability and subsequent poor efficacy, which is one of the predominant reasons for the millions of deaths caused by vaccine-preventable diseases. Research into the mechanism of viral thermostability may provide strategies for developing thermostable vaccines. Using Newcastle disease virus (NDV) as model, we identified the negative surface charge of attachment glycoprotein as a novel determinant of viral thermostability. It prevented the temperature-induced aggregation of glycoprotein and subsequent detachment from virion surface. Then structural stability of virion surface was improved and virus could bind to and infect cells efficiently after heat-treatment. Employing the approach of surface charge engineering, thermal stability of NDV and influenza A virus (IAV) vaccines was successfully improved. The increase in the level of vaccine thermal stability was determined by the value-added in the negative surface charge of the attachment glycoprotein. The engineered live and inactivated vaccines could be used efficiently after storage at 37°C for at least 10 and 60 days, respectively. Thus, our results revealed a novel surface-charge-mediated link between HN protein and NDV thermostability, which could be used to design thermal stable NDV and IAV vaccines rationally.

Background An important task in the interpretation of sequencing data is to highlight pathogenic genes (or detrimental variants) in the field of Mendelian diseases. It is still challenging despite the recent rapid development of genomics and bioinformatics. A typical interpretation workflow includes annotation, filtration, manual inspection and literature review. Those steps are time-consuming and error-prone in the absence of systematic support. Therefore, we developed GTX.Digest.VCF, an online DNA sequencing interpretation system, which prioritizes genes and variants for novel disease-gene relation discovery and integrates text mining results to provide literature evidence for the discovery. Its phenotype-driven ranking and biological data mining approach significantly speed up the whole interpretation process. Results The GTX.Digest.VCF system is freely available as a web portal at http://vcf.gtxlab.com for academic research. Evaluation on the DDD project dataset demonstrates an accuracy of 77% (235 out of 305 cases) for top-50 genes and an accuracy of 41.6% (127 out of 305 cases) for top-5 genes. Conclusions GTX.Digest.VCF provides an intelligent web portal for genomics data interpretation via the integration of bioinformatics tools, distributed parallel computing, biomedical text mining. It can facilitate the application of genomic analytics in clinical research and practices.

BACKGROUND This study aimed to clarify the diagnosis and expand the understanding of dopa-responsive dystonia (DRD). MATERIAL AND METHODS Relevant data from clinical diagnoses and genetic mutational analyses in 3 Han Chinese patients with sporadic DRD were collected and analyzed. Protein structure/function was predicted. RESULTS One novel mutation of c.679A>G (p.T227A) in GCH1 and 3 known mutations of c.457C>T (p.R153X), c.739G>A (p.G247S), and c.698G>A (p.R227H) in tyrosine hydroxylase (TH) have been found and predicted to be damaging or deleterious. All of the mutations were localized in conserved sequences. The iterative threading assembly refinement (I-TASSER) server generated three-dimensional (3D) atomic models based on protein sequences from the novel nonsense mutation of c.679A>G (p.T227A) in GCH1, which showed that residue 227 was located in the GCH1 active site. CONCLUSIONS Patients carrying different non-synonymous variants had remarkable variation in clinical phenotype. This study expands the spectrum of genotypes and phenotypes of DRD in the Han Chinese ethnicity, provides new insights into the molecular mechanism of DRD, and helps the diagnosis and treatment of DRD.

Long noncoding RNAs (lncRNAs) serve important functions in many crucial biological processes; however, the effects of lncRNAs in early gastric cancer (EGC) are not entirely clear. The present study aimed to demonstrate the potential of lncRNAs to be used as biomarkers in EGC. Reverse transcription‑quantitative polymerase chain reaction was used to measure the expression levels of lncRNAs, including X inactive‑specific transcript (XIST), Yiya, brain cytoplasmic RNA 1 (BCYRN1), ribosomal RNA processing 1B (RRP1B), KCNQ1 opposite transcript 1 (KCNQ1OT1) and testes development related 1 (TDRG1), in EGC tissues compared with normal adjacent tissues (NATs). XIST, BCYRN1, RRP1B and TDRG1 were identified as differentially expressed in EGC tissues compared with NATs. The specificity and sensitivity of XIST, BCYRN1, RRP1B and TDRG1 were determined by receiver operating characteristic curve analysis. In addition, RRP1B expression was revealed to be significantly correlated with distal metastasis (P=0.020) and tumor‑node‑metastasis staging (P=0.018), and TDRG1 expression was significantly correlated with lymph node metastasis (P=0.001). Furthermore, BCYRN1, RRP1B and TDRG1 expression levels were compared between EGC tissues and plasma, and the results indicated that there were significant positive correlations of XIST, BCYRN1, RRP1B and TDRG1 expression levels between the EGC tissues and plasma. Therefore, the present study suggested that XIST, BCYRN1, RRP1B and TDRG1 may be served as potential diagnostic biomarkers for EGC.

Acute pancreatitis (AP) is a common non‑bacterial disease compromising pancreatic tissues. Adipocyte‑derived leptin is closely associated with the severity and clinical outcome of pancreatitis. The potential protective effects of exogenous leptin administration on a rat model of severe AP (SAP) remain to be elucidated, and were examined in the present study. Male Wistar rats were divided into a sham operation group (SO), SAP model group (SAP) and leptin group (LEP). Each group was divided into three sub‑groups by observation time (24, 48 and 72 h). The SAP models were prepared by retrograde injection of 6% sodium taurocholate into the pancreatic‑bile duct. Following model establishment, exogenous leptin was intraperitoneally injected into mice at 50 mg/kg in the LEP group. Subsequently, serum amylase, lipase and glucose levels at particular time‑points were analyzed using a fully‑automatic biochemical analyzer, and serum levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑10 were detected using an enzyme‑linked immunosorbent assay. The pathological changes in pancreatic tissues were observed using hematoxylin and eosin staining, and the pancreatic expression of the long form of the leptin receptor (OB‑Rb) was detected and evaluated using Nest‑polymerase chain reaction analysis. The mortality rates of the model rats were compared between the groups. Following the administration of exogenous leptin, the serum level of amylase in the LEP group was significantly decreased at 48 h, compared with that in the SAP group, with serum lipase levels decreased at 48 and 72 h, and blood glucose levels decreased at 72 h. Regarding the serum inflammatory factors, the level of TNF‑α in the LEP group was significantly lower, compared with that in the SAP group at 24 h; whereas no significant difference was observed in the serum level of IL‑10 between the two groups. Regarding the pathological changes in the pancreas, the tissues in the LEP group showed significantly alleviated pancreatic inflammation. In addition, the pancreatic expression of OB‑Rb in the LEP group was significantly higher, compared with that in the SAP group at 24 and 48 h. No significant difference in 3‑day mortality rates were observed between the SAP group and the LEP group. Taken together, exogenous leptin administration regulated inflammatory factors and the expression of OB‑Rb at the early stage of AP, which exerted protective effects by through the immunological and endocrinal pathways.

Most proposed methods for TF-binding site (TFBS) predictions only use low order dependencies for predictions due to the lack of efficient methods to extract higher order dependencies. In this work, we first propose a novel method to extract higher order dependencies by applying CNN on histone modification features. We then propose a novel TFBS prediction method, referred to as CNN_TF, by incorporating low order and higher order dependencies. CNN_TF is first evaluated on 13 TFs in the mES cell. Results show that using higher order dependencies outperforms low order dependencies significantly on 11 TFs. This indicates that higher order dependencies are indeed more effective for TFBS predictions than low order dependencies. Further experiments show that using both low order dependencies and higher order dependencies improves performance significantly on 12 TFs, indicating the two dependency types are complementary. To evaluate the influence of cell-types on prediction performances, CNN_TF was applied to five TFs in five cell-types of humans. Even though low order dependencies and higher order dependencies show different contributions in different cell-types, they are always complementary in predictions. When comparing to several state-of-the-art methods, CNN_TF outperforms them by at least 5.3 percent in AUPR.

Intrauterine growth retardation (IUGR) induces metabolic syndrome, which is often characterized by insulin resistance (IR), in adults. Previous research has shown that microRNAs (miRNAs or miRs) play a role in the target genes involved in this process, but the mechanisms remain unclear. In the present study, we examined miRNA profiles using samples of skeletal muscles from both IUGR and control rat offspring whose mothers were fed either a protein-restricted diet or a diet which involved normal amounts of protein during pregnancy, respectively. miR-29a was found to be upregulated in the skeletal muscles of IUGR offspring. The luciferase reporter assay confirmed the direct interaction between miR-29a and peroxisome proliferator-activated receptor δ (PPARδ). Overexpression of miR-29a in the skeletal muscle cell line C2C12 suppressed the expression of its target gene PPARδ, which, in turn, influenced the expression of its coactivator, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thus, PPARδ/PGC-1α-dependent signals together reduced insulin-dependent glucose uptake and adenosine triphosphate (ATP) production. Overexpression of miR-29a also caused a decrease in levels of glucose transporter 4 (GLUT4), the most important glucose transporter in skeletal muscle, which partially induced a decrease insulin-dependent glucose uptake. These findings provide evidence for a novel micro-RNA-mediated mechanism of PPARδ regulation, and we also noted the IR-promoting actions of miR-29a in skeletal muscles of IUGR.

Most past works for DNA-binding residue prediction did not consider the relationships between residues. In this paper, we propose a novel approach for DNA-binding residue prediction, referred to as EL_LSTM, which includes two main components. The first component is the Long Short-Term Memory (LSTM), which learns pairwise relationships between residues through a bi-gram model and then learns feature vectors for all residues. The second component is an ensemble learning based classifier introduced to tackle the data imbalance problem in binding residue predictions. We use a variant of the bagging strategy in ensemble learning to achieve balanced samples. Evaluations on PDNA-224 and DBP-123 show that adding feature relationships performs better than classifiers without feature relationships by at least 0.028 on MCC, 1.18 percent on ST and 0.012 on AUC. This indicates the usefulness of feature relationships for DNA-binding residue predictions. Evaluation on using ensemble learning indicates that the improvement can reach at least 0.021 on MCC, 1.32 percent on ST, and 0.018 on AUC compared to the use of a single LSTM classifier. Comparisons with the state-of-the-art predictors show that our proposed EL_LSTM outperforms them significantly. Further feature analysis validates the effectiveness of LSTM for the prediction of DNA-binding residues.

In order to investigate the effect of a copper (II) complexes of a coumarin derivative and phenanthroline (hereinafter referred to as the coumarin-copper drug) on lung adenocarcinoma cells in vivo and in vitro, along with the mechanism of action, LA795 lung adenocarcinoma cells were treated with different concentrations of coumarin-copper drug. An MTT assay was performed to determine the cell proliferation ratio, cell apoptosis was detected by Annexin V/propidium iodide staining with flow cytometric analysis and western blot analysis was employed to evaluate the expression levels of apoptosis-associated proteins. In addition, an LA795 cell xenograft tumor model was established in nude mice, with mice receiving intraperitoneal injection once a week for three weeks of either 2 or 4 mg/kg in three divided doses coumarin‑copper drug, or phosphate‑buffered saline. The tumor growth curves were drawn and the tumor growth inhibition rates were calculated. The apoptotic index of subcutaneously transplanted tumor cells was determined by terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end‑labeling assay. The coumarin-copper drug effectively inhibited the proliferation of LA795 cells in a dose‑ and time‑dependent manner, with the half maximal inhibitory concentration equaling 2.0 µmol/l. The coumarin-copper drug also significantly induced LA795 cell apoptosis in a time-dependent manner (P

In a previous study by our group memory impairment in rats with minimal hepatic encephalopathy (MHE) was associated with the inhibition of the glutamate-nitric oxide-cyclic guanosine monophosphate (Glu-NO-cGMP) pathway due to elevated dopamine (DA). However, the effects of DA on the Glu-NO-cGMP pathway localized in primary cortical astrocytes (PCAs) had not been elucidated in rats with MHE. In the present study, it was identified that when the levels of DA in the cerebral cortex of rats with MHE and high-dose DA (3 mg/kg)-treated rats were increased, the co-localization of N-methyl-d-aspartate receptors subunit 1 (NMDAR1), calmodulin (CaM), nitric oxide synthase (nNOS), soluble guanylyl cyclase (sGC) and cyclic guanine monophosphate (cGMP) with the glial fibrillary acidic protein (GFAP), a marker protein of astrocytes, all significantly decreased, in both the MHE and high-dose DA-treated rats (P

TNF 308 gene polymorphism and IL-10 polymorphism provided evidence in diagnosing some types of cancer. We aimed to explore the relation of gene polymorphism with gastric cancer. A total of 360 cases of gastric cancer patients were included in the study. The genotypes GG, GA, and AA of the interleukin-10-1082 gene (IL-10-1082) and the tumor necrosis factor-alpha gene (TNF-α) 308 polymorphism were examined by chromogenic detection. Three hundred healthy individuals' gene as control group were also examined. The GA 308 genotype of TNF-α differed significantly between the control group and the gastric cancer group (c 2 = 9.32, P < 0.05). Genotype frequencies of A/A (17.2%), A/G (26.2%), and G/G (9.1%) of the IL-10-1082 gene polymorphism in the gastric cancer group differed significantly compared to those of the control group ( c 2 = 20.32, P < 0.05). The IL-10-1082 gene and the GA 308 genotype of the TNF-α gene were found to be susceptibility genes for gastric cancer.

ISL1 is expressed in cardiac progenitor cells and plays critical roles in cardiac lineage differentiation and heart development. Cardiac progenitor cells hold great potential for clinical and translational applications. However, the mechanisms underlying ISL1 function in cardiac progenitor cells have not been fully elucidated. Here we uncover a hierarchical role of ISL1 in cardiac progenitor cells, showing that ISL1 directly regulates hundreds of potential downstream target genes that are implicated in cardiac differentiation, through an epigenetic mechanism. Specifically, ISL1 promotes the demethylation of tri-methylation of histone H3K27 (H3K27me3) at the enhancers of key downstream target genes, including Myocd and Mef2c, which are core cardiac transcription factors. ISL1 physically interacts with JMJD3, a H3K27me3 demethylase, and conditional depletion of JMJD3 leads to impaired cardiac progenitor cell differentiation, phenocopying that of ISL1 depletion. Interestingly, ISL1 is not only responsible for the recruitment of JMJD3 to specific target loci during cardiac progenitor differentiation, but also modulates its demethylase activity. In conclusion, ISL1 and JMJD3 partner to alter the cardiac epigenome, instructing gene expression changes that drive cardiac differentiation.

Specific small interfering RNAs (siRNAs) targeting receptor for advanced glycation end products (RAGE) inhibit the expression of RAGE, α-smooth muscle actin and type I collagen in the T6 hepatic stellate cells (HSCs), indicating that RAGE is important for the activation of HSCs and the expression of collagen. The present study aimed to investigate the effect of specific siRNAs targeting RAGE on the development of hepatic fibrosis (HF), using primary rat HSCs, which were isolated and cultured in vitro. The expression vectors for specific siRNAs targeting RAGE were constructed and transfected into primary rat HSCs. Untreated and nonspecific siRNA-transfected primary rat HSCs served as controls. The expression levels of RAGE, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), laminin (LN), hyaluronic acid (HA) and N-terminal procollagen III propeptide (PIIINP) in primary HSCs were detected by reverse transcription quantitative polymerase chain reaction and western blotting. The mRNA and 42 kD protein expression of RAGE in the pAKD-GR126-transfected primary HSCs were significantly downregulated compared with those in the untreated and the pAKD-negative control (NC)-transfected controls. The mRNA and protein expression levels of IL-6, TNF-α, TGF-β1, CTGF, LN, HA and PIIINP in the pAKD-GR126-transfected primary HSCs were also markedly downregulated compared with those in the untreated and pAKD-NC-transfected controls. Therefore, RAGE-specific siRNAs inhibited the expression of RAGE in primary rat HSCs and inhibited the development of HF.

In this study the MTP1 gene, encoding a type III integral transmembrane protein, was isolated from the rice blast fungus Magnaporthe oryzae. The Mtp1 protein is 520 amino acids long and is comparable to the Ytp1 protein of Saccharomyces cerevisiae with 46% sequence similarity. Prediction programs and MTP1-GFP (green fluorescent protein) fusion expression results indicate that Mtp1 is a protein located at several membranes in the cytoplasm. The functions of the MTP1 gene in the growth and development of the fungus were studied using an MTP1 gene knockout mutant. The MTP1 gene was primarily expressed at the hyphal and conidial stages and is necessary for conidiation and conidial germination, but is not required for pathogenicity. The Deltamtp1 mutant grew more efficiently than the wild type strain on non-fermentable carbon sources, implying that the MTP1 gene has a unique role in respiratory growth and carbon source use.

Antiangiogenic therapy is a validated approach for colorectal cancer (CRC) treatment. However, diverse adverse effects inevitably appear due to the off-target effect of the approved antiangiogenic ...

Correlations were examined between habitat characters and clonal structures determined by the RAPD (random amplified polymorphic DNA) assay in five populations of Oryza rufipogonin China. Nine of 175 decameric primers were used in the study because they reproducibly amplified polymorphisms. The extent of clonality together with the clonal and sexual reproductive strategies varied greatly among the five populations and correlated with the habitats where they occur. The populations under serious disturbance or seasonal drought tended to have small clones with relatively high clonal diversity caused by sexual reproduction, whereas the populations with little disturbance and sufficient supply of water were prone to have large clones with relatively low clonal variation and low sexual reproduction. Therefore, the dynamics of sexual vs. clonal reproduction of this species depended mainly on environmental factors, such as external disturbance and water supply, rather than latitudes indicated by previous study. These results have important implications for in situ conservation of O. rufipogon.Adequate external disturbance and water supply control are essential for maintaining high clone diversity of in situ conserved populations. According to the extent of clonality of the populations examined, we recommend that an interval of .12 m should be required for collecting samples for ex situ conservation and for population genetic studies to capture possible genetic diversity for O. rufipogonin China.

Since the receptor for advanced glycation end products (RAGE)-ligand axis has been demonstrated to be important in fibrogenesis, rat models may be used to assess whether specific small interfering RNAs (siRNAs) that target RAGE are able to reduce the progression of hepatic fibrosis. However, the effect of RAGE-targeted siRNA on established hepatic fibrosis remains to be elucidated. In the present study, RAGE-specific siRNA expression vectors were constructed prior to the animal experiment. Sprague-Dawley rats were treated initially with olive oil (2 ml/kg) or 50% CCl4 (2 ml/kg; CCl4/olive oil=1:1) twice per week for six weeks to generate the fibrosis model. The rats were then treated with phosphate‑buffered saline, a RAGE-specific siRNA expression vector, at different doses or a non-specific siRNA expression vector twice weekly via tail vein injection for up to six weeks, and were sacrificed at week two, four or six. Compared with the control groups, RAGE‑specific siRNA therapy significantly decreased RAGE mRNA and protein expression in rat livers (P

The effect of a calpain-selective cell permeant inhibitor, benzyloxycarbonyl Leu-Leu-Tyr diazomethylketone (ZLLY-CHN2), on the serum-stimulated growth of WI-38 human fibroblasts has been investigated. Only cell permeant protease inhibitors with activity against calpains prevented progression into S-phase. Protein blotting experiments indicated that p53 immunoreactivity increased in late G1 cells treated with ZLLY-CHN2. The content of p21Waf1/Cip1 CDK inhibitor also increased, providing a mechanism for the observed failure to enter S-phase. Further studies indicated that p53 could be degraded by a ZLLY-CHN2-sensitive protease immediately prior to S-phase, but that proteolysis did not occur after this critical time point. Chelation of extracellular Ca2+ by addition of EGTA inhibited the p53 degradation. Consistent with proteolysis of p53 in late G1 phase, mu-calpain immunoreactivity transiently accumulated in cell nuclei at this time. ZLLY-CHN2 did not appear to increase p53 mRNA in WI-38 cells. Purified mu-calpain required only 1 to 3 microM Ca2+ to proteolyze p53 in WI-38 cell lysates. These results indicate that ZLLY-CHN2 inhibits progression of WI-38 cells into S-phase by inactivating a calpain-like protease that is responsible for proteolysis of constitutively expressed p53 in late G1.

Recent genome-wide association studies (GWAS) that focus on childhood acute lymphoblastic leukemia (ALL), the most common malignancy in children younger than 15 years old, have found evidence that single nucleotide polymorphisms (SNPs) in IKZF1 (7p12.2), ARID5B (10q21.2) and CEBPE (14q11.2) are strongly related to the risk of childhood ALL. These polymorphisms may lead to abnormal expression and dysfunction of the corresponding transcription factors and are likely to increase the risk of ALL. To validate the relationship between these SNPs and the risk of childhood ALL in Chinese population, we conducted a case-control study of 570 ALL cases and 673 controls. We determined that the SNP rs10821936 in ARID5B was statistically significantly associated with the risk of childhood ALL (P0.0001). The results were also significant for the subgroup analysis of high-risk, medium-risk and low-risk ALL as well as B-lineage ALL. Statistically significant differences were not found in the SNPs for IKZF1 and CEBPE. In conclusion, ARID5B rs10821936 could serve as a potential biomarker for assessing the risk of childhood ALL in Chinese children.

Oxidative DNA damage caused by reactive oxygen species can produce 8-oxoguanine (8-oxoG) in DNA, which is misread and leads to G:CT:A transversions. This can be carcinogenic. Repair of 8-oxoG by the base excision repair pathway involves the activity of human 8-oxoG DNA glycosylase 1 (hOGG1). Accumulating evidence suggests that the hOGG1 Ser326Cys polymorphism affects the activity of hOGG1 and might serve as a genetic marker for susceptibility to several cancers. To determine whether this polymorphism is associated with risk of childhood acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped the hOGG1 Ser326Cys polymorphism (rs1052133) in a case–control study including 415 cases and 511 controls. We found that there was a significant difference in the genotype distributions of the hOGG1 Ser326Cys polymorphism between cases and controls (P = 0.046), and the combined genotypes Ser/Ser and Ser/Cys were associated with a statistically significantly decreased risk of ALL (adjusted odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.49–0.88, P = 0.005). Furthermore, we found a decreased risk for high risk ALL (adjusted OR = 0.60, 95% CI = 0.40–0.88, P = 0.005), low risk ALL (adjusted OR = 0.68, 95% CI = 0.47–0.99, P = 0.042), and B-phenotype ALL (adjusted OR = 0.63, 95% CI = 0.46–0.86, P = 0.003) among children with the Ser/Ser and Ser/Cys genotypes. Our results suggest that the hOGG1 Ser326Cys polymorphism is associated with susceptibility to childhood ALL in a Chinese population. (Cancer Sci 2011; 102: 1123–1127)

Nat. Genet. 42, 759–763 (2010); published online 22 August 2010; corrected after print 27 August 2014 In contrast to the version of this article initially published, the authors now find no evidence to support association with esophageal squamous cell carcinoma susceptibility for rs13042395[T] at 20p13 in their original data, in two independent sets of cases and controls collected in other Chinese populations or in the joint analysis of these three studies.

Conditionally replicative adenovirus (CRAd) mediated tumor specific gene therapy based on transcriptional control is considered a new direction for the treatment of cancer. Our previous studies showed that an HS4 insulator increased the alpha-fetoprotein (AFP) promoter-driven expression in the context of an adenovirus (Ad) vector, while retaining the highly specific gene expression in hepatoma cells in vitro and in vivo. In this study, we constructed two HS4-AFP promoter based CRAd vectors (Ad.HS4.AFP.E1a/TRAIL and Ad.HS4.AFP.E1a) with and without the expression cassette of TNF-related apoptosis-inducing ligand (TRAIL). The TRAIL-expressing virus vector, Ad.HS4.AFP.E1a/TRAIL, exhibited more obvious oncolytic effect than Ad.HS4.AFP.E1a in both high-AFP-producing HCC cell lines (Hep3B and HUH7) and a low-AFP-producing HCC cell line (PLC/PRF/5) examined, indicating endogenous TRAIL over-expression increased CRAd potency. The enhanced hepatoma cell death was mainly mediated through apoptotic mechanism, as evidenced by the activation of caspase-3, binding of annexin V and inhibition by caspase inhibitor z-vad-fmk. In s.c. xenograft of low-AFP-producing PLC/PRF/5 hepatoma model, the administration of Ad.HS4.AFP.E1a/TRAIL resulted in a more potent oncolytic effect compared with the same dose of Ad.HS4.AFP.E1a 28 days after virus exposure. This study demonstrated that the TRAIL in the context of a CRAd vector was able to increase the oncolytic activity in low-AFP-producing HCC cells in vitro and in vivo. Considering that oncolytic viruses destroy tumor cells expressing low levels of the tumor marker is a clinical concern, TRAIL might be a useful tool to improve the efficacy of these vectors.

Eight bovine genomic clones have been identified as members of the aspartyl protease gene family. The clones were prepared in phage vector lambda EMBL3 from Sau3AI partial digests of DNA from a single animal. Restriction maps show that seven of these clones are related and comprise at least five non-overlapping sequences. Allowing for allelic variation these probably represent three or more different genes. The nucleotide sequences show open reading frames (ORFs) corresponding closely to exons 6, 7 and 8 of human and porcine pepsin A. Comparison with other aspartyl proteases shows that these are multiple bovine pepsin A genes. The seven clones would encode at least two different but closely related forms of pepsin A. The 5' splice site at the end of exon 7 in all seven clones is the unusual sequence GC. The eighth clone contains an ORF homologous to exon 2 of the mammalian aspartyl proteases. The corresponding amino acid sequence is more closely related to bovine chymosin than to any of the other known sequences; it may be functionally homologous to chymosin but could be a novel mammalian aspartyl protease. The intron/exon boundaries seen in both this clone and in the bovine pepsin A clones are at the same positions as found in human pepsin A, bovine chymosin and human and mouse renins, further evidence that the general structure of mammalian aspartyl protease genes has been strongly conserved.