2-Hydroxylethyl methacrylate (HEMA), a tooth restoration component, exerts its genotoxic effects in human gingival fibroblasts trough methacrylic acid, an immediate product of its degradation

HEMA (2-hydroxyethyl methacrylate), a methacrylate commonly used in dentistry, was reported to induce genotoxic effects, but their mechanism is not fully understood. HEMA may be degraded by the oral cavity esterases or through mechanical stress following the chewing process. Methacrylic acid (MAA) is the primary product of HEMA degradation. In the present work we compared cytotoxic and genotoxic effects induced by HEMA and MAA in human gingival fibroblasts (HGFs). A 6-h exposure to HEMA or MAA induced a weak decrease in the viability of HGFs. Neither HEMA nor MAA induced strand breaks in the isolated plasmid DNA, but both compounds evoked DNA damage in HGFs, as evaluated by the alkaline comet assay. Oxidative modifications to the DNA bases were monitored by the DNA repair enzymes Endo III and Fpg. DNA damage induced by HEMA and MAA was not persistent and was removed during a 120 min repair incubation. Results from the neutral comet assay indicated that both compounds induced DNA double strand breaks (DSBs) and they were confirmed by the γ-H2AX assay. Both compounds induced apoptosis and perturbed the cell cycle. Therefore, methacrylic acid, a product of HEMA degradation, may be involved in its cytotoxic and genotoxic action

RNAi for Treating Hepatitis B Viral Infection

Chronic hepatitis B virus (HBV) infection is one of the leading causes of liver cirrhosis and hepatocellular carcinoma (HCC). Current treatment strategies of HBV infection including the use of interferon (IFN)-α and nucleotide analogues such as lamivudine and adefovir have met with only partial success. Therefore, it is necessary to develop more effective antiviral therapies that can clear HBV infection with fewer side effects. RNA interference (RNAi), by which a small interfering RNA (siRNA) induces the gene silence at a post-transcriptional level, has the potential of treating HBV infection. The successful use of chemically synthesized siRNA, endogenous expression of small hairpin RNA (shRNA) or microRNA (miRNA) to silence the target gene make this technology towards a potentially rational therapeutics for HBV infection. However, several challenges including poor siRNA stability, inefficient cellular uptake, widespread biodistribution and non-specific effects need to be overcome. In this review, we discuss several strategies for improving the anti-HBV therapeutic efficacy of siRNAs, while avoiding their off-target effects and immunostimulation. There is an in-depth discussion on the (1) mechanisms of RNAi, (2) methods for siRNA/shRNA production, (3) barriers to RNAi-based therapies, and (4) delivery strategies of siRNA for treating HBV infection

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Tightly Regulated Current-fed LLC Resonant Converter Employing Spread Spectrum Technique to Reduce Electromagnetic Interference

A spread spectrum technique (SST) can effectively reduce the conductive noise by spreading the operating frequency without additional components. However, the input-output voltage gain of the resonant converter is highly sensitive to the operating frequency, it is hard to apply the SST to the resonant converter. In this paper, the SST is employed to a current-fed LLC resonant converter with low output voltage ripple. The resonant network design is provided to obtain the insensitive voltage gain according to the operating frequency, which can reduce the output voltage ripple caused by the SST operation. The proposed current-fed LLC resonant converter with the SST is implemented to a 200-W prototype, and its performance is be evaluated in terms of the output voltage ripple and the EMI reduction by experiments

Oenanthe javanica Ethanolic Extract Alleviates Inflammation and Modifies Gut Microbiota in Mice with DSS-Induced Colitis

Oenanthe javanica, commonly known as water dropwort, has long been used to treat acute and chronic hepatitis, abdominal pain, alcohol hangovers, and inflammation in various traditional medicine systems in Asia. However, whether O. javanica has beneficial effects on colitis-induced intestinal damage remains elusive. This study tested the hypothesis that O. javanica has anti-inflammatory and antioxidant activities in mice with dextran sulfate sodium (DSS)-induced colitis. First, treatment of O. javanica ethanol extract (OJE) inhibited the production of inflammatory cytokines in lipopolysaccharide-affected macrophages. Second, in mice with DSS-induced colitis, OJE administration reduced pathological damage to the colon while alleviating weight gain and decreasing colon length, including inflammation and mucosal necrosis. In addition, OJE significantly (p < 0.01) restricted the activation of nuclear factor-κB (NF-κB) and the secretion of pro-inflammatory mediators and increased the expression of Nrf2-phase 2 antioxidant enzymes. The results of 16S rRNA gene sequencing workflows for taxonomic assignment analysis confirmed that the diversity (richness and evenness) of fecal microbiota was markedly elevated in the OJE group. OJE administration reduced the abundance of Proteobacteria including Escherichia and increased the abundance of the genus Muribaculum. These results suggested that OJE exerts beneficial effects on inflammation and gut microbial composition in a mouse model of colitis

Synchronous rectification method for high frequency cllc resonant cnverter

CLLC resonant converter employing wide bandgap devices requires a synchronous rectification (SR) to obtain high power conversion efficiency. Conventional SR methods for the CLLC resonant converter have a duty loss to prevent turn-on and-off switching failure in the SR operation. Especially, turn-on duty loss cannot be avoided to prevent the turn-on switching failure during the discontinuous conduction mode (DCM) operation. The proposed SR method uses the transformer voltage reflected on the third winding and the forward voltage drop of the rectifier, which can minimize the duty loss during the turn-on period. In addition, it can operate during the continuous conduction mode (CCM) as well as the DCM. The operational principles are introduced to design and to implement the proposed SR circuit. Simulation and experimental results verify the performance of the proposed SR method a 40 W prototype bidirectional CLLC resonant converter

Effect of Hypoxia-Inducible Factor 1 on Early Healing in Extraction Sockets

The aim of the present study was to investigate the effect of hypoxia-inducible factor 1 (HIF1A) on the early healing (4 weeks) of extraction sockets exhibiting partial loss of the labial bone. Two extraction sockets of the maxillary incisors from each of six dogs were assigned to two treatment modalities: deproteinized bovine bone mineral (i) with 10% collagen (DBBM-C) soaked with HIF1A and covered by a collagen membrane (CM) (HIF group) or (ii) treated with DBBM-C only and covered by a CM (control group). Microcomputed tomography revealed some degree of collapse of the labial contour. The totally augmented volume and new bone volume did not differ significantly between two groups ( > 0.05). The histological analysis revealed that the apical area of the socket was mostly filled with newly formed bone, while there was less newly formed bone in the coronal area and incomplete cortex formation. The histomorphometric analysis revealed that the area of newly formed bone was significantly larger in the HIF group than the control group (12.16 ± 3.04 versus 9.48 ± 2.01 mm, < 0.05), while there was no significant intergroup difference in the total augmented area. In conclusion, even though DBBM-C soaked with HIF1A enhanced histomorphometric bone formation, this intervention did not demonstrate superiority in preventing ridge shrinkage compared to DBBM-C alone. Clinical relevance of these findings should be further studied

Effect of Hypoxia-Inducible Factor 1α on Early Healing in Extraction Sockets

The aim of the present study was to investigate the effect of hypoxia-inducible factor 1α (HIF1A) on the early healing (4 weeks) of extraction sockets exhibiting partial loss of the labial bone. Two extraction sockets of the maxillary incisors from each of six dogs were assigned to two treatment modalities: deproteinized bovine bone mineral (i) with 10% collagen (DBBM-C) soaked with HIF1A and covered by a collagen membrane (CM) (HIF group) or (ii) treated with DBBM-C only and covered by a CM (control group). Microcomputed tomography revealed some degree of collapse of the labial contour. The totally augmented volume and new bone volume did not differ significantly between two groups (P>0.05). The histological analysis revealed that the apical area of the socket was mostly filled with newly formed bone, while there was less newly formed bone in the coronal area and incomplete cortex formation. The histomorphometric analysis revealed that the area of newly formed bone was significantly larger in the HIF group than the control group (12.16±3.04 versus 9.48±2.01 mm2, P<0.05), while there was no significant intergroup difference in the total augmented area. In conclusion, even though DBBM-C soaked with HIF1A enhanced histomorphometric bone formation, this intervention did not demonstrate superiority in preventing ridge shrinkage compared to DBBM-C alone. Clinical relevance of these findings should be further studied