Impact of Alcohol Dehydrogenase 7 Polymorphism and Alcohol Consumption on Risk of Head and Neck Squamous Cell Carcinoma: A Korean Case-Control Study.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is closely associated with alcohol consumption and individual genetic susceptibility, such as single nucleotide polymorphism (SNP) of alcohol dehydrogenase (ADH). This study aimed to investigate the association of ADH7 SNPs with the risk of HNSCC. METHODS: We analyzed ADH7 rs1573496C>G, rs3737482T>C, rs1154460G>A, and rs284787T>C SNPs in 250 patients with HNSCC and 322 controls in the Korean populations. Genotyping was conducted using the TaqMan assay. Linkage disequilibrium and haplotypes were analyzed. RESULTS: The odds ratios (OR) and 95% confidence intervals (CI) of the CT and CC genotypes of ADH7 rs3737482T>C were 0.48 (0.29-0.78) and 0.69 (0.49-0.96), indicating a significantly decreased risk. In SNP of rs1154460G>A, the OR and 95% CI of the AA genotype was 1.63 (1.11-2.40), showing a significant increase in the risk. Furthermore, SNPs of ADH7 rs3737482T>C and ADH7 rs1154460G>A exhibit synergistic interactions with alcohol composition on the risk of HNSCC. None of the haplotypes were associated with the risk of HNSCC. CONCLUSIONS: ADH7 rs3737482T>C and rs1154460G>A SNPs are associated with the risk of development of HNSCC in Koreans. They could serve as molecular biological markers to screen high-risk groups for HNSCC.

Galectin-4 increases the ability of M2 macrophages to enhance antiviral CD4+ T-cell responses.

Galectin-4 (Gal-4) is a ß-galactoside-binding protein belonging to the galectin family. Although Gal-4 is known to be involved in several physiologic processes of the gastrointestinal tract, its immunomodulatory roles remain unclear. In this study, we investigated whether Gal-4 influences the function of M1 and M2 macrophages. Gal-4 treatment drove more robust changes in the gene expression of M2 macrophages compared to M1 macrophages. Antiviral immune response-related genes were significantly upregulated in Gal-4-treated M2 macrophages. Gal-4 significantly enhanced the immunostimulatory activity of M2 macrophages upon Toll-like receptor 7 stimulation or infection with lymphocytic choriomeningitis virus (LCMV). Moreover, the antibody production against LCMV infection and the antiviral CD4+ T-cell responses, but not the antiviral CD8+ T-cell responses, were greatly increased by Gal-4-treated M2 macrophages in vivo. The present results indicate that Gal-4 enhances the ability of M2 macrophages to promote antiviral CD4+ T-cell responses. Thus, Gal-4 could be used to boost antiviral immune responses.

Emerging role for R-loop formation in hepatocellular carcinoma.

The pathophysiological characteristics of hepatocellular carcinoma (HCC) is closely associated with genomic instability. Genomic instability has long been considered to be a hallmark of both human genetic disease and cancers. It is now well accepted that regulating R-loop formation to minimized levels is one of critical modulation to maintain genome integrity, and that improper regulation of R-loop metabolism causes genomic instability via DNA breakage, ultimately resulting in replicative senescence and even tumorigenesis. Given that R-loop is natural by-product formed during normal transcription condition, and that several types of cancer have defense mechanism against the genomic instability resulted from R-loop formation, modulating functional implication of proteins involved in the intrinsic and specific mechanisms of abnormal R-loop formation in cancers therefore could play an important part in appropriated therapeutic strategies for HCC cohorts. In this review, we highlight the latest understanding on how R-loops promote genomic instability and address how alterations in these pathways link to human HCC.

c-Jun N-terminal kinase 1 (JNK1) phosphorylates OTX2 transcription factor that regulates early retinal development.

BACKGROUND: The transcription factor orthodenticle homeobox 2 (OTX2) has critical functions in brain and eye development, and its mutations in humans are related to retinal diseases, such as ocular coloboma and microphthalmia. However, the regulatory mechanisms of OTX2 are poorly identified. OBJECTIVE: The identification of JNK1 as an OTX2 regulatory protein through the protein interaction and phosphorylation. METHODS: To identify the binding partner of OTX2, we performed co-immunoprecipitation and detected with a pooled antibody that targeted effective kinases. The protein interaction between JNK1 and OTX2 was identified with the co-immunoprecipitation and immunocytochemistry. In vivo and in vitro kinase assay of JNK1 was performed to detect the phosphorylation of OTX2 by JNK1. RESULTS: JNK1 directly interacted with OTX2 through the transactivation domain at the c-terminal region. The protein-protein interaction and co-localization between JNK1 and OTX2 were further validated in the developing P0 mouse retina. In addition, we confirmed that the inactivation of JNK1 K55N mutant significantly reduced the JNK1-mediated phosphorylation of OTX2 by performing an immune complex protein kinase assay. CONCLUSION: c-Jun N-terminal kinase 1 (JNK1) phosphorylates OTX2 transcription factor through the protein-protein interaction.

Inhibition of KIF20A suppresses the replication of influenza A virus by inhibiting viral entry.

The influenza A virus (IAV) has caused several pandemics, and therefore there are many ongoing efforts to identify novel antiviral therapeutic strategies including vaccines and antiviral drugs. However, influenza viruses continuously undergo antigenic drift and shift, resulting in the emergence of mutated viruses. In turn, this decreases the efficiency of existing vaccines and antiviral drugs to control IAV infection. Therefore, this study sought to identify alternative therapeutic strategies targeting host cell factors rather than viruses to avoid infection by mutated viruses. Particularly, we investigated the role of KIF20A that is one of kinesin superfamily proteins in the replication of IAV. The KIF20A increased viral protein levels in IAV-infected cells by regulating the initial entry stage during viral infection. Furthermore, the KIF20A inhibitor significantly suppressed viral replication, which protected mice from morbidity and mortality. Therefore, our findings demonstrated that KIF20A is highly involved in the viral replication process and viral propagation both in vitro and in vivo, and could thus be used as a target for the development of novel antiviral drugs.

Inhibitory effects of Rocaglamide-A on PPARγ-driven adipogenesis through regulation of mitotic clonal expansion involving the JAK2/STAT3 pathway.

Inhibition of adipogenesis is an important strategy for obesity treatment. Rocaglamide-A (Roc-A) is a natural herbal medicine isolated from the genus Aglaia (family Meliaceae), which has a cyclopenta[b]benzofuran core structure. Roc-A exhibits various pharmacological effects against diverse human cancer cells. However, the exact role of Roc-A during adipogenesis in adipocytes has not been studied at all. In this study, we demonstrate that Roc-A is crucial for reducing adipogenesis via downregulating PPARγ transcriptional activity. Consistently, Western-blot and RT-PCR analyses clearly showed that Roc-A inhibits the expression of PPARγ target genes and lipogenic markers in a dose-dependent manner along with suppression of lipid accumulation, in both 3T3-L1 cells and mouse adipose-derived stem cells. Mechanistically, Roc-A significantly decreased STAT3 phosphorylation in a dose-dependent manner in 3T3-L1 adipocytes. In particular, we confirmed that Roc-A effectively suppressed the expression of genes involved in cell-cycle regulation, such as cyclin A, B, D1, and E1, early during mitotic clonal expansion in 3T3-L1 adipocytes, and this effect was abolished by the JAK2/STAT3 activator FGF2. Taken together, our results demonstrated that Roc-A reduces adipogenesis by inhibiting PPARγ transactivation and STAT3 phosphorylation and thus may serve as a therapeutic target in obesity.

The Role of Epigenetic Changes in the Progression of Alcoholic Steatohepatitis.

Alcoholic steatohepatitis (ASH) is a progression hepatitis with severe fatty liver and its mortality rate for 30-days in patients are over 30%. Additionally, ASH is well known for one-fifth all alcoholic related liver diseases in the world. Excessive chronic alcohol consumption is one of the most common causes of the progression of ASH and is associated with poor prognosis and liver failure. Alcohol abuse dysregulates the lipid homeostasis and causes oxidative stress and inflammation in the liver. Consequently, metabolic pathways stimulating hepatic accumulation of excessive lipid droplets are induced. Recently, many studies have indicated a link between ASH and epigenetic changes, showing differential expression of alcohol-induced epigenetic genes in the liver. However, the specific mechanisms underlying the pathogenesis of ASH remain elusive. Thus, we here summarize the current knowledge about the roles of epigenetics in lipogenesis, inflammation, and apoptosis in the context of ASH pathophysiology. Especially, we highlight the latest findings on the roles of Sirtuins, a conserved family of class-III histone deacetylases, in ASH. Additionally, we discuss the involvement of DNA methylation, histone modifications, and miRNAs in ASH as well as the ongoing efforts for the clinical translation of the findings in ASH-related epigenetic changes.

Near-Field to Far-Field RCS Prediction on Arbitrary Scanning Surfaces Based on Spherical Wave Expansion.

Near-field to far-field transformation (NFFFT) is a frequently-used method in antenna and radar cross section (RCS) measurements for various applications. For weapon systems, most measurements are captured in the near-field area in an anechoic chamber, considering the security requirements for the design process and high spatial costs of far-field measurements. As the theoretical RCS value is the power ratio of the scattered wave to the incident wave in the far-field region, a scattered wave measured in the near-field region needs to be converted into field values in the far-field region. Therefore, this paper proposes a near-field to far-field transformation algorithm based on spherical wave expansion for application in near-field RCS measurement systems. If the distance and angular coordinates of each measurement point are known, the spherical wave functions in an orthogonal relationship can be calculated. If each weight is assumed to be unknown, a system of linear equations as numerous as the number of samples measured in the near electric field can be generated. In this system of linear equations, each weight value can be calculated using the iterative least squares QR-factorization method. Based on this theory, the validity of the proposed NFFFT is verified for several scatterer types, frequencies and measurement distances.

The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening.

The growth of telomerase-deficient cancers depends on the alternative lengthening of telomeres (ALT), a homology-directed telomere-maintenance pathway. ALT telomeres exhibit a unique chromatin environment and generally lack the nucleosome remodeler ATRX, pointing to an epigenetic basis for ALT. Recently, we identified a protective role for the ATRX-interacting macroH2A1.2 histone variant during homologous recombination and replication stress (RS). Consistent with an inherent susceptibility to RS, we show that human ALT telomeres are highly enriched for macroH2A1.2. However, in contrast to ATRX-proficient cells, ALT telomeres transiently lose macroH2A1.2 during acute RS to facilitate DNA double-strand break (DSB) formation, a process that is almost completely prevented by ectopic ATRX expression. Telomeric macroH2A1.2 is re-deposited in a DNA damage response (DDR)-dependent manner to promote homologous recombination-associated ALT pathways. Our findings thus identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link among ATRX loss, RS-induced DDR initiation and telomere maintenance via homologous recombination.

The histone variant macroH2A1 is a splicing-modulated caretaker of genome integrity and tumor growth.

The macroH2A1.2 histone variant facilitates the response to replication stress with implications for genome maintenance and cell growth. A mutually exclusive splice variant, macroH2A1.1, has opposing effects on DNA repair outcome and proliferation. Here we discuss the potential impact of splicing-modulated macroH2A1 chromatin organization for cell function and malignant transformation.

Replication Stress Shapes a Protective Chromatin Environment across Fragile Genomic Regions.

Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at regions of recurrent replication stress (RS). Upon aberrant fork stalling, DNA damage signaling and concomitant H2AX phosphorylation coordinate the FACT-dependent deposition of macroH2A1.2, a histone variant that promotes DNA repair by homologous recombination (HR). MacroH2A1.2, in turn, facilitates the accumulation of the tumor suppressor and HR effector BRCA1 at replication forks to protect from RS-induced DNA damage. Consequently, replicating primary cells steadily accrue macroH2A1.2 at fragile regions, whereas macroH2A1.2 loss in these cells triggers DNA damage signaling-dependent senescence, a hallmark of RS. Altogether, our findings demonstrate that recurrent DNA damage contributes to the chromatin landscape to ensure the epigenomic integrity of dividing cells.

Descriptions of three new species of the genus Symmorphus Wesmael, 1836 (Hymenoptera: Vespidae: Eumeninae) from South Korea, with an updated revised key to Far Eastern species.

Three new species of the genus Symmorphus Wesmael, 1836 are described with materials from South Korea and Far eastern Russia: Symmorphus kurzenkoi Kim sp. nov., S. truncatoclypeus Kim sp. nov., S. yamanei Kim sp. nov. All are members of the subgenus Symmorphus Wesmael 1836. S. kurzenkoi Kim sp. nov. is likely to be closely related to Symmorphus fuscipes in having well developed and completely closed propodeal submedian carina, but is clearly different from the latter in the shape of metasomal tergum 1 that is not markedly narrowed toward base. Within the S. murarius group proposed by Cumming 1989, Symmorphus truncatoclypeus Kim sp. nov. is unique in having a clypeus with apical margin completely truncated. S. yamanei Kim sp. nov. is separated from congeners by following combination of characteristics: uniformly lengthened mesosomal setae; vestigial epicnemial carina; areolate mesepimeron; propodeal submedian carina that is somewhat strongly developed though doubled and not clearly closed dorsally; weakly raised basal transverse carina on metasomal tergum 1; faintly foveate-reticulate dorsomedian portion of metasomal tergum 1. Re-description of S. tsushimanus Yamane 1990, which is the most poorly known species in the Far East, is presented based on the holotype. Finally, an updated revised determination key to Far Eastern species, supplemented by digital images and line drawings, is given.

Co-occurrence of ecologically equivalent cryptic species of spider wasps.

Many cryptic species have been discovered in various taxonomic groups based on molecular phylogenetic analyses and mating experiments. Some sympatric cryptic species share equivalent resources, which contradicts the competitive exclusion principle. Two major theories have been proposed to explain the apparent lack of competitive exclusion, i.e. niche-based coexistence and neutral model, but a conclusive explanation is lacking. Here, we report the co-occurrence of cryptic spider wasp species appearing to be ecologically equivalent. Molecular phylogenetic analyses and mating experiments revealed that three phylogenetically closely related species are found sympatrically in Japan. These species share the same resources for larval food, and two of the species have the same niche for nesting sites, indicating a lack of competitive exclusion. This evidence may suggest that ecologically equivalent species can co-occur stably if their shared resources are sufficiently abundant that they cannot be over-exploited.

Role of TLRs in the production of chemical mediators in nasal polyp fibroblasts by fungi.

OBJECTIVE: Fibroblasts are major supporting cells in nasal mucosa and can induce inflammatory process with recruitment of inflammatory cells. Airborne fungi have been suggested as an etiologic factor of chronic rhinosinusitis (CRS). The aim of this study was to investigate the interaction between airborne fungi and pattern recognition receptors (PRRs) in nasal fibroblasts. METHODS: Primary nasal polyp fibroblasts were cultured with Alternaria and Aspergillus for 48h. To determine the production of chemical mediators interleukine-6 (IL-6), IL-8, granulocyte-macrophage colony stimulating factor (GM-CSF), eotaxin, and regulated on activation normal T expressed and secreted (RANTES) were measured with enzyme immunoassay methods. PRRs for toll-like receptors (TLRs) and protease-activated receptors (PARs) mRNA were determined with reverse transcription polymerase chain reaction (RT-PCR). To determine the role of PRRs, fibroblasts were treated with small interfering RNA (siRNA). RESULTS: IL-6 and IL-8 productions were significantly increased by 50 and 100µg/ml of Alternaria. However, GM-CSF, eotaxin, and RANTES productions did not change. Aspergillus did not influence the production of chemical mediators from nasal polyp fibroblasts. TLR2 and TLR5 mRNA expressions were significantly increased by fungi and these two TLRs were associated with the production of IL-6 and IL-8. CONCLUSION: Alternaria interacts as a pathogen-associated molecular pattern with the PRRs, such as TLR2 and TLR5, which induce the production of inflammatory chemical mediators from nasal polyp fibroblasts. Airborne fungi enhance the innate immune defense mechanism and may be associated with the pathogenesis of nasal inflammatory diseases.

Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability.

DNA double-strand breaks (DSBs) and their repair can cause extensive epigenetic changes. As a result, DSBs have been proposed to promote transcriptional and, ultimately, physiological dysfunction via both cell-intrinsic and cell-non-autonomous pathways. Studying the consequences of DSBs in higher organisms has, however, been hindered by a scarcity of tools for controlled DSB induction. Here, we describe a mouse model that allows for both tissue-specific and temporally controlled DSB formation at ∼140 defined genomic loci. Using this model, we show that DSBs promote a DNA damage signaling-dependent decrease in gene expression in primary cells specifically at break-bearing genes, which is reversed upon DSB repair. Importantly, we demonstrate that restoration of gene expression can occur independently of cell cycle progression, underlining its relevance for normal tissue maintenance. Consistent with this, we observe no evidence for persistent transcriptional repression in response to a multi-day course of continuous DSB formation and repair in mouse lymphocytes in vivo Together, our findings reveal an unexpected capacity of primary cells to maintain transcriptome integrity in response to DSBs, pointing to a limited role for DNA damage as a mediator of cell-autonomous epigenetic dysfunction.

Taxonomy of Eumenes punctatus-complex (Hymenoptera: Vespidae: Eumeninae) from Korea with DNA barcoding and key to Far Eastern species of the genus Eumenes Latreille, 1802.

Based on DNA barcoding analysis and morphological comparison, new synonymy is proposed for Eumenes punctatus de Saussure, 1852 =E. asioboreus Kim & Sk. Yamane, 2001, syn. nov. Independent status of the Far Eastern species E. rubrofemoratus Giordani Soika, 1941 from the transpalearctic E. coarctatus (Linnaeus, 1758) is supported, suggesting their recent origin with comparatively low genetic divergence. A revised key to the Far Eastern species of the genus Eumenes is provided. Distribution of E. quadratus Smith, 1852 is corrected and E. rubrofemoratus Giordani Soika, 1941 is newly recorded from South Korea. For future taxonomic comprehension of the Far Eastern Eumenes, problematic species pairs requiring additional molecular tests are hereby suggested and discussed.

Anti-allergic effect of bee venom in an allergic rhinitis mouse model.

Bee venom (BV) has been used as an anti-inflammatory and immune modulating agent in Oriental medicine. This study used a mouse model to investigate the anti-allergic effect of BV, which is used in the treatment of various inflammatory diseases in traditional medicine. BV was obtained from the National Institute of Agricultural Science and Technology of Korea. Female BALB/C mice were sensitized by intraperitoneal injection of ovalbumin (OVA). BV was administered nasally prior to the intranasal instillation of OVA. Allergic behavior, serum OVA-specific immunoglobulin E (IgE), interleukin (IL)-4, IL-10, and interferon-gamma (INF-γ) levels in nasal lavage fluid were measured. Hematoxylin-eosin and periodic acid-Schiff staining were performed to evaluate histological change. BV attenuated nasal symptoms and inhibited the production of OVA-specific IgE and IL-4 in sensitized mice. The degree of inflammatory cell infiltration and goblet cell hyperplasia was attenuated by BV. Thus, BV effectively reduced allergic inflammation in a mouse model of allergic rhinitis, suggesting its potential as a useful therapeutic agent to treat allergic rhinitis.

A macrohistone variant links dynamic chromatin compaction to BRCA1-dependent genome maintenance.

Appropriate DNA double-strand break (DSB) repair factor choice is essential for ensuring accurate repair outcome and genomic integrity. The factors that regulate this process remain poorly understood. Here, we identify two repressive chromatin components, the macrohistone variant macroH2A1 and the H3K9 methyltransferase and tumor suppressor PRDM2, which together direct the choice between the antagonistic DSB repair mediators BRCA1 and 53BP1. The macroH2A1/PRDM2 module mediates an unexpected shift from accessible to condensed chromatin that requires the ataxia telangiectasia mutated (ATM)-dependent accumulation of both proteins at DSBs in order to promote DSB-flanking H3K9 dimethylation. Remarkably, loss of macroH2A1 or PRDM2, as well as experimentally induced chromatin decondensation, impairs the retention of BRCA1, but not 53BP1, at DSBs. As a result, macroH2A1 and/or PRDM2 depletion causes epistatic defects in DSB end resection, homology-directed repair, and the resistance to poly(ADP-ribose) polymerase (PARP) inhibition-all hallmarks of BRCA1-deficient tumors. Together, these findings identify dynamic, DSB-associated chromatin reorganization as a critical modulator of BRCA1-dependent genome maintenance.

Review of the genus Tachytes Panzer (Hymenoptera: Crabronidae: Crabroninae) of South Korea, with description of one new species.

Korean species of the genus Tachytes Panzer are reviewed. Four previously known species are confirmed, and one new species, Tachytes gyusanus is described. The new species is very similar to T. modestus, but it differs critically in the form of male genitalic capsule. A revised key to South Korean species, a description of the new species, and digital images and line drawings of diagnostic characteristics are provided.

Effects of fungi and eosinophils on mucin gene expression in rhinovirus-infected nasal epithelial cells.

PURPOSE: Fungi, rhinoviruses (RVs), and eosinophils are associated with upper respiratory diseases. We evaluated the effects of fungal stimulation and eosinophil co-culture on the expression of mucin genes in RV-infected nasal polyp epithelial cells. METHODS: Nasal polyp epithelial cells were obtained from chronic rhinosinusitis patients. Cultured epithelial cells were stimulated with Alternaria and Aspergillus with or without RV-16 infection. The epithelial cells were co-cultured with eosinophils for 16 h. MUC4, MUC5AC, MUC5B, and MUC8 mRNA expressions in the epithelial cells were quantified using real-time RT-PCR. To determine the underlying mechanism, nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and mitogen-activated protein kinase (MAPK) inhibitors were used to inhibit mucin gene expression. RESULTS: Fungi and RV-16 induced mucin gene expression in nasal polyp epithelial cells. However, there was no synergistic increase in mucin gene expression, with the exception of MUC4 mRNA expression stimulated by 25 µg/mL Aspergillus. When RV-16-infected epithelial cells were stimulated with fungi and then co-cultured with eosinophils, MUC4, MUC5B, and MUC8 mRNA expressions increased. Mucin gene expression was inhibited by NF-κB inhibitors. CONCLUSIONS: RV-16, airborne fungi, and eosinophils may exacerbate the inflammatory process in nasal mucosal diseases by enhancing mucin gene expression.