Prolonged inhibitory effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine against replication of Epstein-Barr virus.

The effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), a new antiviral drug, and acyclovir (ACV) [9-(2-hydroxyethoxymethyl)guanine] on the replication of Epstein-Barr virus (EBV) were compared. Both drugs inhibited EBV DNA replication in P3HR-1 cells and superinfected Raji cells, but neither inhibited replication of the plasmid form of the EBV genome in latently infected Raji cells. However, DHPG had a more prolonged inhibitory effect than ACV. Although the effect of the drugs is prompt, the kinetics of inhibition of EBV replication indicated that a drug exposure of 14 days was needed to reduce the EBV genome copy number to the residual plasmid level (30 copies per cell). The inhibitory effect of ACV was readily reversed within 11 days after removal of the drug, in contrast to the more prolonged effect exerted by DHPG, which persisted for more than 21 days. The 50% inhibitory doses for cell growth of ACV and DHPG were estimated to be 250 and 200 microM, respectively. The viral 50% and 90% effective doses of inhibition were, respectively, 0.3 and 9 microM for ACV and 0.05 and 3 microM for DHPG. The therapeutic indices (50% inhibitory dose/50% effective dose) for ACV and DHPG were 833 and 4,000, respectively. Synthesis of EBV-associated polypeptides was also affected. In superinfected Raji cells, ACV (100 microM) and DHPG (30 microM) inhibited synthesis of polypeptides with molecular weights of 145,000 and 140,000; in addition, synthesis of polypeptides with molecular weights of 110,000 and 85,000 was markedly reduced by DHPG but not by ACV. However, after drug removal, the inhibitory effect of ACV on polypeptide synthesis was abolished in contrast to the more persistent effect of DHPG

Activation of latent Epstein-Barr virus genomes: selective stimulation of synthesis of chromosomal proteins by a tumor promoter.

The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) is a potent inducer of Epstein-Barr virus (EBV) gene expression. The optimal conditions for maximum activation of latent EBV genomes by TPA were determined. Although TPA is able to induce replication of EBV genomes in P3HR-1 cells in all phases of growth, the greatest increase in viral genome copies per cell (15-fold above the control level) occurred in nonproliferating cells as opposed to cells growing exponentially (6-fold above the control level). The synthesis of chromosomal proteins in nonproliferating cells under the conditions that induce maximum activation of latent virus genomes by TPA was studied. Selective stimulation in chromosomal protein synthesis accompanied the increase in EBV genomes in P3HR-1 cells despite an overall reduction in total cellular protein synthesis. Comparison of the chromosomal proteins from TPA-induced P3HR-1 cells and from superinfected Raji cells revealed comigrating chromosomal polypeptides of 145K, 140K, 135K, 110K, 85K, and 55K that are presumably EBV associated. The selective stimulation of synthesis of these chromosomal proteins in TPA-treated P3HR-1 cells was closely associated with the activation of latent EBV genomes

Epstein–Barr virus BRLF1 inhibits transcription of IRF3 and IRF7 and suppresses induction of interferon-β

Activation of interferon regulatory factors (IRFs) 3 and 7 is essential for the induction of Type I interferons (IFN) and innate antiviral responses, and herpesviruses have evolved mechanisms to evade such responses. We previously reported that Epstein-Barr Virus BZLF1, an immediate-early (IE) protein, inhibits the function of IRF7, but the role of BRLF1, the other IE transactivator, in IRF regulation has not been examined. We now show that BRLF1 expression decreased induction of IFN-β, and reduced expression of IRF3 and IRF7; effects were dependent on N- and C-terminal regions of BRLF1 and its nuclear localization signal. Endogenous IRF3 and IRF7 RNA and protein levels were also decreased during cytolytic EBV infection. Finally, production of IFN-β was decreased during lytic EBV infection and was associated with increased susceptibility to superinfection with Sendai virus. These data suggest a new role for BRLF1 in the ability of to evade host innate immune responses

Epstein–Barr virus BRLF1 inhibits transcription of IRF3 and IRF7 and suppresses induction of interferon-β

Activation of interferon regulatory factors (IRFs) 3 and 7 is essential for the induction of Type I interferons (IFN) and innate antiviral responses, and herpesviruses have evolved mechanisms to evade such responses. We previously reported that Epstein-Barr Virus BZLF1, an immediate-early (IE) protein, inhibits the function of IRF7, but the role of BRLF1, the other IE transactivator, in IRF regulation has not been examined. We now show that BRLF1 expression decreased induction of IFN-β, and reduced expression of IRF3 and IRF7; effects were dependent on N- and C-terminal regions of BRLF1 and its nuclear localization signal. Endogenous IRF3 and IRF7 RNA and protein levels were also decreased during cytolytic EBV infection. Finally, production of IFN-β was decreased during lytic EBV infection and was associated with increased susceptibility to superinfection with Sendai virus. These data suggest a new role for BRLF1 in the ability of to evade host innate immune responses

Differential effects of acyclovir and 9-(1,3-dihydroxy-2-propoxymethyl)guanine on herpes simplex virus and Epstein-Barr virus in a dually infected human lymphoblastoid cell line.

We investigated the effects of acyclovir and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on a lymphoblastoid cell line dually infected with Epstein-Barr virus and herpes simplex virus (HSV) type 1. The numbers of Epstein-Barr virus genomes were reduced during 70 days of treatment with either drug. Both drugs suppressed HSV replication in a dose-related manner. In the continued presence of the drugs, HSV developed resistance, rapidly to acyclovir and much more slowly to 30 microM DHPG. Analysis of HSV glycoprotein C production and viral DNA showed that treatment with 100 microM DHPG eliminated HSV production, curing the cell line of HSV persistent infection

Menthol Cigarette Smoking and Obesity in Young Adult Daily Smokers in Hawaii

This study investigates 1) the relationship between menthol cigarette smoking and obesity and 2) the association of body mass index with the nicotine metabolite ratio among menthol and non-menthol daily smokers aged 18–35 (n = 175). A brief survey on smoking and measures of height and weight, carbon monoxide, and saliva samples were collected from participants from May to December 2013 in Honolulu, Hawaii. Multiple regression was used to estimate differences in body mass index among menthol and non-menthol smokers and the association of menthol smoking with obesity. We calculated the log of the nicotine metabolite ratio to examine differences in the nicotine metabolite ratio among normal, overweight, and obese smokers. Sixty-eight percent of smokers used menthol cigarettes. Results showed that 62% of normal, 54% of overweight, and 91% of obese smokers used menthol cigarettes (p = .000). The mean body mass index was significantly higher among menthol compared with non-menthol smokers (29.4 versus 24.5, p = .000). After controlling for gender, marital status, educational attainment, employment status, and race/ethnicity, menthol smokers were more than 3 times as likely as non-menthol smokers to be obese (p = .04). The nicotine metabolite ratio was significantly lower for overweight menthol smokers compared with non-menthol smokers (.16 versus .26, p = .02) in the unadjusted model, but was not significant after adjusting for the covariates. Consistent with prior studies, our data show that menthol smokers are more likely to be obese compared with non-menthol smokers. Future studies are needed to determine how flavored tobacco products influence obesity among smokers

Comparison of polychlorinated biphenyl levels across studies of human neurodevelopment.

Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain, and detectable amounts are in the blood of almost every person in most populations that have been examined. Extensive evidence from animal studies shows that PCBs are neurotoxins, even at low doses. Interpretation of human data regarding low-level, early-life PCB exposure and subsequent neurodevelopment is problematic because levels of exposure were not similarly quantified across studies. We expressed the exposure levels from 10 studies of PCB and neurodevelopment in a uniform manner using a combination of data from original investigators, laboratory reanalyses, calculations based on published data, and expert opinion. The mainstay of our comparison was the median level of PCB 153 in maternal pregnancy serum. The median concentration of PCB 153 in the 10 studies ranged from 30 to 450 ng/g serum lipid, and the median of the 10 medians was 110 ng/g. We found that (a)) the distribution of PCB 153 exposure in most studies overlapped substantially, (b)) exposure levels in the Faroe Islands study were about 3-4-fold higher than in most other studies, and (c)) the exposure levels in the two recent U.S. studies were about one-third of those in the four earlier U.S. studies or recent Dutch, German, and northern Québec studies. Our results will facilitate a direct comparison of the findings on PCBs and neurodevelopment when they are published for all 10 studies

Measurement of the t(t)over-bar production cross section in the dilepton channel in pp collisions at √s=8 TeV

The top-antitop quark (t (t) over bar) production cross section is measured in proton-proton collisions at root s = 8 TeV with the CMS experiment at the LHC, using a data sample corresponding to an integrated luminosity of 5.3 fb(-1). The measurement is performed by analysing events with a pair of electrons or muons, or one electron and one muon, and at least two jets, one of which is identified as originating from hadronisation of a bottom quark. The measured cross section is 239 +/- 2 (stat.) +/- 11 (syst.) +/- 6 (lum.) pb, for an assumed top-quark mass of 172.5 GeV, in agreement with the prediction of the standard model

Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis

Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.publishedVersio