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Search Results: 1 - 10 of 130 matches for " Ravit Arav-Boger "
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Activation of Nucleotide Oligomerization Domain 2 (NOD2) by Human Cytomegalovirus Initiates Innate Immune Responses and Restricts Virus Replication
Arun Kapoor, Michael Forman, Ravit Arav-Boger
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092704
Abstract: Nucleotide-binding oligomerization domain 2 (NOD2) is an important innate immune sensor of bacterial pathogens. Its induction results in activation of the classic NF-κB pathway and alternative pathways including type I IFN and autophagy. Although the importance of NOD2 in recognizing RNA viruses has recently been identified, its role in sensing DNA viruses has not been studied. We report that infection with human cytomegalovirus (HCMV) results in significant induction of NOD2 expression, beginning as early as 2 hours post infection and increasing steadily 24 hours post infection and afterwards. Infection with human herpesvirus 1 and 2 does not induce NOD2 expression. While the HCMV-encoded glycoprotein B is not required for NOD2 induction, a replication competent virion is necessary. Lentivirus-based NOD2 knockdown in human foreskin fibroblasts (HFFs) and U373 glioma cells leads to enhanced HCMV replication along with decreased levels of interferon beta (IFN-β) and the pro-inflammatory cytokine, IL8. NOD2 induction in HCMV-infected cells activates downstream NF-κB and interferon pathways supported by reduced nuclear localization of NF-κB and pIRF3 in NOD2 knockdown HFFs. Stable overexpression of NOD2 in HFFs restricts HCMV replication in association with increased levels of IFN-β and IL8. Similarly, transient overexpression of NOD2 in U373 cells or its downstream kinase, RIPK2, results in decreased HCMV replication and enhanced cytokine responses. However, overexpression of a mutant NOD2, 3020insC, associated with severe Crohn's disease, results in enhanced HCMV replication and decreased levels of IFN-β in U373 cells. These results show for the first time that NOD2 plays a significant role in HCMV replication and may provide a model for studies of HCMV recognition by the host cell and HCMV colitis in Crohn's disease.
The Use of Artificial Neural Networks in Prediction of Congenital CMV Outcome from Sequence Data
Ravit Arav-Boger,Yuval S. Boger,Charles B. Foster,Zvi Boger
Bioinformatics and Biology Insights , 2008,
The Use of Artificial Neural Networks in Prediction of Congenital CMV Outcome from Sequence Data
Ravit Arav-Boger,Yuval S. Boger,Charles B. Foster,Zvi Boger
Bioinformatics and Biology Insights , 2008,
Abstract: A large number of CMV strains has been reported to circulate in the human population, and the biological significance of these strains is currently an active area of research. The analysis of complex genetic information may be limited using conventional phylogenetic techniques. We constructed artificial neural networks to determine their feasibility in predicting the outcome of congenital CMV disease (defined as presence of CMV symptoms at birth) based on two data sets: 54 sequences of CMV gene UL144 obtained from 54 amniotic fluids of women who contracted acute CMV infection during their pregnancy, and 80 sequences of 4 genes (US28, UL144, UL146 and UL147) obtained from urine, saliva or blood of 20 congenitally infected infants that displayed different outcomes at birth. When data from all four genes was used in the 20-infants’ set, the artificial neural network model accurately identified outcome in 90% of cases. While US28 and UL147 had low yield in predicting outcome, UL144 and UL146 predicted outcome in 80% and 85% respectively when used separately. The model identified specific nucleotide positions that were highly relevant to prediction of outcome. The artificial neural network classified genotypes in agreement with classic phylogenetic analysis. We suggest that artificial neural networks can accurately and efficiently analyze sequences obtained from larger cohorts to determine specific outcomes.The ANN training and analysis code is commercially available from Optimal Neural Informatics (Pikesville, MD).
An Artemisinin-Derived Dimer Has Highly Potent Anti-Cytomegalovirus (CMV) and Anti-Cancer Activities
Ran He, Bryan T. Mott, Andrew S. Rosenthal, Douglas T. Genna, Gary H. Posner, Ravit Arav-Boger
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024334
Abstract: We recently reported that two artemisinin-derived dimers (dimer primary alcohol 606 and dimer sulfone 4-carbamate 832-4) are significantly more potent in inhibiting human cytomegalovirus (CMV) replication than artemisinin-derived monomers. In our continued evaluation of the activities of artemisinins in CMV inhibition, twelve artemisinin-derived dimers and five artemisinin-derived monomers were used. Dimers as a group were found to be potent inhibitors of CMV replication. Comparison of CMV inhibition and the slope parameter of dimers and monomers suggest that dimers are distinct in their anti-CMV activities. A deoxy dimer (574), lacking the endoperoxide bridge, did not have any effect on CMV replication, suggesting a role for the endoperoxide bridge in CMV inhibition. Differences in anti-CMV activity were observed among three structural analogs of dimer sulfone 4-carbamate 832-4 indicating that the exact placement and oxidation state of the sulfur atom may contribute to its anti-CMV activity. Of all tested dimers, artemisinin-derived diphenyl phosphate dimer 838 proved to be the most potent inhibitor of CMV replication, with a selectivity index of approximately 1500, compared to our previously reported dimer sulfone 4-carbamate 832-4 with a selectivity index of about 900. Diphenyl phosphate dimer 838 was highly active against a Ganciclovir-resistant CMV strain and was also the most active dimer in inhibition of cancer cell growth. Thus, diphenyl phosphate dimer 838 may represent a lead for development of a highly potent and safe anti-CMV compound.
Polymorphisms in Toll-like receptor genes influence antibody responses to cytomegalovirus glycoprotein B vaccine
Ravit Arav-Boger, Genevieve L Wojcik, Priya Duggal, Roxann G Ingersoll, Terri Beaty, Robert F Pass, Robert H Yolken
BMC Research Notes , 2012, DOI: 10.1186/1756-0500-5-140
Abstract: We genotyped 142 women previously vaccinated with three doses of CMV gB for single nucleotide polymorphisms (SNPs) in TLR 1-4, 6, 7, 9, and 10, and their associated intracellular signaling genes. SNPs in the platelet-derived growth factor receptor (PDGFRA) and integrins were also selected based on their role in binding gB. Specific SNPs in TLR7 and IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) were associated with antibody responses to gB vaccine. Homozygous carriers of the minor allele at four SNPs in TLR7 showed higher vaccination-induced antibody responses to gB compared to heterozygotes or homozygotes for the common allele. SNP rs1953090 in IKBKE was associated with changes in antibody level from second to third dose of vaccine; homozygotes for the minor allele exhibited lower antibody responses while homozygotes for the major allele showed increased responses over time.These data contribute to our understanding of the immunogenetic mechanisms underlying variations in the immune response to CMV vaccine.Infection with CMV is common in humans, causing severe morbidity and mortality in congenitally-infected newborns and in immunocompromised patients [1-3]. The importance of CMV as the leading infectious cause of mental retardation and deafness in children has been emphasized by its categorization by the Institute of Medicine as a level I vaccine candidate [4]. The rationale for developing a CMV vaccine is based on clinical and animal studies showing that immunity to CMV reduces the frequency and severity of disease [5,6]. In addition, animal studies demonstrated that immunization with subunit vaccines prevented disease and transplacental transmission of CMV [5-7]. Two recent phase II clinical trials with glycoprotein B (gB)-MF59 led to major enthusiasm and hope for the future success of CMV vaccine. The first was performed in young women recruited on postpartum wards [4], and showed 50% efficacy in preventing maternal CMV infection. Analysis of
Recombinant luciferase-expressing human cytomegalovirus (CMV) for evaluation of CMV inhibitors
Ran He, Gordon Sandford, Gary S Hayward, William H Burns, Gary H Posner, Michael Forman, Ravit Arav-Boger
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-40
Abstract: Infection with Cytomegalovirus (CMV) continues to be a major threat in organ transplant recipients and congenitally-infected children [1,2]. Although existing systemic therapies are effective in suppressing virus replication, serious side effects and the emergence of resistant viral strains pose significant treatment dilemmas [3]. The need to identify and develop new anti-CMV compounds coincides with the advancement of rapid, sensitive, and high-throughput methods for screening of lead compounds. While the plaque reduction assay remains the gold-standard for screening of anti-viral compounds, new techniques based on recombinant DNA technology and highly sensitive molecular assays have recently been suggested as alternatives [4-6]. Real-time PCR, the standard of care in the management of CMV disease in high- risk patient populations, may also provide a sensitive tool for drug screening [7-12]In earlier studies, a series of chloramphenicol acetyl transferase (CAT) recombinants expressing CAT under the control of UL54 (DNA polymerase, POL) or UL99 (pp28) promoters were constructed. The expression of CAT in infected cells highly mimicked the expression pattern of the endogenous UL54 and UL99 [4,13]. Thus, these two gene promoters were selected to construct luciferase-recombinant CMV for quatification of CMV replication in a rapid and reproducuble way. We report on the evaluation of two luciferase recombinant viruses (pp28 and POL) and the correlation of the pp28-luciferase system with plaque reduction and real-time PCR in evaluation of CMV inhibition by anti-CMV compounds.Recombinant CMV based on the laboratory-adapted strain, Towne, was constructed by homologous recombination in transfected-infected cells. A β- galactosidase (β -gal)-expressing Towne virus was first constructed using an intergenic insertion site between US9 and US10. Prior studies in which a β-glucuronidase expression cassette was inserted in this intergenic region of the laboratory-adapted AD169 virus
Detection of a Single Identical Cytomegalovirus (CMV) Strain in Recently Seroconverted Young Women
Suchetha Murthy,Gary S. Hayward,Sarah Wheelan,Michael S. Forman,Jin-Hyun Ahn,Robert F. Pass,Ravit Arav-Boger
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015949
Abstract: Infection with multiple CMV strains is common in immunocompromised hosts, but its occurrence in normal hosts has not been well-studied.
Artemisinin-Derived Dimers Have Greatly Improved Anti-Cytomegalovirus Activity Compared to Artemisinin Monomers
Ravit Arav-Boger,Ran He,Chuang-Jiun Chiou,Jianyong Liu,Lauren Woodard,Andrew Rosenthal,Lorraine Jones-Brando,Michael Forman,Gary Posner
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010370
Abstract: Artesunate, an artemisinin-derived monomer, was reported to inhibit Cytomegalovirus (CMV) replication. We aimed to compare the in-vitro anti-CMV activity of several artemisinin-derived monomers and newly synthesized artemisinin dimers.
Human Induced Pluripotent Stem Cell-Derived Models to Investigate Human Cytomegalovirus Infection in Neural Cells
Leonardo D'Aiuto, Roberto Di Maio, Brianna Heath, Giorgio Raimondi, Jadranka Milosevic, Annie M. Watson, Mikhil Bamne, W. Tony Parks, Lei Yang, Bo Lin, Toshio Miki, Jocelyn Danielle Mich-Basso, Ravit Arav-Boger, Etienne Sibille, Sarven Sabunciyan, Robert Yolken, Vishwajit Nimgaonkar
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049700
Abstract: Human cytomegalovirus (HCMV) infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS) cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs), neural progenitor cells (NPCs) and neurons suggests that (i) iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii) Neural stem cells have impaired differentiation when infected by HCMV; (iii) NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv) most iPS-derived neurons are not permissive to HCMV infection; and (v) infected neurons have impaired calcium influx in response to glutamate.
Groups actions, and D equivalences of categories of coherent sheaves of symplectic resolutions
Dorin Boger
Mathematics , 2015,
Abstract: Let k be an algebraically closed field of characteristic p>>0. Let $X\rightarrow Y$ be a symplectic resolution. There are two questions which motivates this work. One question is a construction of an action of a group on the category $\mathcal{C}:=D^b(Coh(X))$ - The bounded derived category of coherent sheaves of the symplectic resolution X. Second question is understanding equivalence functors between derived categories of coherent sheaves for different symplectic resolutions of Y. Let G/k be a reductive group. In this paper, we construct a local system on a topological space called $V^0_{\mathbb{C}}$ with value the category $D^b(Coh(T^*G/P))$ for a parabolic subgroup P. This induces an action of $\pi_1 V^0_{\mathbb{C}}$ on the category. In another paper we further explain how a refinement of this local system construction, gives an answer to the second question, showing that these equivalence functors, are parametrized by homotopy classes of maps between certain points in the base space. We also lift the result to characteristic zero.
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