Abstract Epstein–Barr virus (EBV) infection contributes to the development of several different types of human malignancy, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. ...As a herpesvirus, EBV can establish latent or lytic infection in cells. EBV-positive tumors are composed almost exclusively of cells with latent EBV infection. Strategies for inducing the lytic form of EBV infection in tumor cells are being investigated as a potential therapy for EBV-positive tumors. In this article, we review how cellular and viral proteins regulate the latent-lytic EBV switch in infected B cells and epithelial cells, and discuss how harnessing lytic viral reactivation might be used therapeutically.
Gender, culture, and mathematics performance Hyde, Janet S; Mertz, Janet E
Proceedings of the National Academy of Sciences - PNAS,
06/2009, Letnik:
106, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Using contemporary data from the U.S. and other nations, we address 3 questions: Do gender differences in mathematics performance exist in the general population? Do gender differences exist among ...the mathematically talented? Do females exist who possess profound mathematical talent? In regard to the first question, contemporary data indicate that girls in the U.S. have reached parity with boys in mathematics performance, a pattern that is found in some other nations as well. Focusing on the second question, studies find more males than females scoring above the 95th or 99th percentile, but this gender gap has significantly narrowed over time in the U.S. and is not found among some ethnic groups and in some nations. Furthermore, data from several studies indicate that greater male variability with respect to mathematics is not ubiquitous. Rather, its presence correlates with several measures of gender inequality. Thus, it is largely an artifact of changeable sociocultural factors, not immutable, innate biological differences between the sexes. Responding to the third question, we document the existence of females who possess profound mathematical talent. Finally, we review mounting evidence that both the magnitude of mean math gender differences and the frequency of identification of gifted and profoundly gifted females significantly correlate with sociocultural factors, including measures of gender equality across nations.
In fall 1972, Paul Berg’s laboratory published articles in PNAS describing two methods for constructing recombinant DNAs in vitro. He received half of the 1980 Nobel Prize in Chemistry for this ...landmark accomplishment. Here, we describe how this discovery came about, revolutionizing both biological research and the pharmaceutical industry.
In fall 1972, Paul Berg’s laboratory published articles in PNAS describing two methods for constructing recombinant DNAs in vitro. He received half of the 1980 Nobel Prize in Chemistry for this landmark accomplishment. Here, we describe how this discovery came about, revolutionizing both biological research and the pharmaceutical industry.
Epstein-Barr virus (EBV) is a human herpesvirus associated with B-cell and epithelial cell malignancies. EBV lytically infects normal differentiated oral epithelial cells, where it causes a tongue ...lesion known as oral hairy leukoplakia (OHL) in immunosuppressed patients. However, the cellular mechanism(s) that enable EBV to establish exclusively lytic infection in normal differentiated oral epithelial cells are not currently understood. Here we show that a cellular transcription factor known to promote epithelial cell differentiation, KLF4, induces differentiation-dependent lytic EBV infection by binding to and activating the two EBV immediate-early gene (BZLF1 and BRLF1) promoters. We demonstrate that latently EBV-infected, telomerase-immortalized normal oral keratinocyte (NOKs) cells undergo lytic viral reactivation confined to the more differentiated cell layers in organotypic raft culture. Furthermore, we show that endogenous KLF4 expression is required for efficient lytic viral reactivation in response to phorbol ester and sodium butyrate treatment in several different EBV-infected epithelial cell lines, and that the combination of KLF4 and another differentiation-dependent cellular transcription factor, BLIMP1, is highly synergistic for inducing lytic EBV infection. We confirm that both KLF4 and BLIMP1 are expressed in differentiated, but not undifferentiated, epithelial cells in normal tongue tissue, and show that KLF4 and BLIMP1 are both expressed in a patient-derived OHL lesion. In contrast, KLF4 protein is not detectably expressed in B cells, where EBV normally enters latent infection, although KLF4 over-expression is sufficient to induce lytic EBV reactivation in Burkitt lymphoma cells. Thus, KLF4, together with BLIMP1, plays a critical role in mediating lytic EBV reactivation in epithelial cells.
Epstein-Barr virus (EBV) maintains a lifelong latent infection within a subset of its host's memory B cells, while lytic EBV replication takes place in plasma cells and differentiated epithelial ...cells. Therefore, cellular transcription factors, such as BLIMP1, that are key mediators of differentiation likely contribute to the EBV latent-to-lytic switch. Previous reports showed that ectopic BLIMP1 expression induces reactivation in some EBV-positive (EBV(+)) B-cell lines and transcription from Zp, with all Z(+) cells in oral hairy leukoplakia being BLIMP1(+). Here, we examined BLIMP1's role in inducing EBV lytic gene expression in numerous EBV(+) epithelial and B-cell lines and activating transcription from Rp. BLIMP1 addition was sufficient to induce reactivation in latently infected epithelial cells derived from gastric cancers, nasopharyngeal carcinomas, and normal oral keratinocytes (NOK) as well as some, but not all B-cell lines. BLIMP1 strongly induced transcription from Rp as well as Zp, with there being three or more synergistically acting BLIMP1-responsive elements (BRE) within Rp. BLIMP1's DNA-binding domain was required for reactivation, but BLIMP1 did not directly bind the nucleotide (nt) -660 Rp BRE. siRNA knockdown of BLIMP1 inhibited 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced lytic reactivation in NOK-Akata cells, cells that can be reactivated by R, but not Z. Thus, we conclude that BLIMP1 expression is both necessary and sufficient to induce EBV lytic replication in many (possibly all) EBV(+) epithelial-cell types, but in only a subset of EBV(+) B-cell types; it does so, at least in part, by strongly activating expression of both EBV immediately early genes, BZLF1 and BRLF1.
This study is the first one to show that the cellular transcription factor BLIMP1, a key player in both epithelial and B-cell differentiation, induces reactivation of the oncogenic herpesvirus Epstein-Barr virus (EBV) out of latency into lytic replication in a variety of cancerous epithelial cell types as well as in some, but not all, B-cell types that contain this virus in a dormant state. The mechanism by which BLIMP1 does so involves strongly turning on expression of both of the immediate early genes of the virus, probably by directly acting upon the promoters as part of protein complexes or indirectly by altering the expression or activities of some cellular transcription factors and signaling pathways. The fact that EBV(+) cancers usually contain mostly undifferentiated cells may be due in part to these cells dying from lytic EBV infection when they differentiate and express wild-type BLIMP1.
When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas ...(HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV's natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a lytic-induction therapy for treating some EBV-associated malignancies.
The immediate-early (IE) BZLF1 gene of Epstein-Barr virus (EBV) regulates the switch between latent and lytic infection by EBV. We previously showed that the cellular transcription factor ZEB1 binds ...to a sequence element, ZV, located at nt -17 to -12 relative to the transcription initiation site of the BZLF1 promoter, Zp, repressing transcription from Zp in a transient transfection assay. Here, we report the phenotype in the context of a whole EBV genome of a variant of EBV strain B95.8 containing a 2-bp substitution mutation in the ZV element of Zp that reduced, but did not eliminate, ZEB1 binding to Zp. Strikingly, epithelial 293 cells latently infected with the EBV ZV mutant spontaneously produced IE-, early-, and late-gene products and infectious virus, while wild-type (WT)-infected 293 cells did not and have never been reported to do so. Furthermore, treatment with the chemical inducers sodium butyrate and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) led to an additional order-of-magnitude production of infectious virus in the ZV mutant-infected 293 cells, but still no virus in the WT-infected 293 cells. Similarly, ZV mutant-infected Burkitt's lymphoma BJAB cells accumulated at least 10-fold more EBV IE mRNAs than did WT-infected BJAB cells, with TPA or sodium butyrate treatment leading to an additional 5- to 10-fold accumulation of EBV IE mRNAs in the ZV mutant-infected cells. Thus, we conclude that ZEB1 binding to Zp plays a central role in regulating the latent-lytic switch in EBV-infected epithelial and B cells, suggesting ZEB1 as a target for lytic-induction therapies in EBV-associated malignancies.
The emergence of recombinant DNA technology occurred via the appropriation of known tools and procedures in novel ways that had broad applications for analyzing and modifying gene structure and ...organization of complex genomes. Although revolutionary in their impact, the tools and procedures per se were not revolutionary. Rather, the novel ways in which they were applied was what transformed biology.
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