It is more than 50 years since the Epstein-Barr virus (EBV), the first human tumour virus, was discovered. EBV has subsequently been found to be associated with a diverse range of tumours of both ...lymphoid and epithelial origin. Progress in the molecular analysis of EBV has revealed fundamental mechanisms of more general relevance to the oncogenic process. This Timeline article highlights key milestones in the 50-year history of EBV and discusses how this virus provides a paradigm for exploiting insights at the molecular level in the diagnosis, treatment and prevention of cancer.
Although a pathogenic role for the Epstein-Barr virus (EBV) is largely undisputed for tumors that are consistently EBV genome positive (eg, nasopharyngeal carcinoma, endemic Burkitt lymphoma), this ...is not the case for classical Hodgkin lymphoma (cHL), a tumor with only a variable EBV association. In light of recent developments in immunotherapeutics and small molecules targeting EBV, we believe it is now timely to reevaluate the role of EBV in cHL pathogenesis.
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This rigorous explanation of plasmas is relevant to diverse plasma applications such as controlled fusion, astrophysical plasmas, solar physics, magnetospheric plasmas, and plasma thrusters. More ...thorough than previous texts, it exploits new powerful mathematical techniques to develop deeper insights into plasma behavior. After developing the basic plasma equations from first principles, the book explores single particle motion with particular attention to adiabatic invariance. The author then examines types of plasma waves and the issue of Landau damping. Magnetohydrodynamic equilibrium and stability are tackled with emphasis on the topological concepts of magnetic helicity and self-organization. Advanced topics follow, including magnetic reconnection, nonlinear waves, and the Fokker–Planck treatment of collisions. The book concludes by discussing unconventional plasmas such as non-neutral and dusty plasmas. Written for beginning graduate students and advanced undergraduates, this text emphasizes the fundamental principles that apply across many different contexts.
Epstein-Barr virus (EBV) infects most of the world's population and is causally associated with several human cancers, but little is known about how EBV genetic variation might influence infection or ...EBV-associated disease. There are currently no published wild-type EBV genome sequences from a healthy individual and very few genomes from EBV-associated diseases. We have sequenced 71 geographically distinct EBV strains from cell lines, multiple types of primary tumor, and blood samples and the first EBV genome from the saliva of a healthy carrier. We show that the established genome map of EBV accurately represents all strains sequenced, but novel deletions are present in a few isolates. We have increased the number of type 2 EBV genomes sequenced from one to 12 and establish that the type 1/type 2 classification is a major feature of EBV genome variation, defined almost exclusively by variation of EBNA2 and EBNA3 genes, but geographic variation is also present. Single nucleotide polymorphism (SNP) density varies substantially across all known open reading frames and is highest in latency-associated genes. Some T-cell epitope sequences in EBNA3 genes show extensive variation across strains, and we identify codons under positive selection, both important considerations for the development of vaccines and T-cell therapy. We also provide new evidence for recombination between strains, which provides a further mechanism for the generation of diversity. Our results provide the first global view of EBV sequence variation and demonstrate an effective method for sequencing large numbers of genomes to further understand the genetics of EBV infection.
Most people in the world are infected by Epstein-Barr virus (EBV), and it causes several human diseases, which occur at very different rates in different parts of the world and are linked to host immune system variation. Natural variation in EBV DNA sequence may be important for normal infection and for causing disease. Here we used rapid, cost-effective sequencing to determine 71 new EBV sequences from different sample types and locations worldwide. We showed geographic variation in EBV genomes and identified the most variable parts of the genome. We identified protein sequences that seem to have been selected by the host immune system and detected variability in known immune epitopes. This gives the first overview of EBV genome variation, important for designing vaccines and immune therapy for EBV, and provides techniques to investigate relationships between viral sequence variation and EBV-associated diseases.
E-cadherin-mediated cell-cell adhesion and signaling plays an essential role in development and maintenance of healthy epithelial tissues. Adhesiveness mediated by E-cadherin is conferred by its ...extracellular cadherin domains and is regulated by an assembly of intracellular adaptors and enzymes associated with its cytoplasmic tail. We used proximity biotinylation and quantitative proteomics to identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin. In addition, we used proteomics to identify proteins associated with E-cadherin-containing adhesion plaques from a cell-glass interface, which enabled the assignment of cellular localization to putative E-cadherin-interacting proteins. Moreover, by tagging identified proteins with GFP (green fluorescent protein), we determined the subcellular localization of 83 putative E-cadherin-proximal proteins and identified 24 proteins that were previously uncharacterized as part of adherens junctions. We constructed and characterized a comprehensive E-cadherin interaction network of 79 published and 394 previously uncharacterized proteins using a structure-informed database of protein-protein interactions. Finally, we found that calcium chelation, which disrupts the interaction of the extracellular E-cadherin domains, did not disrupt most intracellular protein interactions with E-cadherin, suggesting that the E-cadherin intracellular interactome is predominantly independent of cell-cell adhesion.
Undercover agents: The biaryl coupling of an aryltrifluoroborate with an aryl bromide involves in situ hydrolysis of the boron reagent. The hydrolysis products are key components in ensuring that the ...reaction proceeds with high efficiency and avoids the extensive generation of undesired phenolic and homocoupling side products.
Induced waves of calcium fluxes initiate multiple signalling pathways that play an important role in the differentiation and maturation of B-cells. Finely tuned transient Ca
fluxes from the ...endoplasmic reticulum in response to B-cell receptor (BCR) or chemokine receptor activation are followed by more sustained calcium influxes from the extracellular environment and contribute to the mechanisms responsible for the proliferation of B-cells, their migration within lymphoid organs and their differentiation. Dysregulation of these well-balanced mechanisms in B-cell lymphomas results in uncontrolled cell proliferation and resistance to apoptosis. Consequently, several cytotoxic drugs (and anti-proliferative compounds) used in standard chemotherapy regimens for the treatment of people with lymphoma target calcium-dependent pathways. Furthermore, ~10% of lymphoma associated mutations are found in genes with functions in calcium-dependent signalling, including those affecting B-cell receptor signalling pathways. In this review, we provide an overview of the Ca
-dependent signalling network and outline the contribution of its key components to B cell lymphomagenesis. We also consider how the oncogenic Epstein-Barr virus, which is causally linked to the pathogenesis of a number of B-cell lymphomas, can modify Ca
-dependent signalling.
•A method forecast segments from noisy data is proposed.•Segment forecasts are de-aggregated to customer level.•Customer-level forecasts are more accurate than traditional methods.•The proposed ...method is applicable in many domains.
Optimization of the supply chain relates on data that describes actual or future situation. Besides in many situations available data may not correspond directly to what is expected for the different models because of too large quantity and imprecision of the data that may lead to suboptimal or even bad decisions. Actual problem considers the availability of a large and noisy dataset concerning historical information about each customer that will be used to make improved prediction models, that may fit models to optimize the supply chain.
When dealing with large datasets, market segmentation is frequently employed in business forecasting; many customers are grouped based on some measure of similarity. Segment-level forecasting is then employed to represent the population within each segment. Challenges with successfully applying market segmentation include how to create segments when descriptive customer information is lacking and how to apply the segment-level demand forecasts to individual customers. This research proposes a method to create customer segments based on noisy historical transaction data, create segment-level forecasts, and then apply the forecasts to individual customers. The proposed method utilizes existing data mining and forecasting tools, but applies them in a unique combination that results in a higher level of customer-level forecast accuracy than other traditional methods. The proposed forecasting method has significant management applications in any domain where forecasts are needed for a large population of customers and the only available data is delivery data.
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