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Simple Summary The C promoter of Epstein–Barr virus is assumed to be important for B cell growth and transformation. However, we present evidence that promoter activity is not only unneeded for transformation but also that absence of the promoter increased the transformation activity of the virus. We found that the C promoter was lost in some Epstein–Barr virus-associated lymphoma specimens. Therefore, deletion of the promoter could partially account for the tumorigenesis of Epstein–Barr virus-associated lymphomas. Abstract The Epstein–Barr virus (EBV) is the cause of several malignancies, including diffuse large B cell lymphoma (DLBCL). We recently found that EBV genomes in EBV-positive cancer specimens have various deletions (Okuno et al. Nat Microbiol. 2019). Here, we focus on the deletion of C promoter (Cp), which transcribes EBV nuclear antigen (EBNA) genes in type III latency. The Cp deletion found in a DLBCL patient (332 bp) was introduced into EBV-BAC of the B95-8 strain. Interestingly, the dCp virus transformed B cells more efficiently than WT and revertant strains. Deletion of Cp also promoted tumor formation and severe pathogenicity in a mouse xenograft model. RNA sequencing and qRT–PCR analyses revealed that Cp transcription was undetectable in the dCp cells. Instead, transcription from the W promoter (Wp), an alternative promoter for EBNA, was activated in the dCp mutant. We also found that the expression of latent membrane protein 2A (LMP2A) was somehow induced in the dCp mutant. Double knockout of Cp and LMP2A indicated that LMP2A is crucial for B cell transformation, but the increased transformation induced by Cp deletion cannot be explained by LMP2A alone. We also tested the effect of an anti-apoptotic viral BCL2 homolog, BHRF1, because its expression was reportedly induced more efficiently by that of Wp. However, increased growth transformation via Cp deletion was not due to the BHRF1 gene. Taken together, the results indicated that deletion of a specific region in Cp increased in vitro transformation and the rate of progression of EBV-positive lymphoproliferative disorders in vivo. Our data suggest that genomic alteration not only of the host but also the virus promotes EBV-positive tumor generation and expansion, although the molecular mechanism underlying this phenomenon is still unclear. However, LMP2A and BHRF1 are not involved.

Our student populations are more complex and diverse than ever before, and if English departments seek to serve these students, they will need to commit to transformative learning experiences that meet students where they are and invest in their possibilities for growth. Many of our students have, like me, quietly suffered oppressive forces that reach out to silence them and to tell them they are not valuable. When English teachers operate under deficit models, focusing on how students fail to conform to writing conventions rather than focusing on how they create meaning through writing, we are telling students that they, and their stories, do not belong in an English department. In this era of decreased state funding, in which institutions of higher education count students in terms of dollar signs, it is more important than ever that our faculty and our disciplines learn to adapt proactively and ethically on the side of our students. If our discipline can open itself up to an integrative and multimodal approach to writing that considers students as complex human beings moving through time and space, we will make a more ambitious investment in our students' lives and their futures.

Development of Micro and Small enterprises (MSEs) is one mechanism for alleviating unemployment, especially for women. Ethiopia has developed policy as part of the Growth Transformation and Plan (GTP) to develop MSEs to generate employment at the initial stage and transform the enterprises into medium and large enterprises in the long run. However, contrary to this objective, the growth of these enterprises has been very slow by every standard. This study evaluates the factors behind the slow growth of the enterprises by estimating the enterprise growth model captured by employment growth over the span of the period that the firm has operated. We find that women owners, in particular, face more severe credit, market and working premises constraints. We also find that while enterprise growth is inversely related to initial size, financial literacy and desirable managerial qualities of owners and managers positively contribute to enterprise growth.

Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection. We used BH3 profiling to query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL-2) to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1 mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis. DOI: http://dx.doi.org/10.7554/eLife.22509.001, eLife digest Over 90% of adults around the world are infected with the Epstein-Barr virus. Like other closely related viruses, such as those that cause chicken pox and cold sores, an infection lasts for the rest of the person’s life, although the virus generally remains in a latent or dormant state. However, under certain conditions the latent viruses can cause cancers to develop; in fact, it is estimated that such infections are responsible for nearly 2% of all cancer deaths worldwide. One way that healthy human cells prevent cancer is by triggering their own death in a process called apoptosis. The Epstein-Barr virus can block apoptosis, therefore making the cells more likely to become cancerous. Previous research identified one protein in the Epstein-Barr virus that promotes cancer by preventing infected cells from dying as normal. However, even in the absence of this protein, Epstein-Barr virus-infected cells remain resistant to apoptosis. This suggests that the virus has another way of blocking cell death. Price et al. have now used a technique that stresses living cells in a way that reveals which proteins prevent apoptosis to study human cells infected with the Epstein-Barr virus. This revealed that soon after infection, the virus could force the human cell to produce MCL-1, a protein that prevents cell death. Later, the Epstein-Barr virus enlisted a second human protein called BFL-1, which makes the infected cell further resistant to apoptosis. Price et al. discovered that a protein in the Epstein-Barr virus called EBNA3A controls the production of the MCL-1 and BFL-1 proteins. In the future, developing therapies that target these proteins may lead to new treatments for cancers caused by the Epstein-Barr virus. Such treatments would be likely to have fewer side effects for patients than traditional chemotherapies. DOI: http://dx.doi.org/10.7554/eLife.22509.002

The growth of biological tissues is described as the volumic production of mass of so-called germs, considered as potential sites for tissue renewal/resorption. The growth is characterized by a growth transformation gradient. The continuous change of the domain occupied by each germ during growth is analysed, hence, the mechanical balance laws are written considering the additional terms due to the domain variation. The principle of virtual power is then expressed, leading to the balance of momentum, assuming that the power of internal forces originates from both volumic and surfacic potentials. The equilibrium equations of the growing germ split into volumic, surfacic and lineic contributions. Viewing growth as an irreversible phenomenon, the writing of the second principle of thermodynamics for a germ continuously receiving matter due to transport phenomena allows to identify the driving forces linked to growth. In the second part, the growth and evolution are viewed as finding the best configuration of...

Cellular automata simulation of recrystallization in two dimensions is carried out. The simulated microstrutural evolution is compared in detail with the predictions from mathematically exact analytical theories considering both kinetic and geometrical aspects. Very good agreement is observed between the cellular automata simulation and the theoretical results. Moreover, the simulated data is used to test new expressions recently derived to describe the evolution of the interfaces between recrystallized grains. This work focuses on recrystallization but its results are applicable to any nucleation and growth transformation.

The growth of biological tissues is described as the volumetric production of mass within tissue elements, considered as one component potential sites for tissue renewal/resorption at a mesoscopic scale of description. The growth is characterized by a growth transformation gradient, which is accompanied by an additional accommodation transformation, so that the total transformation gradient defines a compatible global displacement field. The continuous change of the domain occupied by each tissue element during growth is considered, hence the mechanical balance laws are written, accounting for the additional terms due to the domain variation. The principle of virtual power is then expressed, considering that the power of internal forces originates from both volumic and surface potentials. The surface potential is thought to express configurational forces tied to the interface motion, extent and orientation. The equilibrium equations of the growing tissue element then follow, associated to surface and line boundary conditions. The writing of the second principle of thermodynamics for a tissue element continuously receiving matter due to transport phenomena allows to identify the driving forces linked to growth, and provides the evolution laws for the growth velocity. The large strains compatibility conditions that characterize the accommodation tensor are further considered as an important aspect of growth. A first insight into the numerical solutions of the compatibility conditions is given, envisaging the situation of radial growth.

Epstein–Barr virus (EBV) was first discovered in cells from a patient with Burkitt lymphoma (BL), and is now known to be a contributory factor in 1–2% of all cancers, for which there are as yet, no EBV-targeted therapies available. Like other herpesviruses, EBV adopts a persistent latent infection in vivo and only rarely reactivates into replicative lytic cycle. Although latency is associated with restricted patterns of gene expression, genes are never expressed in isolation; always in groups. Here, we discuss (1) the ways in which the latent genes of EBV are known to modulate cell death, (2) how these mechanisms relate to growth transformation and lymphomagenesis, and (3) how EBV genes cooperate to coordinately regulate key cell death pathways in BL and lymphoblastoid cell lines (LCLs). Since manipulation of the cell death machinery is critical in EBV pathogenesis, understanding the mechanisms that underpin EBV regulation of apoptosis therefore provides opportunities for novel therapeutic interventions.

The establishment of the British National Health Service in 1948 was a watershed for the nonprofit sector, as the voluntary hospitals were taken into public ownership. This article surveys the voluntary hospitals of London in the last two peacetime decades of their existence. Although this was a period of significant expansion for the hospitals, there were also difficulties looming. City-wide data and records of individual institutions are used to explore the risk of deficit, the hospitals’ asset base, the demand for expenditure, and the changing basis of income. The analysis confirms and augments earlier discussion of gathering financial hardship. Finally, the growth of the municipal hospital service is detailed. The London County Council’s enthusiastic development of publicly funded institutions added to the problems of the voluntary sector. Public/nonprofit partnership remained underdeveloped, voluntary fundraising was undermined, and principled opposition was articulated by council members.

The structure and dielectric properties of thin lead zirconate titanate films grown ex situ on Pt/SiO2/Si substrates were studied. It was shown that with a crystallization temperature increase in the range of 540 to 580°C, the mechanism of perovskite phase growth changes and the ferroelectric parameters change according to this transformation.

In the preface to this book, the author Dipak K. Gupta reveals that he hails from “a long line of terrorists and their adversaries.” 1 More importantly when he arrived at college in Calcutta he ali...

The applicability of popular thermal analysis methods like the one proposed by Ozawa and Kissinger, or the one derived from the Avrami kinetic formalism, to non-isothermal nucleation and growth transformation kinetics, is reassessed. Restrictions and limitations of both techniques are reevaluated, in order to clarify when and under which transformation conditions is each method justified.

A nucleation and growth transformation implicates the existence of a natural size ξ. We discusse the competition between ξ and the linear dimension L of the system. The transformation kinetics varies from Avrami size independent behaviour at large size (L ≫ ξ) to a strongly size dependent behaviour at L ≪ξ.

The unexercised limb bones of a male patient with hydrocephalus, who had been bedridden for 16 years, were observed and measured in order to examine growth transformation and growth direction. Although length growth was not markedly disturbed, transverse growth and the thickness of periosteal deposition were delayed. These findings confirmed that stress is necessary for growth of bone thickness. No differences in the circumference and area of the medullary cavity were evident between this subject and the femora of the average adult male, in spite of the delayed thickness growth. Therefore it was considered that lack of exercise disturbs the thickness growth of bone, but does not disturb bone resorption in the medullary cavity.

The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapy-related high-risk acute leukemia. Here, we investigated the biological effects of MLL.AF4, AF4.MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several parameters like cell growth, cell cycling capacity, apoptotic behavior and growth transformation were investigated under physiological and stress conditions. Co-transfected cells displayed the highest resistance against apoptotic triggers, cell cycling capacity and loss-of-contact inhibition. These analyses were complemented by gene expression profiling experiments and specific gene signatures were established for each of the three cell lines. Interestingly, co-transfected cells strongly upregulate the homeobox gene Nanog. In combination with Oct4, the Nanog homeoprotein is steering maintenance of pluripotency and self-renewal in embryonic stem cells. Transcription of Nanog and other stem cell factors, like Oct4 and Bmi1, was verified in biopsy material of t(4;11) patient cells which express both reciprocal t(4;11) fusion genes. In conclusion, the presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia, suggesting that each of the two fusion proteins contribute specific properties and, in combination, also synergistic effects to the leukemic phenotype.

The effect of non-random nuclei location and the efficiency of microstructural descriptors in assessing such a situation are studied. Cellular automata simulation of recrystallization in two dimensions is carried out to simulate microstrutural evolution for nuclei distribution ranging from a periodic arrangement to clusters of nuclei. The simulation results are compared in detail with microstrutural descriptors normally used to follow transformation evolution. It is shown that the contiguity is particularly relevant to detect microstructural deviations from randomness. This work focuses on recrystallization but its results are applicable to any nucleation and growth transformation.

Publisher Summary This chapter describes the application of various cellular assays for examining the growth transformation caused by GPCR oncogenes that promote the aberrant activation of Rho family small GTPases. A critical step in the validation of the role of candidate oncogenes in oncogenesis involves a demonstration of their ability to endow non-neoplastic cells with growth properties characteristics of tumor cells. Three types of focus formation assays can be used to evaluate the transforming potential of oncoproteins that cause persistent activation of Rho family proteins. The most commonly used assay is the primary focus formation assay, which provides a straightforward method for quantitation of transforming potential. A second assay is a primary focus formation cooperation assay, where activated Raf is coexpressed along with the oncogene under evaluation. Ras-induced foci should be readily visible after 7 to 10 days, whereas various Dbl or Rho family protein-induced foci may not be visible until 14 to 21 days. The second type of focus formation assay is a secondary focus formation assay, which employs NIH 3T3 cells stably expressing a weakly transforming oncoprotein.

EBNA2 transcriptional activation and regulated EBNALP coactivation are critical for Epstein-Barr virus-infected primary B-lymphocyte growth transformation. EBNALP coactivation requires the EBNA2 acidic activation domain (E2AD); EBNALP can bind to E2AD. EBNALP has now been found to bind less well to EBNA2 amino acids 1 to 58, which has been identified to be a second transcriptional activation domain, E2AD2. E2AD2 was specifically coactivated by EBNALP. Moreover, E2AD, E2AD2, EBNA2 RG domain, and the intermediate domain between RG and E2AD had significant roles in EBNA2-mediated activation and EBNALP coactivation.

Previous genetic and biochemical analyses have indicated that the Epstein-Barr virus EBNA-2 amino terminus is important for primary B-lymphocyte growth transformation and may be involved in self-association. We now report that EBNA-2 has at least two domains, amino acids 1 to 60 and 96 to 210, which independently mediate homotypic association, 1 to 60 with 1 to 60 and 96 to 210 with 96 to 210. EBNA-2 self-association is likely to be critical to the ability of EBNA-2 to interact simultaneously with multiple cellular transcription factors, coactivators, and histone acetyltransferases through its RBPJκ binding and acidic activating domains.

A new type of instability in superalloys has been observed in advanced alloys containing high levels of refractory elements. One instability occurs under the diffusion zone of coatings and has been called secondary reaction zone or SRZ. Similar instabilities, in the form of cellular colonies, have been observed along grain boundaries and in dendrite cores. These microstructural instabilities are characterized and interpreted in terms of a nucleation and growth transformation. The similarities and differences between a similar phenomenon, cellular recrystallization, are outlined. The degradation of properties due to the SRZ and cellular colonies is described. Methods are shown that have successfully reduced or eliminated these instabilities. Finally, the implications of these new types of instabilities on superalloys in general are discussed.

The concentration of growth-transforming factor (GTF) β1 in blood serum was analysed in its dynamics in 103 patients with diaphyseal fractures of long bones depending upon the course of restorative osteogenesis, i.e. with the normal and delayed healing of the fracture. In order to exclude the factors, which could influence the restorative regeneration, the patients in both groups were distributed by their sex, age, type and localization of the fracture, technique of the osteosynthesis performed. Data were received about an early (4-6 weeks after the fracture) reduction in GTF β1 level in blood serum of the patients with a delayed consolidation. It was found out that GTF β1 was the main key molecule, which controlled the fracture healing, and could serve as a marker of a delayed consolidation.

Magnesium ferrite of composition Mg0.993Fe2.007O4 was quenched from 1000°, 1150°, and 1295°C. The rate of inversion at 450°C was followed by Curie temperature measurements in a thermo-gravimetric analyzer. The inversion process possessed the features of a nucleation and growth transformation. It is postulated that short range order within the octahedral sub-lattice plays an important role in cation ordering in Mg ferrite.

In the present paper, growth pattern and age composition of the sea bream, Chrysophrys major, are estimated by scale length and fork length of the fish. During the period from April 1958 to September 1959, 1010 specimens caught in Wakasa Bay were examined in the Nishi Maizuru Fish Market, Kyoto Prefecture. They were measured in the fork length, body depth, head length, body weight and on the scales. In this case the scales were collected from the mid part of the body, namely the 5th and 6th scales in the vertical line downwards from the 13-15th lateral line scales. Scale length and each annual ring size were measured along the line from the focus to the basilateral angles. The results obtained are the following. 1. The monthly change of growth rate of marginal region (α) on scale with 1-5 annual rings (under 5 years old) of the fish were examined so as to conjecture the month when the annual ring was formed. Succesive collections of the scales throughout the year have led the writer to believe that scale annual ring is formed in the spring, from March to May (Fig. 2). 2. Average actual annual ring sizes (rn, γn+1) of the scale are plotted against each age in accordance with Walford's growth transformation (Fig. 3). Each point is so well distributed on two lines that these meat at the 6th point. 3. Estimated annual ring size is given from the result of the Walford's growth transfor-mation (Table 1). Fig. 4 shows the relation between fork length (L in mm) and scale length (R in mm). The relation formula is as follows: L=34.2+16.5R+1.7R2. 4. In Table 1, estimated fork length at the time when each annual ring of scale was just formed is obtained by application of the estimated annual ring size of each age to the relation formula. Although results obtained present slightly lower rate, they agree in general with the average actual fork length on the whole, especially whithin the first dozen years or so. Compared with the sea bream of the Inland Sea of Japan, it seemed to me that the sea bream of Wakasa Bay has inferior growth rate about one year in early stage (from 1 to about 7 years old) and two or three years in older age.

Interpretation of walleye (Stizostedion vitreum vitreum) scales by three investigators revealed some differences in detail, but the data derived appeared to be basically reliable. Most fish were collected in experimental gill nets. Lengths at annuli were calculated using straight-line relationship with an intercept of 3.26 inches, total length. Growth rate of a year class, as indicated by mean length at the third annulus, was negatively correlated with abundance of the year class (r = −0.78, 11 d.f.). Walford's growth transformation did not give an entirely satisfactory fit but gave a maximum length of 31.1 inches and a k of 0.836. Variations in these values with different treatment of the data were indicated. Fitting a Walford transformation to increments gave: Lt+1 = 28.8 inches (0.172) + 0.828 Lt. The correlation coefficient, r, between the annual increment indexes and the mean May to September temperatures was 0.565. Adding April and October temperatures lowered the correlation. Instantaneous...

Herpesvirus saimiri (HVS), the rhadinovirus prototype, is apathogenic in the persistently infected natural host, the squirrel monkey, but causes acute T cell leukemia in other New World primate species. In contrast to subgroups A and B, only strains of HVS subgroup C such as C488 are capable of transforming primary human T cells to stable antigen-independent growth in culture. Here, we report the complete 155-kb genome sequence of the transformation-competent HVS strain C488. The A+T-rich unique L-DNA of 113,027 bp encodes at least 77 open reading frames and 5 URNAs. In addition to the viral oncogenes stp and tip, only a few genes including the transactivator orf50 and the glycoprotein orf51 are highly divergent. In a series of new primary HVS isolates, the subgroup-specific divergence of the orf50/orf51 alleles was studied. In these new isolates, the orf50/orf51 alleles of the respective subgroup segregate with the stp and/or tip oncogene alleles, which are essential for transformation.

Studies in vitro of oncogenic agents have attained an ever increasing importance mainly because of the precision and ease by which events at the cellular and sub-cellular level can be followed. This article will examine the relevance of such data for the understanding of a much more complicated process — the development of spontaneous malignant tumors in vivo. This seems particularly important in view of the enormous current interest in the possibility that human cancers may be caused by RNA viruses — a hypothesis largely resting on observations in vitro.