RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus

Epstein-Barr virus (EBV) immortalizes resting B-cells and is a key etiologic agent in the development of numerous cancers. The essential EBV-encoded protein EBNA 2 activates the viral C promoter (Cp) producing a message of ~120 kb that is differentially spliced to encode all EBNAs required for immortalization. We have previously shown that EBNA 2-activated transcription is dependent on the activity of the RNA polymerase II (pol II) C-terminal domain (CTD) kinase pTEFb (CDK9/cyclin T1). We now demonstrate that Cp, in contrast to two shorter EBNA 2-activated viral genes (LMP 1 and 2A), displays high levels of promoter-proximally stalled pol II despite being constitutively active. Consistent with pol II stalling, we detect considerable pausing complex (NELF/DSIF) association with Cp. Significantly, we observe substantial Cp-specific pTEFb recruitment that stimulates high-level pol II CTD serine 2 phosphorylation at distal regions (up to +75 kb), promoting elongation. We reveal that Cp-specific pol II accumulation is directed by DNA sequences unfavourable for nucleosome assembly that increase TBP access and pol II recruitment. Stalled pol II then maintains Cp nucleosome depletion. Our data indicate that pTEFb is recruited to Cp by the bromodomain protein Brd4, with polymerase stalling facilitating stable association of pTEFb. The Brd4 inhibitor JQ1 and the pTEFb inhibitors DRB and Flavopiridol significantly reduce Cp, but not LMP1 transcript production indicating that Brd4 and pTEFb are required for Cp transcription. Taken together our data indicate that pol II stalling at Cp promotes transcription of essential immortalizing genes during EBV infection by (i) preventing promoter-proximal nucleosome assembly and ii) necessitating the recruitment of pTEFb thereby maintaining serine 2 CTD phosphorylation at distal regions

'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention

Evidence for the classical integrability of the complete AdS(4) x CP(3) superstring

We construct a zero-curvature Lax connection in a sub-sector of the superstring theory on AdS(4) x CP(3) which is not described by the OSp(6|4)/U(3) x SO(1,3) supercoset sigma-model. In this sub-sector worldsheet fermions associated to eight broken supersymmetries of the type IIA background are physical fields. As such, the prescription for the construction of the Lax connection based on the Z_4-automorphism of the isometry superalgebra OSp(6|4) does not do the job. So, to construct the Lax connection we have used an alternative method which nevertheless relies on the isometry of the target superspace and kappa-symmetry of the Green-Schwarz superstring.Comment: 1+26 pages; v2: minor typos corrected, acknowledgements adde

Astronomical Spectroscopy

Spectroscopy is one of the most important tools that an astronomer has for studying the universe. This chapter begins by discussing the basics, including the different types of optical spectrographs, with extension to the ultraviolet and the near-infrared. Emphasis is given to the fundamentals of how spectrographs are used, and the trade-offs involved in designing an observational experiment. It then covers observing and reduction techniques, noting that some of the standard practices of flat-fielding often actually degrade the quality of the data rather than improve it. Although the focus is on point sources, spatially resolved spectroscopy of extended sources is also briefly discussed. Discussion of differential extinction, the impact of crowding, multi-object techniques, optimal extractions, flat-fielding considerations, and determining radial velocities and velocity dispersions provide the spectroscopist with the fundamentals needed to obtain the best data. Finally the chapter combines the previous material by providing some examples of real-life observing experiences with several typical instruments.Comment: An abridged version of a chapter to appear in Planets, Stars and Stellar Systems, to be published in 2011 by Springer. Slightly revise

Fixed duration pursuit-evasion differential game with integral constraints

We investigate a pursuit-evasion differential game of countably many pursuers and one evader. Integral constraints are imposed on control functions of the players. Duration of the game is fixed and the payoff of the game is infimum of the distances between the evader and pursuers when the game is completed. Purpose of the pursuers is to minimize the payoff and that of the evader is to maximize it. Optimal strategies of the players are constructed, and the value of the game is found. It should be noted that energy resource of any pursuer may be less than that of the evader

The Pioneer Anomaly

Radio-metric Doppler tracking data received from the Pioneer 10 and 11 spacecraft from heliocentric distances of 20-70 AU has consistently indicated the presence of a small, anomalous, blue-shifted frequency drift uniformly changing with a rate of ~6 x 10^{-9} Hz/s. Ultimately, the drift was interpreted as a constant sunward deceleration of each particular spacecraft at the level of a_P = (8.74 +/- 1.33) x 10^{-10} m/s^2. This apparent violation of the Newton's gravitational inverse-square law has become known as the Pioneer anomaly; the nature of this anomaly remains unexplained. In this review, we summarize the current knowledge of the physical properties of the anomaly and the conditions that led to its detection and characterization. We review various mechanisms proposed to explain the anomaly and discuss the current state of efforts to determine its nature. A comprehensive new investigation of the anomalous behavior of the two Pioneers has begun recently. The new efforts rely on the much-extended set of radio-metric Doppler data for both spacecraft in conjunction with the newly available complete record of their telemetry files and a large archive of original project documentation. As the new study is yet to report its findings, this review provides the necessary background for the new results to appear in the near future. In particular, we provide a significant amount of information on the design, operations and behavior of the two Pioneers during their entire missions, including descriptions of various data formats and techniques used for their navigation and radio-science data analysis. As most of this information was recovered relatively recently, it was not used in the previous studies of the Pioneer anomaly, but it is critical for the new investigation.Comment: 165 pages, 40 figures, 16 tables; accepted for publication in Living Reviews in Relativit

EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice

Background We have previously shown that EphrinA1/EphA expression profile changes in response to myocardial infarction (MI), exogenous EphrinA1-Fc administration following MI positively influences wound healing, and that deletion of the EphA2 Receptor (EphA2-R) exacerbates injury and remodeling. To determine whether or not ephrinA1-Fc would be of therapeutic value in the hyperglycemic infarcted heart, it is critical to evaluate how ephrinA1/EphA signaling changes in the hyperglycemic myocardium in response to MI. Methods Streptozotocin (STZ)-induced hyperglycemia in wild type (WT) and EphA2-receptor mutant (EphA2-R-M) mice was initiated by an intraperitoneal injection of STZ (150 mg/kg) 10 days before surgery. MI was induced by permanent ligation of the left anterior descending coronary artery and analyses were performed at 4 days post-MI. ANOVAs with Student-Newman Keuls multiple comparison post-hoc analysis illustrated which groups were significantly different, with significance of at least p < 0.05. Results Both WT and EphA2-R-M mice responded adversely to STZ, but only hyperglycemic EphA2-R-M mice had lower ejection fraction (EF) and fractional shortening (FS). At 4 days post-MI, we observed greater post-MI mortality in EphA2-R-M mice compared with WT and this was greater still in the EphA2-R-M hyperglycemic mice. Although infarct size was greater in hyperglycemic WT mice vs normoglycemic mice, there was no difference between hyperglycemic EphA2-R-M mice and normoglycemic EphA2-R-M mice. The hypertrophic response that normally occurs in viable myocardium remote to the infarct was noticeably absent in epicardial cardiomyocytes and cardiac dysfunction worsened in hyperglycemic EphA2-R-M hearts post-MI. The characteristic interstitial fibrotic response in the compensating myocardium remote to the infarct also did not occur in hyperglycemic EphA2-R-M mouse hearts to the same extent as that observed in the hyperglycemic WT mouse hearts. Differences in neutrophil and pan-leukocyte infiltration and serum cytokines implicate EphA2-R in modulation of injury and the differences in ephrinA1 and EphA6-R expression in governing this are discussed. Conclusions We conclude that EphA2-mutant mice are more prone to hyperglycemia-induced increased injury, decreased survival, and worsened LV remodeling due to impaired wound healing

Is IRAS 01072+4954 a True-Seyfert 2? Hints from Near Infrared Integral Field Spectroscopy

In contrast to the predictions of the unified model, some X-ray unobscured Seyfert 2 galaxies have been discovered in the last decade. One of them, the starburst/Seyfert composite galaxy IRAS 01072+4954 (z=0.0236), has a typical Type~1 X-ray emission, while its optical spectrum resembles an HII galaxy and lacks the expected broad lines. We performed near-infrared integral-field observations of this object with the aim to determine the nature of its nuclear emission and to find indications for the existence or absence of a broad-line region. Several reasons have been proposed to explain such peculiar emission. We studied the validity of such hypotheses, including the possibility for it to be True-Seyfert~2. We found little obscuration towards the nucleus A_V = 2.5 mag, and a nuclear star-formation rate Sigma_SFR < 11.6 Msun yr^{-1} kpc^{-2}, which is below the average in Seyferts. Unresolved hot-dust emission with T ~ 1150 K seems to indicate the presence of a torus with its axis close to the line of sight. We found that IRAS 01072+4954 hosts a low mass black hole with an estimated mass of M_BH ~ 10^5 Msun and an upper limit of 2.5x10^6 Msun. Its bolometric luminosity is L_bol ~ 2.5x10^{42} erg/s, which yields a high accretion rate with an Eddington ratio ~ 0.2. If the relations found in more massive systems also apply to this case, then IRAS 01072+4954 should show broad emission lines with FWHM_{broad} ~(400-600) km/s. Indeed, some indications for such narrow broad-line components are seen in our data, but the evidence is not yet conclusive. This source thus seems not to be a True-Seyfert 2, but an extreme case of a narrow line Seyfert 1, which, due to the faintness of the active nucleus, does not have strong FeII emission in the optical.Comment: 16 pages, 11 figures. A&A Accepted versio

Постать Тараса Шевченка в рецепції Ліни Костенко

У статті розглядається поетика творення Ліною Костенко образу Кобзаря крізь призму власного "я", через пережиті відчуття поета-шістдесятника, що своєю проекцією нагадують душевні терзання великого поета.В статье рассмотрена поэтика создания Линой Костенко образа Тараса Шевченко сквозь призму собственного "я", через пережитые ощущения поэта-шестидесятника, своей проекцией напоминающие душевные терзания великого поэта.The article deals with the problem of the poetics creation by Lina Kostenko Taras Shevchenko’ image through a prism her own mind, through sensations of the poet-sixtier, by the projection reminding sincere torments the great poet is considered

Phase separation process preventing thermal embrittlement of a Zr-Cu-Fe-Al bulk metallic glass

The structural changes and mechanical properties of a Zr 63 Cu 22 Fe 5 Al 10 bulk metallic glass (BMG), and a Zr 63 Cu 27 Al 10 one made for comparison, were studied on annealing below the crystallization temperature. The phase composition of the samples was studied by conventional X-ray diffractometry and high-resolution transmission electron microscopy including the atomic-scale elemental mapping. The samples were mechanically tested in compression. The Zr 63 Cu 22 Fe 5 Al 10 bulk metallic glass shows a high strength and good deformability at room temperature both in the as-cast state and after prolonged structural relaxation below the crystallization temperature. The reasons for such behavior are discussed in the present work