Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression

Lytic replication of the human gamma herpes virus Epstein-Barr virus (EBV) is an essential prerequisite for the spread of the virus. Differential regulation of a limited number of cellular genes has been reported in B-cells during the viral lytic replication cycle. We asked whether a viral bZIP transcription factor, Zta (BZLF1, ZEBRA, EB1), drives some of these changes. Using genome-wide chromatin immunoprecipitation coupled to next-generation DNA sequencing (ChIP-seq) we established a map of Zta interactions across the human genome. Using sensitive transcriptome analyses we identified 2263 cellular genes whose expression is significantly changed during the EBV lytic replication cycle. Zta binds 278 of the regulated genes and the distribution of binding sites shows that Zta binds mostly to sites that are distal to transcription start sites. This differs from the prevailing view that Zta activates viral genes by binding exclusively at promoter elements. We show that a synthetic Zta binding element confers Zta regulation at a distance and that distal Zta binding sites from cellular genes can confer Zta-mediated regulation on a heterologous promoter. This leads us to propose that Zta directly reprograms the expression of cellular genes through distal elements

The evidence for and against astronomical impacts on climate change and mass extinctions: A review

Numerous studies over the past 30 years have suggested there is a causal connection between the motion of the Sun through the Galaxy and terrestrial mass extinctions or climate change. Proposed mechanisms include comet impacts (via perturbation of the Oort cloud), cosmic rays and supernovae, the effects of which are modulated by the passage of the Sun through the Galactic midplane or spiral arms. Supposed periodicities in the fossil record, impact cratering dates or climate proxies over the Phanerozoic (past 545 Myr) are frequently cited as evidence in support of these hypotheses. This remains a controversial subject, with many refutations and replies having been published. Here I review both the mechanisms and the evidence for and against the relevance of astronomical phenomena to climate change and evolution. This necessarily includes a critical assessment of time series analysis techniques and hypothesis testing. Some of the studies have suffered from flaws in methodology, in particular drawing incorrect conclusions based on ruling out a null hypothesis. I conclude that there is little evidence for intrinsic periodicities in biodiversity, impact cratering or climate on timescales of tens to hundreds of Myr. Furthermore, Galactic midplane and spiral arm crossings seem to have little or no impact on biological or climate variation above background level. (truncated)Comment: 51 pages, 7 figures, 140 references. To appear in the International Journal of Astrobiology. For hyperref version with full resolution figures see http://www.mpia-hd.mpg.de/homes/calj/astimpact_ija.pd

Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc − Activity in the Medial Prefrontal Cortex

Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc −, a cystine–glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis. Objectives: Our goal was to determine whether increased system xc − activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating. Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc −, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3–3 mg/kg, sc). N-Acetylcysteine (10–100 μM) and the system xc − inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc − activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc − activity. Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10–100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc −. Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc − independent mechanisms, but that increasing cystine–glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine

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

Games for health for children - current status and needed research

Videogames for health (G4H) offer exciting, innovative, potentially highly effective methods for increasing knowledge, delivering persuasive messages, changing behaviors, and influencing health outcomes. Although early outcome results are promising, additional research is needed to determine the game design and behavior change procedures that best promote G4H effectiveness and to identify and minimize possible adverse effects. Guidelines for ideal use of different types of G4H by children and adolescents should be elucidated to enhance effectiveness and minimize adverse effects. G4H stakeholders include organizational implementers, policy makers, players and their families, researchers, designers, retailers, and publishers. All stakeholders should be involved in G4H development and have a voice in setting goals to capitalize on their insights to enhance effectiveness and use of the game. In the future, multiple targeted G4H should be available to meet a population's diverse health needs in developmentally appropriate ways. Substantial, consistent, and sophisticated research with appropriate levels of funding is needed to realize the benefits of G4H

Second-order L2L^2-regularity in nonlinear elliptic problems

A second-order regularity theory is developed for solutions to a class of quasilinear elliptic equations in divergence form, including the $p$-Laplace equation, with merely square-integrable right-hand side. Our results amount to the existence and square integrability of the weak derivatives of the nonlinear expression of the gradient under the divergence operator. This provides a nonlinear counterpart of the classical $L^2$-coercivity theory for linear problems, which is missing in the existing literature. Both local and global estimates are established. The latter apply to solutions to either Dirichlet or Neumann boundary value problems. Minimal regularity on the boundary of the domain is required. If the domain is convex, no regularity of its boundary is needed at all

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

Physical activity and risk of colon adenoma: A meta-analysis

BACKGROUND: Little evidence is available on the relation of physical activity with colon adenomas, a colon cancer precursor. METHODS: We conducted a systematic literature review and meta-analysis of published studies (in English) through April 2010, examining physical activity or exercise and risk or prevalence of colon adenoma or polyp. Random effects models were used to estimate relative risks (RRs) and corresponding confidence intervals (CIs). A total of 20 studies were identified that examined the association and provided RRs and corresponding 95% CIs. RESULTS: A significant inverse association between physical activity and colon adenomas was found with an overall RR of 0.84 (CI: 0.77–0.92). The association was similar in men (RR=0.81, CI: 0.67–0.98) and women (RR=0.87, CI: 0.74–1.02). The association appeared slightly stronger in large/advanced polyps (RR=0.70, CI: 0.56–0.88). CONCLUSION: This study confirms previous reports of a significant inverse association of physical activity and colon adenoma, and suggests that physical activity can have an important role in colon cancer prevention

Plantar pressure and foot temperature responses to acute barefoot and shod running

Purpose. Increased contact pressure and skin friction may lead to higher skin temperature. Here, we hypothesized a relationship between plantar pressure and foot temperature. To elicit different conditions of stress to the foot, participants performed running trials of barefoot and shod running. Methods. Eighteen male recreational runners ran shod and barefoot at a self-selected speed for 15 min over different days. Before and immediately after running, plantar pressure during standing (via a pressure mapping system) and skin temperature (using thermography) were recorded. Results. No significant changes were found in plantar pressure after barefoot or shod conditions (p > 0.9). Shod running elicited higher temperatures in the forefoot (by 0.5-2.2 ºC or 0.1-1.2% compared with the whole foot, p -0.5, p > 0.05). Conclusions. The increase in temperature after the shod condition was most likely the result of footwear insulation. However, variation of the temperature in the rearfoot was higher after barefoot running, possible due to a higher contact load. Changes in temperature could not predict changes in plantar pressure and vice-versa