Suppression of planar cell polarity signaling and migration in glioblastoma by Nrdp1-mediated Dvl polyubiquitination.

The lethality of the aggressive brain tumor glioblastoma multiforme (GBM) results in part from its strong propensity to invade surrounding normal brain tissue. Although oncogenic drivers such as epidermal growth factor receptor activation and Phosphatase and Tensin homolog inactivation are thought to promote the motility and invasiveness of GBM cells via phosphatidylinostitol 3-kinase activation, other unexplored mechanisms may also contribute to malignancy. Here we demonstrate that several components of the planar cell polarity (PCP) arm of non-canonical Wnt signaling including VANGL1, VANGL2 and FZD7 are transcriptionally upregulated in glioma and correlate with poorer patient outcome. Knockdown of the core PCP pathway component VANGL1 suppresses the motility of GBM cell lines, pointing to an important mechanistic role for this pathway in glioblastoma malignancy. We further observe that restoration of Nrdp1, a RING finger type E3 ubiquitin ligase whose suppression in GBM also correlates with poor prognosis, reduces GBM cell migration and invasiveness by suppressing PCP signaling. Our observations indicate that Nrdp1 physically interacts with the Vangl1 and Vangl2 proteins to mediate the K63-linked polyubiquitination of the Dishevelled, Egl-10 and Pleckstrin (DEP) domain of the Wnt pathway protein Dishevelled (Dvl). Ubiquitination hinders Dvl binding to phosphatidic acid, an interaction necessary for efficient Dvl recruitment to the plasma membrane upon Wnt stimulation of Fzd receptor and for the propagation of downstream signals. We conclude that the PCP pathway contributes significantly to the motility and hence the invasiveness of GBM cells, and that Nrdp1 acts as a negative regulator of PCP signaling by inhibiting Dvl through a novel polyubiquitination mechanism. We propose that the upregulation of core PCP components, together with the loss of the key negative regulator Nrdp1, act coordinately to promote GBM invasiveness and malignancy

Optimal strategies for a game on amenable semigroups

The semigroup game is a two-person zero-sum game defined on a semigroup S as follows: Players 1 and 2 choose elements x and y in S, respectively, and player 1 receives a payoff f(xy) defined by a function f from S to [-1,1]. If the semigroup is amenable in the sense of Day and von Neumann, one can extend the set of classical strategies, namely countably additive probability measures on S, to include some finitely additive measures in a natural way. This extended game has a value and the players have optimal strategies. This theorem extends previous results for the multiplication game on a compact group or on the positive integers with a specific payoff. We also prove that the procedure of extending the set of allowed strategies preserves classical solutions: if a semigroup game has a classical solution, this solution solves also the extended game.Comment: 17 pages. To appear in International Journal of Game Theor

Black Holes in Gravity with Conformal Anomaly and Logarithmic Term in Black Hole Entropy

We present a class of exact analytic and static, spherically symmetric black hole solutions in the semi-classical Einstein equations with Weyl anomaly. The solutions have two branches, one is asymptotically flat and the other asymptotically de Sitter. We study thermodynamic properties of the black hole solutions and find that there exists a logarithmic correction to the well-known Bekenstein-Hawking area entropy. The logarithmic term might come from non-local terms in the effective action of gravity theories. The appearance of the logarithmic term in the gravity side is quite important in the sense that with this term one is able to compare black hole entropy up to the subleading order, in the gravity side and in the microscopic statistical interpretation side.Comment: Revtex, 10 pages. v2: minor changes and to appear in JHE

Seroprevalence and factors associated with herpes simplex virus type 2 among HIV-negative high-risk men who have sex with men from Rio de Janeiro, Brazil: a cross-sectional study

Submitted by Frederico Azevedo ([email protected]) on 2010-11-04T17:19:23Z No. of bitstreams: 1 seroprevalence_and_factors.pdf: 273577 bytes, checksum: 742e51b14ff9ef765bf31b52f3fc8f1a (MD5)Made available in DSpace on 2010-11-04T17:19:23Z (GMT). No. of bitstreams: 1 seroprevalence_and_factors.pdf: 273577 bytes, checksum: 742e51b14ff9ef765bf31b52f3fc8f1a (MD5) Previous issue date: 2009Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Comunicação e Informação Científica e Tecnológica em Saúde. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Background: Herpes simplex virus type 2 (HSV-2) is the leading cause of genital ulcer disease in developing countries, including Brazil, and is especially prevalent among men who have sex with men (MSM). HSV-2 infection represents a risk factor for the acquisition and transmission of other sexually transmitted diseases. The goal of the present cross-sectional study was to estimate HSV- 2 seroprevalence and to determine the factors associated with HSV-2 seropositivity in HIVnegative high-risk MSM from Rio de Janeiro, Brazil. Methods: Stored sera were tested to estimate HSV-2 seroprevalence, while socio-demographic and sexual behavior data were used to measure associations between risk factors and HSV-2 seropositivity. Using the Poisson regression model with robust variance, prevalence ratios (PR) were used to estimate de degree of association between risk factors and HSV-2 seropositivity in bivariate and multivariate analyses. Results: Seroprevalence of HSV-2 was of 45.7% (184 out of 403). Factors independently associated with HSV-2 seroprevalence in the multivariate model were: older age (≥ 26 years, PR: 1.41 95% Confidence Interval: 1.11–1.78), non-white race (PR: 1.32 95%CI: 1.06–1.64), positive serology for syphilis (PR: 1.65 95%CI: 1.33–2.05), positive serology for hepatitis B (PR: 1.25 95%CI: 0.99–1.57), stable male partner in the past 6 months (PR: 1.42 95%CI: 1.12–1.79), and unprotected anal sex with a stable female partner (PR: 1.46 95%CI: 1.05–2.04) in the 6 months preceding the crosssectional assessment. Conclusion: The present study made evident a high prevalence of HSV-2 infection in a sample of HIV-negative high-risk MSM from Rio de Janeiro. This finding indicates the need and urgency for implementing integrated programs for the prevention of HSV-2 and other sexually transmitted diseases, and, in particular, programs targeting high-risk MSM

The Entropy for General Extremal Black Holes

We use the Kerr/CFT correspondence to calculate the entropy for all known extremal stationary and axisymmetric black holes. This is done with the help of two ansatzs that are general enough to cover all such known solutions. Considering only the contribution from the Einstein-Hilbert action to the central charge(s), we find that the entropy obtained by using Cardy's formula exactly matches with the Bekenstein-Hawking entropy.Comment: Minor corrections, section 5 refined, references added

Quantum corrections to Schwarzschild black hole

Using effective field theory techniques, we compute quantum corrections to spherically symmetric solutions of Einstein’s gravity and focus in particular on the Schwarzschild black hole. Quantum modifications are covariantly encoded in a non-local effective action. We work to quadratic order in curvatures simultaneously taking local and non-local corrections into account. Looking for solutions perturbatively close to that of classical general relativity, we find that an eternal Schwarzschild black hole remains a solution and receives no quantum corrections up to this order in the curvature expansion. In contrast, the field of a massive star receives corrections which are fully determined by the effective field theory

Trace anomalies in chiral theories revisited

Motivated by the search for possible CP violating terms in the trace of the energy-momentum tensor in theories coupled to gravity we revisit the problem of trace anomalies in chiral theories. We recalculate the latter and ascertain that in the trace of the energy-momentum tensor of theories with chiral fermions at one-loop the Pontryagin density appears with an imaginary coefficient. We argue that this may break unitarity, in which case the trace anomaly has to be used as a selective criterion for theories, analogous to the chiral anomalies in gauge theories. We analyze some remarkable consequences of this fact, that seem to have been overlooked in the literature

The High-Risk Plaque Initiative: Primary Prevention of Atherothrombotic Events in the Asymptomatic Population

The High-Risk Plaque (HRP) Initiative is a research and development effort to advance the understanding, recognition, and management of asymptomatic individuals at risk for a near-term atherothrombotic event such as myocardial infarction or stroke. Clinical studies using the newest technologies have been initiated, including the BioImage Study in which novel approaches are tested in a typical health plan population. Asymptomatic at-risk individuals were enrolled, including a survey-only group (n = 865), a group undergoing traditional risk factor scoring (n = 718), and a group in which all were assessed for both risk factors and subclinical atherosclerosis (n = 6104). The latter two groups underwent baseline examination in a dedicated mobile facility equipped with advanced imaging tools suitable for noninvasive screening for subclinical atherosclerosis (coronary artery calcium by computed tomography [CT], carotid and aortic disease by ultrasound, and ankle-brachial index). Selected participants were offered advanced imaging (contrast-enhanced CT, magnetic resonance imaging, and positron emission tomography/CT). Plasma, PAXgene RNA, and DNA samples were obtained for biomarker discovery studies. All individuals will be followed until 600 major atherothrombotic events have occurred in those undergoing imaging

Gender-related differences of renal mass supply and metabolic demand after living donor kidney transplantation

Kidney donation from female donors to male recipients has been reported to be associated with decreased allograft survival. Whether there was a gender-related inadequacy between donor nephron supply and recipient functional demand was investigated in this study. One hundred ninety-five living donor kidney transplant recipients that had neither ischemic injury, episode of rejection, nor any complication were included. Weights and heights of both donors and recipients were recorded to calculate body surface area, lean body weight, and body mass index. The donated kidney was weighed just after cold flush, and the recipient's serum creatinine (Scr) was measured on a daily basis post-operatively. When the recipient's Scr reached the baseline, a 24-h urine was collected for the amount of proteinuria (Upr), creatinine excretion (Ucr) and creatinine clearance (Ccr) calculation. The effect of donor and recipient gender was analysed by independent sample t -test. On average, male donors and recipients were heavier and taller than females. However, the mass of kidneys donated from men and women were not statistically different. The gender-related differences in post-transplant Scr and Ucr of recipients were associated with the differences in the parameters of metabolic demands of recipients rather than with the weight of implanted kidney (renal mass supply) or with pre-operative renal functions of donors (functional supply). The early graft function is not determined by donor gender. The effect of recipient gender on the graft function depends on the metabolic demands, which are higher in male recipients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73185/1/j.1399-0012.2005.00459.x.pd