The EBV-encoded latent membrane proteins, LMP2A and LMP2B, limit the actions of interferon by targeting interferon receptors for degradation

Although frequently expressed in Epstein–Barr virus (EBV)-positive malignancies, the role that latent membrane protein 2A and 2B (LMP2A and LMP2B) have in the oncogenic process remains obscure. Here we show a novel function for these proteins in epithelial cells, namely, their ability to modulate signalling from type I/II interferon receptors (IFNRs). We show that LMP2A- and LMP2B-expressing epithelial cells show decreased responsiveness to interferon (IFN)α and IFNγ, as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated binding to IFN-stimulated response element and IFNγ-activated factor sequence elements and luciferase reporter activation. Transcriptional profiling highlighted the extent of this modulation, with both viral proteins impacting ‘globally’ on IFN-stimulated gene expression. Although not affecting the levels of cell-surface IFNRs, LMP2A and LMP2B accelerated the turnover of IFNRs through processes requiring endosome acidification. This function may form part of EBV's strategy to limit anti-viral responses and define a novel function for LMP2A and LMP2B in modulating signalling from receptors that participate in innate immune responses

The EBV-encoded oncoprotein, LMP1, induces an epithelial-to-mesenchymal transition (EMT) via Its CTAR1 domain through integrin-mediated ERK-MAPK signalling

The Epstein⁻Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) oncogene can induce profound effects on epithelial growth and differentiation including many of the features of the epithelial-to-mesenchymal transition (EMT). To better characterise these effects, we used the well-defined Madin Darby Canine Kidney (MDCK) epithelial cell model and found that LMP1 expression in these cells induces EMT as defined by characteristic morphological changes accompanied by loss of E-cadherin, desmosomal cadherin and tight junction protein expression. The induction of the EMT phenotype required a functional CTAR1 domain of LMP1 and studies using pharmacological inhibitors revealed contributions from signalling pathways commonly induced by integrin⁻ligand interactions: extracellular signal-regulated kinases/mitogen-activated protein kinases (ERK-MAPK), PI3-Kinase and tyrosine kinases, but not transforming growth factor beta (TGFβ). More detailed analysis implicated the CTAR1-mediated induction of Slug and Twist in LMP1-induced EMT. A key role for β1 integrin signalling in LMP1-mediated ERK-MAPK and focal adhesion kianse (FAK) phosphorylation was observed, and β1 integrin activation was found to enhance LMP1-induced cell viability and survival. These findings support an important role for LMP1 in disease pathogenesis through transcriptional reprogramming that enhances tumour cell survival and leads to a more invasive, metastatic phenotype

Viscosity in the escape-rate formalism

We apply the escape-rate formalism to compute the shear viscosity in terms of the chaotic properties of the underlying microscopic dynamics. A first passage problem is set up for the escape of the Helfand moment associated with viscosity out of an interval delimited by absorbing boundaries. At the microscopic level of description, the absorbing boundaries generate a fractal repeller. The fractal dimensions of this repeller are directly related to the shear viscosity and the Lyapunov exponent, which allows us to compute its values. We apply this method to the Bunimovich-Spohn minimal model of viscosity which is composed of two hard disks in elastic collision on a torus. These values are in excellent agreement with the values obtained by other methods such as the Green-Kubo and Einstein-Helfand formulas.Comment: 16 pages, 16 figures (accepted in Phys. Rev. E; October 2003

Gallavotti-Cohen theorem, Chaotic Hypothesis and the zero-noise limit

The Fluctuation Relation for a stationary state, kept at constant energy by a deterministic thermostat - the Gallavotti-Cohen Theorem -- relies on the ergodic properties of the system considered. We show that when perturbed by an energy-conserving random noise, the relation follows trivially for any system at finite noise amplitude. The time needed to achieve stationarity may stay finite as the noise tends to zero, or it may diverge. In the former case the Gallavotti-Cohen result is recovered, while in the latter case, the crossover time may be computed from the action of `instanton' orbits that bridge attractors and repellors. We suggest that the `Chaotic Hypothesis' of Gallavotti can thus be reformulated as a matter of stochastic stability of the measure in trajectory space. In this form this hypothesis may be directly tested

Numerical convergence of the block-maxima approach to the Generalized Extreme Value distribution

In this paper we perform an analytical and numerical study of Extreme Value distributions in discrete dynamical systems. In this setting, recent works have shown how to get a statistics of extremes in agreement with the classical Extreme Value Theory. We pursue these investigations by giving analytical expressions of Extreme Value distribution parameters for maps that have an absolutely continuous invariant measure. We compare these analytical results with numerical experiments in which we study the convergence to limiting distributions using the so called block-maxima approach, pointing out in which cases we obtain robust estimation of parameters. In regular maps for which mixing properties do not hold, we show that the fitting procedure to the classical Extreme Value Distribution fails, as expected. However, we obtain an empirical distribution that can be explained starting from a different observable function for which Nicolis et al. [2006] have found analytical results.Comment: 34 pages, 7 figures; Journal of Statistical Physics 201

Prevention of childhood poisoning in the home: overview of systematic reviews and a systematic review of primary studies

Unintentional poisoning is a significant child public health problem. This systematic overview of reviews, supplemented with a systematic review of recently published primary studies synthesizes evidence on non-legislative interventions to reduce childhood poisonings in the home with particular reference to interventions that could be implemented by Children's Centres in England or community health or social care services in other high income countries. Thirteen systematic reviews, two meta-analyses and 47 primary studies were identified. The interventions most commonly comprised education, provision of cupboard/drawer locks, and poison control centre (PCC) number stickers. Meta-analyses and primary studies provided evidence that interventions improved poison prevention practices. Twenty eight per cent of studies reporting safe medicine storage (OR from meta-analysis 1.57, 95% CI 1.22–2.02), 23% reporting safe storage of other products (OR from meta-analysis 1.63, 95% CI 1.22–2.17) and 46% reporting availability of PCC numbers (OR from meta-analysis 3.67, 95% CI 1.84–7.33) demonstrated significant effects favouring the intervention group. There was a lack of evidence that interventions reduced poisoning rates. Parents should be provided with poison prevention education, cupboard/drawer locks and emergency contact numbers to use in the event of a poisoning. Further research is required to determine whether improving poison prevention practices reduces poisoning rates

Cumulative Disaster Exposure and Mental and Physical Health Symptoms Among a Large Sample of Gulf Coast Residents

A large body of research has linked disaster exposure to adverse mental and physical health outcomes. Few studies, however, have explored the cumulative impact of exposure to multiple disasters. Participants (N = 8,366) from the National Institute of Environmental Health Sciences Gulf Long-Term Follow-Up Study were classified as having been exposed to both, either, or neither Hurricane Katrina and the Deepwater Horizon oil spill (DHOS). Participants also reported on a range of mental and physical health symptoms. Logistic regression models found that participants who were exposed to both disasters had significantly higher odds of probable generalized anxiety disorder, odds ratio (OR) = 1.72, 95% CI [1.52, 1.96]; major depression, OR = 1.53, 95% CI [1.32, 1.77]; and posttraumatic stress disorder, OR = 2.51, 95% CI [2.03, 3.10], than participants who were exposed to only one disaster, ps <.001. Additionally, a linear regression model found that participants who were exposed to both disasters had significantly more physical health symptoms at the time of the spill than those who were exposed to only one disaster, B = 0.99, SE =.20, p <.001. The results indicate that cumulative disaster exposure confers enhanced risk for adverse mental and physical health outcomes. The findings demonstrate that screening for prior exposure among disaster-affected individuals might identify those at greatest risk for adverse health outcomes

Data-driven models of dominantly-inherited Alzheimer’s disease progression

Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease-progression modelling to characterise dominantly-inherited Alzheimer’s disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset (EYO). We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers: 163 PSEN1; 17 PSEN2; and 31 APP) and a baseline visit (age 19–66; up to four visits each, 1·1±1·9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential-equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then sub-cortical regions (approximately 24±11 years before onset); CSF p-tau (17±8 years), tau and Aβ42 changes; neurodegeneration first in the putamen and nucleus accumbens (up to 6±2 years); then cognitive decline (7±6 years), cerebral hypometabolism (4±4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than EYO: root-mean-squared error of 1·35 years versus 5·54 years. The models reveal hidden detail on dominantly-inherited Alzheimer's disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials

Epigenome-wide SRC-1 mediated gene silencing represses cellular differentiation in advanced breast cancer

Abstract Purpose: Despite the clinical utility of endocrine therapies for estrogen receptor–positive (ER) breast cancer, up to 40% of patients eventually develop resistance, leading to disease progression. The molecular determinants that drive this adaptation to treatment remain poorly understood. Methylome aberrations drive cancer growth yet the functional role and mechanism of these epimutations in drug resistance are poorly elucidated. Experimental Design: Genome-wide multi-omics sequencing approach identified a differentially methylated hub of prodifferentiation genes in endocrine resistant breast cancer patients and cell models. Clinical relevance of the functionally validated methyl-targets was assessed in a cohort of endocrine-treated human breast cancers and patient-derived ex vivo metastatic tumors. Results: Enhanced global hypermethylation was observed in endocrine treatment resistant cells and patient metastasis relative to sensitive parent cells and matched primary breast tumor, respectively. Using paired methylation and transcriptional profiles, we found that SRC-1–dependent alterations in endocrine resistance lead to aberrant hypermethylation that resulted in reduced expression of a set of differentiation genes. Analysis of ER-positive endocrine-treated human breast tumors (n = 669) demonstrated that low expression of this prodifferentiation gene set significantly associated with poor clinical outcome (P = 0.00009). We demonstrate that the reactivation of these genes in vitro and ex vivo reverses the aggressive phenotype. Conclusions: Our work demonstrates that SRC-1-dependent epigenetic remodeling is a ’high level’ regulator of the poorly differentiated state in ER-positive breast cancer. Collectively these data revealed an epigenetic reprograming pathway, whereby concerted differential DNA methylation is potentiated by SRC-1 in the endocrine resistant setting. Clin Cancer Res; 24(15); 3692–703. ©2018 AACR.</jats:p

Superconductors with Magnetic Impurities: Instantons and Sub-gap States

When subject to a weak magnetic impurity potential, the order parameter and quasi-particle energy gap of a bulk singlet superconductor are suppressed. According to the conventional mean-field theory of Abrikosov and Gor'kov, the integrity of the energy gap is maintained up to a critical concentration of magnetic impurities. In this paper, a field theoretic approach is developed to critically analyze the validity of the mean field theory. Using the supersymmetry technique we find a spatially homogeneous saddle-point that reproduces the Abrikosov-Gor'kov theory, and identify instanton contributions to the density of states that render the quasi-particle energy gap soft at any non-zero magnetic impurity concentration. The sub-gap states are associated with supersymmetry broken field configurations of the action. An analysis of fluctuations around these configurations shows how the underlying supersymmetry of the action is restored by zero modes. An estimate of the density of states is given for all dimensionalities. To illustrate the universality of the present scheme we apply the same method to study `gap fluctuations' in a normal quantum dot coupled to a superconducting terminal. Using the same instanton approach, we recover the universal result recently proposed by Vavilov et al. Finally, we emphasize the universality of the present scheme for the description of gap fluctuations in d-dimensional superconducting/normal structures.Comment: 18 pages, 9 eps figure