Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis ( 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells

Application of the Higher-Order Hamilton Approach to the Nonlinear Free Vibrations Analysis of Porous FG Nano-Beams in a Hygrothermal Environment Based on a Local/Nonlocal Stress Gradient Model of Elasticity

Nonlinear transverse free vibrations of porous functionally-graded (FG) Bernoulli–Euler nanobeams in hygrothermal environments through the local/nonlocal stress gradient theory of elasticity were studied. By using the Galerkin method, the governing equations were reduced to a nonlinear ordinary differential equation. The closed form analytical solution of the nonlinear natural flexural frequency was then established using the higher-order Hamiltonian approach to nonlinear oscillators. A numerical investigation was developed to analyze the influence of different parameters both on the thermo-elastic material properties and the structural response, such as material gradient index, porosity volume fraction, nonlocal parameter, gradient length parameter, mixture parameter, and the amplitude of the nonlinear oscillator on the nonlinear flexural vibrations of metal–ceramic FG porous Bernoulli–Euler nano-beams

In vitro cultured progenitors and precursors of cardiac cell lineages from human normal and post-ischemic hearts.

The demonstration of the presence of dividing primitive cells in damaged hearts has sparked increased interest about myocardium regenerative processes. We examined the rate and the differentiation of in vitro cultured resident cardiac primitive cells obtained from pathological and normal human hearts in order to evaluate the activation of progenitors and precursors of cardiac cell lineages in post-ischemic human hearts. The precursors and progenitors of cardiomyocyte, smooth muscle and endothelial lineage were identified by immunocytochemistry and the expression of characteristic markers was studied by western blot and RT-PCR.The amount of proteins characteristic for cardiac cells (alpha-SA and MHC, VEGFR-2 and FVIII, SMA for the precursors of cardiomyocytes, endothelial and smooth muscle cells, respectively) inclines toward an increase in both alpha-SA and MHC. The increased levels of FVIII and VEGFR2 are statistically significant, suggesting an important re-activation of neoangiogenesis. At the same time, the augmented expression of mRNA for Nkx 2.5, the trascriptional factor for cardiomyocyte differentiation, confirms the persistence of differentiative processes in terminally injured hearts. Our study would appear to confirm the activation of human heart regeneration potential in pathological conditions and the ability of its primitive cells to maintain their proliferative capability in vitro. The cardiac cell isolation method we used could be useful in the future for studying modifications to the microenvironment that positively influence cardiac primitive cell differentiation or inhibit, or retard, the pathological remodeling and functional degradation of the heart

Language Emptiness of Continuous-Time Parametric Timed Automata

Parametric timed automata extend the standard timed automata with the possibility to use parameters in the clock guards. In general, if the parameters are real-valued, the problem of language emptiness of such automata is undecidable even for various restricted subclasses. We thus focus on the case where parameters are assumed to be integer-valued, while the time still remains continuous. On the one hand, we show that the problem remains undecidable for parametric timed automata with three clocks and one parameter. On the other hand, for the case with arbitrary many clocks where only one of these clocks is compared with (an arbitrary number of) parameters, we show that the parametric language emptiness is decidable. The undecidability result tightens the bounds of a previous result which assumed six parameters, while the decidability result extends the existing approaches that deal with discrete-time semantics only. To the best of our knowledge, this is the first positive result in the case of continuous-time and unbounded integer parameters, except for the rather simple case of single-clock automata

An excess power statistic for detection of burst sources of gravitational radiation

We examine the properties of an excess power method to detect gravitational waves in interferometric detector data. This method is designed to detect short-duration (< 0.5 s) burst signals of unknown waveform, such as those from supernovae or black hole mergers. If only the bursts' duration and frequency band are known, the method is an optimal detection strategy in both Bayesian and frequentist senses. It consists of summing the data power over the known time interval and frequency band of the burst. If the detector noise is stationary and Gaussian, this sum is distributed as a chi-squared (non-central chi-squared) deviate in the absence (presence) of a signal. One can use these distributions to compute frequentist detection thresholds for the measured power. We derive the method from Bayesian analyses and show how to compute Bayesian thresholds. More generically, when only upper and/or lower bounds on the bursts duration and frequency band are known, one must search for excess power in all concordant durations and bands. Two search schemes are presented and their computational efficiencies are compared. We find that given reasonable constraints on the effective duration and bandwidth of signals, the excess power search can be performed on a single workstation. Furthermore, the method can be almost as efficient as matched filtering when a large template bank is required. Finally, we derive generalizations of the method to a network of several interferometers under the assumption of Gaussian noise.Comment: 22 pages, 6 figure

Best network chirplet-chain: Near-optimal coherent detection of unmodeled gravitation wave chirps with a network of detectors

The searches of impulsive gravitational waves (GW) in the data of the ground-based interferometers focus essentially on two types of waveforms: short unmodeled bursts and chirps from inspiralling compact binaries. There is room for other types of searches based on different models. Our objective is to fill this gap. More specifically, we are interested in GW chirps with an arbitrary phase/frequency vs. time evolution. These unmodeled GW chirps may be considered as the generic signature of orbiting/spinning sources. We expect quasi-periodic nature of the waveform to be preserved independent of the physics which governs the source motion. Several methods have been introduced to address the detection of unmodeled chirps using the data of a single detector. Those include the best chirplet chain (BCC) algorithm introduced by the authors. In the next years, several detectors will be in operation. The joint coherent analysis of GW by multiple detectors can improve the sight horizon, the estimation of the source location and the wave polarization angles. Here, we extend the BCC search to the multiple detector case. The method amounts to searching for salient paths in the combined time-frequency representation of two synthetic streams. The latter are time-series which combine the data from each detector linearly in such a way that all the GW signatures received are added constructively. We give a proof of principle for the full sky blind search in a simplified situation which shows that the joint estimation of the source sky location and chirp frequency is possible.Comment: 22 pages, revtex4, 6 figure

Chemistry and antigerminative activity of essential oils and monoterpenoids from Mediterranean plants

The Mediterranean flora is characterized by the abundance of aromatic plants. The feature differentiating these plants from all others, in spite of the fact that they belong to many different families, is the production of chemically related secondary compounds, the low molecular weight and volatile isoprenoids. This remarkable presence of aromatic species is important in determining the allelopathic potential within this ecosystem. Such plants make a significant contribution to phryganic Mediterranean ecosystems both in terms of species number and biomass. Thus, the essential oils play an important role in this ecological context. Mediating various processes in the frame of an ecosystem, they become indirectly beneficial to the plants, considering their involvement in processes of adaptative character in Mediterranean ecosystem . For this reason, our research group carried out a series of studies on the possible allelopathic properties of aromatic plants that, being rich in active principles, are considered a primary source of potential allelochemicals.The focus of this overview is direct to have an overall idea about the chemistry and antigerminative activity of essential oils of some Mediterranean aromatic plants and their main constituent

The course and correlates of everyday functioning in schizophrenia

AbstractPreviously institutionalized older patients with schizophrenia show changes in cognitive and functional capacity over time. This study examined changes in real-world functioning in a sample of people with schizophrenia who varied in their history of long-term institutionalization and related changes in real world functioning to changes in cognition and functional capacity over the follow-up period.Older patients with schizophrenia (n=111) were examined with assessments of cognitive functioning, functional capacity, clinical symptoms, and everyday functioning. They were then followed up to 45 months and examined up to two times. Mixed-model regression was used to examine changes in real-world functioning in social, everyday living, and vocational domains over the follow-up period and identify potential predictors of change.Everyday functioning worsened over time in all three domains. Although length of longest hospitalization predicted worsening, this influence was eliminated when the course of functional capacity was used to predict the course of everyday functioning. For both vocational and everyday living domains, as well as the composite score on functional status, worsening in performance based measures of everyday functioning and social competence predicted worsening in real world functioning. Changes in negative symptoms further predicted worsening in the everyday living domain.Worsening in everyday functioning is found in people with schizophrenia and those with a history of greater chronicity and severity of illness seem more affected. These influences seem to be expressed through worsening in the ability to perform everyday functional skills. Potential causes of these changes and implications for reducing these impairments are discussed