Combinative effects of β-Lapachone and APO866 on pancreatic cancer cell death through reactive oxygen species production and PARP-1 activation.

UNLABELLED: Pancreatic cancer (PC) is one of the most lethal human malignancies and a major health problem. Patients diagnosed with PC and treated with conventional approaches have an overall 5-year survival rate of less than 5%. Novel strategies are needed to treat this disease. Herein, we propose a combinatorial strategy that targets two unrelated metabolic enzymes overexpressed in PC cells: NAD(P)H: quinone oxidoreductase-1 (NQO1) and nicotinamide phosphoribosyl transferase (NAMPT) using β-lapachone (BL) and APO866, respectively. We show that BL tremendously enhances the antitumor activity of APO866 on various PC cell lines without affecting normal cells, in a PARP-1 dependent manner. The chemopotentiation of APO866 with BL was characterized by the following: (i) nicotinamide adenine dinucleotide (NAD) depletion; (ii) catalase (CAT) degradation; (iii) excessive H2O2 production; (iv) dramatic drop of mitochondrial membrane potential (MMP); and finally (v) autophagic-associated cell death. H2O2 production, loss of MMP and cell death (but not NAD depletion) were abrogated by exogenous supplementation with CAT or pharmacological or genetic inhibition of PARP-1. Our data demonstrates that the combination of a non-lethal dose of BL and low dose of APO866 optimizes significantly cell death on various PC lines over both compounds given separately and open new and promising combination in PC therapy.

Classical line shapes based on analytical solutions of bimolecular trajectories in collision induced emission. II. Reactive collisions

The classical theory of collision induced emission (CIE) from pairs of dissimilar rare gas atoms was developed in Paper I [D. Reguera and G. Birnbaum, J. Chem. Phys. 125, 184304 (2006)] from a knowledge of the straight line collision trajectory and the assumption that the magnitude of the dipole could be represented by an exponential function of the inter-nuclear distance. This theory is extended here to deal with other functional forms of the induced dipole as revealed by ab initio calculations. Accurate analytical expression for the CIE can be obtained by least square fitting of the ab initio values of the dipole as a function of inter-atomic separation using a sum of exponentials and then proceeding as in Paper I. However, we also show how the multi-exponential fit can be replaced by a simpler fit using only two analytic functions. Our analysis is applied to the polar molecules HF and HBr. Unlike the rare gas atoms considered previously, these atomic pairs form stable bound diatomic molecules. We show that, interestingly, the spectra of these reactive molecules are characterized by the presence of multiple peaks. We also discuss the CIE arising from half collisions in excited electronic states, which in principle could be probed in photo-dissociation experiments.

Probabilistic age classification with Bayesian networks: a study on the ossification status of the medial clavicular epiphysis

In the past few decades, the rise of criminal, civil and asylum cases involving young people lacking valid identification documents has generated an increase in the demand of age estimation. The chronological age or the probability that an individual is older or younger than a given age threshold are generally estimated by means of some statistical methods based on observations performed on specific physical attributes. Among these statistical methods, those developed in the Bayesian framework allow users to provide coherent and transparent assignments which fulfill forensic and medico-legal purposes. The application of the Bayesian approach is facilitated by using probabilistic graphical tools, such as Bayesian networks. The aim of this work is to test the performances of the Bayesian network for age estimation recently presented in scientific literature in classifying individuals as older or younger than 18 years of age. For these exploratory analyses, a sample related to the ossification status of the medial clavicular epiphysis available in scientific literature was used. Results obtained in the classification are promising: in the criminal context, the Bayesian network achieved, on the average, a rate of correct classifications of approximatively 97%, whilst in the civil context, the rate is, on the average, close to the 88%. These results encourage the continuation of the development and the testing of the method in order to support its practical application in casework.

Reactive Recruitment of Attentional Control in Math Anxiety: An ERP Study of Numeric Conflict Monitoring and Adaptation

This study uses event-related brain potentials (ERPs) to investigate the electrophysiological correlates of numeric conflict monitoring in math-anxious individuals, by analyzing whether math anxiety is related to abnormal processing in early conflict detection (as shown by the N450 component) and/or in a later, response-related stage of processing (as shown by the conflict sustained potential; Conflict-SP). Conflict adaptation effects were also studied by analyzing the effect of the previous trial"s congruence in current interference. To this end, 17 low math-anxious (LMA)and 17 high math-anxious (HMA) individuals were presented with a numerical Stroop task. Groups were extreme in math anxiety but did not differ in trait or state anxiety or in simple math ability. The interference effect of the current trial (incongruent-congruent) and the interference effect preceded by congruence and by incongruity were analyzed both for behavioral measures and for ERPs. A greater interference effect was found for response times in the HMA group than in the LMA one. Regarding ERPs, the LMA group showed a greater N450 component for the interference effect preceded by congruence than when preceded by incongruity, while the HMA group showed greater Conflict-SP amplitude for the interference effect preceded by congruence than when preceded by incongruity. Our study showed that the electrophysiological correlates of numeric interference in HMA individuals comprise the absence of a conflict adaptation effect in the first stage of conflict processing (N450) and an abnormal subsequent up-regulation of cognitive control in order to overcome the conflict (Conflict-SP). More concretely, our study shows that math anxiety is related to a reactive and compensatory recruitment of control resources that is implemented only when previously exposed to a stimuli presenting conflicting information

Transition mutation in codon 248 of the p53 tumor suppressor gene induced by reactive oxygen species and a nitric oxide-releasing compound.

Exposing the human bronchial epithelial cell line BEAS-2B to the nitric oxide (NO) donor sodium 1-(N,N-diethylamino)diazen-1-ium-1, 2-diolate (DEA/NO) at an initial concentration of 0.6 mM while generating superoxide ion at the rate of 1 microM/min with the hypoxanthine/xanthine oxidase (HX/XO) system induced C:G-->T:A transition mutations in codon 248 of the p53 gene. This pattern of mutagenicity was not seen by 'fish-restriction fragment length polymorphism/polymerase chain reaction' (fish-RFLP/PCR) on exposure to DEA/NO alone, however, exposure to HX/XO led to various mutations, suggesting that co-generation of NO and superoxide was responsible for inducing the observed point mutation. DEA/NO potentiated the ability of HX/XO to induce lipid peroxidation as well as DNA single- and double-strand breaks under these conditions, while 0.6 mM DEA/NO in the absence of HX/XO had no significant effect on these parameters. The results show that a point mutation seen at high frequency in certain common human tumors can be induced by simultaneous exposure to reactive oxygen species and a NO source.

Probabilistic graphical models to deal with age estimation of living persons

Due to the rise of criminal, civil and administrative judicial situations involving people lacking valid identity documents, age estimation of living persons has become an important operational procedure for numerous forensic and medicolegal services worldwide. The chronological age of a given person is generally estimated from the observed degree of maturity of some selected physical attributes by means of statistical methods. However, their application in the forensic framework suffers from some conceptual and practical drawbacks, as recently claimed in the specialised literature. The aim of this paper is therefore to offer an alternative solution for overcoming these limits, by reiterating the utility of a probabilistic Bayesian approach for age estimation. This approach allows one to deal in a transparent way with the uncertainty surrounding the age estimation process and to produce all the relevant information in the form of posterior probability distribution about the chronological age of the person under investigation. Furthermore, this probability distribution can also be used for evaluating in a coherent way the possibility that the examined individual is younger or older than a given legal age threshold having a particular legal interest. The main novelty introduced by this work is the development of a probabilistic graphical model, i.e. a Bayesian network, for dealing with the problem at hand. The use of this kind of probabilistic tool can significantly facilitate the application of the proposed methodology: examples are presented based on data related to the ossification status of the medial clavicular epiphysis. The reliability and the advantages of this probabilistic tool are presented and discussed.

Pose-based SLAM with probabilistic scan matching algorithm using a mechanical scanned imaging sonar

This paper proposes a pose-based algorithm to solve the full SLAM problem for an autonomous underwater vehicle (AUV), navigating in an unknown and possibly unstructured environment. The technique incorporate probabilistic scan matching with range scans gathered from a mechanical scanning imaging sonar (MSIS) and the robot dead-reckoning displacements estimated from a Doppler velocity log (DVL) and a motion reference unit (MRU). The proposed method utilizes two extended Kalman filters (EKF). The first, estimates the local path travelled by the robot while grabbing the scan as well as its uncertainty and provides position estimates for correcting the distortions that the vehicle motion produces in the acoustic images. The second is an augment state EKF that estimates and keeps the registered scans poses. The raw data from the sensors are processed and fused in-line. No priory structural information or initial pose are considered. The algorithm has been tested on an AUV guided along a 600 m path within a marina environment, showing the viability of the proposed approach

Conservation Laws in Cellular Automata

Conservation laws in physics are numerical invariants of the dynamics of a system. In cellular automata (CA), a similar concept has already been defined and studied. To each local pattern of cell states a real value is associated, interpreted as the “energy” (or “mass”, or . . . ) of that pattern.The overall “energy” of a configuration is simply the sum of the energy of the local patterns appearing on different positions in the configuration. We have a conservation law for that energy, if the total energy of each configuration remains constant during the evolution of the CA. For a given conservation law, it is desirable to find microscopic explanations for the dynamics of the conserved energy in terms of flows of energy from one region toward another. Often, it happens that the energy values are from non-negative integers, and are interpreted as the number of “particles” distributed on a configuration. In such cases, it is conjectured that one can always provide a microscopic explanation for the conservation laws by prescribing rules for the local movement of the particles. The onedimensional case has already been solved by Fuk´s and Pivato. We extend this to two-dimensional cellular automata with radius-0,5 neighborhood on the square lattice. We then consider conservation laws in which the energy values are chosen from a commutative group or semigroup. In this case, the class of all conservation laws for a CA form a partially ordered hierarchy. We study the structure of this hierarchy and prove some basic facts about it. Although the local properties of this hierarchy (at least in the group-valued case) are tractable, its global properties turn out to be algorithmically inaccessible. In particular, we prove that it is undecidable whether this hierarchy is trivial (i.e., if the CA has any non-trivial conservation law at all) or unbounded. We point out some interconnections between the structure of this hierarchy and the dynamical properties of the CA. We show that positively expansive CA do not have non-trivial conservation laws. We also investigate a curious relationship between conservation laws and invariant Gibbs measures in reversible and surjective CA. Gibbs measures are known to coincide with the equilibrium states of a lattice system defined in terms of a Hamiltonian. For reversible cellular automata, each conserved quantity may play the role of a Hamiltonian, and provides a Gibbs measure (or a set of Gibbs measures, in case of phase multiplicity) that is invariant. Conversely, every invariant Gibbs measure provides a conservation law for the CA. For surjective CA, the former statement also follows (in a slightly different form) from the variational characterization of the Gibbs measures. For one-dimensional surjective CA, we show that each invariant Gibbs measure provides a conservation law. We also prove that surjective CA almost surely preserve the average information content per cell with respect to any probability measure.

Does cotinine act upon reactive oxygen species and peroxidases?

Nicotine, an oxidizing agent, is certainly one of the most widely used alkaloids in the world. It is, together with its main metabolite, cotinine, responsible for tobacco-dependence. The use of tobacco is closely associated with lung disease, morphological leukocyte modification and generation of oxidant species. The aim of this study was to look for a possible relationship between cotinine, oxidant species generation and oxidative processes. After studying the action of cotinine in some chemical oxidation models and on the enzymatic kinetics of peroxidases (myeloperoxidase and horseradish peroxidase), we concluded that cotinine does not act directly upon H2O2, HOCl, taurine chloramines, horseradish peroxidase or myeloperoxidase.

On Undecidable Dynamical Properties of Reversible One-Dimensional Cellular Automata

Cellular automata are models for massively parallel computation. A cellular automaton consists of cells which are arranged in some kind of regular lattice and a local update rule which updates the state of each cell according to the states of the cell's neighbors on each step of the computation. This work focuses on reversible one-dimensional cellular automata in which the cells are arranged in a two-way in_nite line and the computation is reversible, that is, the previous states of the cells can be derived from the current ones. In this work it is shown that several properties of reversible one-dimensional cellular automata are algorithmically undecidable, that is, there exists no algorithm that would tell whether a given cellular automaton has the property or not. It is shown that the tiling problem of Wang tiles remains undecidable even in some very restricted special cases. It follows that it is undecidable whether some given states will always appear in computations by the given cellular automaton. It also follows that a weaker form of expansivity, which is a concept of dynamical systems, is an undecidable property for reversible one-dimensional cellular automata. It is shown that several properties of dynamical systems are undecidable for reversible one-dimensional cellular automata. It shown that sensitivity to initial conditions and topological mixing are undecidable properties. Furthermore, non-sensitive and mixing cellular automata are recursively inseparable. It follows that also chaotic behavior is an undecidable property for reversible one-dimensional cellular automata.

Reactive dissolution of sedimentary rocks in flue gas desulfurization : modeling and experimental investigation

Svavel förekommer i kol och olja och oxideras vid förbränning till svaveldioxid (SO2). Årligen utsläpps stora mängder svaveldioxid som åstadkommer sura regn, minskning av stratosfäriskt ozon och sjukdomar. Av dessa orsaker är det nödvändigt att minska utsläppen av svaveldioxid. Den teknologi som rör planering av reaktorer och processer för rökgasavsvavling (FGD) har utvecklats kraftigt och idag använder man olika typer av lösningar. De vanligaste alternativen för FGD är våtskrubber- och semitorra skrubbersystem (Spray Dry Scrubbers, SDS) och injektionsprocesser för absorbenter. SDS-processer har studerats bland annat av Ahlbeck [4] och Klingspor [5] och injektionsprocesser av Alvfors [6]. Kalksten, som i huvusak består av kalciumkarbonat, används i rökgasavsvavling på grund av sin förmåga att binda svavel i form av sulfatsalter. Den vanligaste rökgasavsvavlingsmetoden är våtskrubbning, där det sedimentära stenmaterialets upplösningshastighet är en av de faktorer som påverkar resultatet mest. Utvärdering av kalkstensreaktivitet är därför speciellt viktig vid planering och drift av anläggningar för rökgasavsvavling. Målsättningen med detta arbete var att modellera upplösningen av olika typers kalksten för att få en kvantitativ utvärdering av kvaliteten på de analyserade proverna. Därtill testades även karbonatbiprodukter från stålindustrin för att utvärdera möjligheter att använda andra råmaterial. Det transienta förloppet har analyserats, varvid upplösningshastigheten modellerades bl.a. i avseende på tid och pH. Under arbetets gång har antalet empiriska korrelationer minskats till fördel för fysikaliska modeller av diffusiva och konvektiva masstransportfenomen. En målsättning var att skapa en effektiv och snabb metod för att testa olika absorbenter för rökgasavsvavling under transienta förlopp. I arbetet användes PSD-analys, gjordes pH-mätningar och andra utvärderingar av de fysikaliska parametrar som ingår i beräkningarna. On-line mätningar för de icke-stationära variablerna tid och pH ger möjlighet att eliminera osäkerheter. Vissa modeller kan vara komplicerade. En modell för upplösningshastigheten med mer detaljerad utvärdering av parametrar och färre approximationer är därför nödvändig då man vill utvärdera reaktionshastigheten för fasta partiklar i sur miljö. Arbetet utfördes under fyra år och fem peer review-artiklar ingår i avhandlingen.