Cell death induced by the application of alternating magnetic fields to nanoparticle-loaded dendritic cells

In this work, the capability of primary, monocyte-derived dendritic cells (DCs) to uptake iron oxide magnetic nanoparticles (MNPs) is assessed and a strategy to induce selective cell death in these MNP-loaded DCs using external alternating magnetic fields (AMFs) is reported. No significant decrease in the cell viability of MNP-loaded DCs, compared to the control samples, was observed after five days of culture. The amount of MNPs incorporated into the cytoplasm was measured by magnetometry, which confirmed that 1 to 5 pg of the particles were uploaded per cell. The intracellular distribution of these MNPs, assessed by transmission electron microscopy, was found to be primarily inside the endosomic structures. These cells were then subjected to an AMF for 30 min, and the viability of the blank DCs (i.e., without MNPs), which were used as control samples, remained essentially unaffected. However, a remarkable decrease of viability from approximately 90% to 2-5% of DCs previously loaded with MNPs was observed after the same 30 min exposure to an AMF. The same results were obtained using MNPs having either positive (NH2+) or negative (COOH-) surface functional groups. In spite of the massive cell death induced by application of AMF to MNP-loaded DCs, the amount of incorporated magnetic particles did not raise the temperature of the cell culture. Clear morphological changes at the cell structure after magnetic field application were observed using scanning electron microscopy. Therefore, local damage produced by the MNPs could be the main mechanism for the selective cell death of MNP-loaded DCs under an AMF. Based on the ability of these cells to evade the reticuloendothelial system, these complexes combined with an AMF should be considered as a potentially powerful tool for tumour therapy.Comment: In Press. 33 pages, 11 figure

Application of magnetically induced hyperthermia on the model protozoan Crithidia fasciculata as a potential therapy against parasitic infections

Magnetic hyperthermia is currently an EU-approved clinical therapy against tumor cells that uses magnetic nanoparticles under a time varying magnetic field (TVMF). The same basic principle seems promising against trypanosomatids causing Chagas disease and sleeping sickness, since therapeutic drugs available display severe side effects and drug-resistant strains. However, no applications of this strategy against protozoan-induced diseases have been reported so far. In the present study, Crithidia fasciculata, a widely used model for therapeutic strategies against pathogenic trypanosomatids, was targeted with Fe_{3}O_{4} magnetic nanoparticles (MNPs) in order to remotely provoke cell death using TVMFs. The MNPs with average sizes of d approx. 30 nm were synthesized using a precipitation of FeSO_{4}4 in basic medium. The MNPs were added to Crithidia fasciculata choanomastigotes in exponential phase and incubated overnight. The amount of uploaded MNPs per cell was determined by magnetic measurements. Cell viability using the MTT colorimetric assay and flow cytometry showed that the MNPs were incorporated by the cells with no noticeable cell-toxicity effects. When a TVMF (f = 249 kHz, H = 13 kA/m) was applied to MNP-bearing cells, massive cell death was induced via a non-apoptotic mechanism. No effects were observed by applying a TVMF on control (without loaded MNPs) cells. No macroscopic rise in temperature was observed in the extracellular medium during the experiments. Scanning Electron Microscopy showed morphological changes after TVMF experiments. These data indicate (as a proof of principle) that intracellular hyperthermia is a suitable technology to induce the specific death of protozoan parasites bearing MNPs. These findings expand the possibilities for new therapeutic strategies that combat parasitic infections.Comment: 9 pages, four supplementary video file

A lower bound on CNF encodings of the at-most-one constraint

Constraint "at most one" is a basic cardinality constraint which requires that at most one of its $n$ boolean inputs is set to $1$. This constraint is widely used when translating a problem into a conjunctive normal form (CNF) and we investigate its CNF encodings suitable for this purpose. An encoding differs from a CNF representation of a function in that it can use auxiliary variables. We are especially interested in propagation complete encodings which have the property that unit propagation is strong enough to enforce consistency on input variables. We show a lower bound on the number of clauses in any propagation complete encoding of the "at most one" constraint. The lower bound almost matches the size of the best known encodings. We also study an important case of 2-CNF encodings where we show a slightly better lower bound. The lower bound holds also for a related "exactly one" constraint.Comment: 38 pages, version 3 is significantly reorganized in order to improve readabilit

On Optimization Modulo Theories, MaxSMT and Sorting Networks

Optimization Modulo Theories (OMT) is an extension of SMT which allows for finding models that optimize given objectives. (Partial weighted) MaxSMT --or equivalently OMT with Pseudo-Boolean objective functions, OMT+PB-- is a very-relevant strict subcase of OMT. We classify existing approaches for MaxSMT or OMT+PB in two groups: MaxSAT-based approaches exploit the efficiency of state-of-the-art MAXSAT solvers, but they are specific-purpose and not always applicable; OMT-based approaches are general-purpose, but they suffer from intrinsic inefficiencies on MaxSMT/OMT+PB problems. We identify a major source of such inefficiencies, and we address it by enhancing OMT by means of bidirectional sorting networks. We implemented this idea on top of the OptiMathSAT OMT solver. We run an extensive empirical evaluation on a variety of problems, comparing MaxSAT-based and OMT-based techniques, with and without sorting networks, implemented on top of OptiMathSAT and {\nu}Z. The results support the effectiveness of this idea, and provide interesting insights about the different approaches.Comment: 17 pages, submitted at Tacas 1

Exploiting Resolution-based Representations for MaxSAT Solving

Most recent MaxSAT algorithms rely on a succession of calls to a SAT solver in order to find an optimal solution. In particular, several algorithms take advantage of the ability of SAT solvers to identify unsatisfiable subformulas. Usually, these MaxSAT algorithms perform better when small unsatisfiable subformulas are found early. However, this is not the case in many problem instances, since the whole formula is given to the SAT solver in each call. In this paper, we propose to partition the MaxSAT formula using a resolution-based graph representation. Partitions are then iteratively joined by using a proximity measure extracted from the graph representation of the formula. The algorithm ends when only one partition remains and the optimal solution is found. Experimental results show that this new approach further enhances a state of the art MaxSAT solver to optimally solve a larger set of industrial problem instances

Target oriented relational model finding

Lecture Notes in Computer Science 8411, 2014Model finders are becoming useful in many software engineering problems. Kodkod is one of the most popular, due to its support for relational logic (a combination of first order logic with relational algebra operators and transitive closure), allowing a simpler specification of constraints, and support for partial instances, allowing the specification of a priori (exact, but potentially partial) knowledge about a problem's solution. However, in some software engineering problems, such as model repair or bidirectional model transformation, knowledge about the solution is not exact, but instead there is a known target that the solution should approximate. In this paper we extend Kodkod's partial instances to allow the specification of such targets, and show how its model finding procedure can be adapted to support them (using both PMax-SAT solvers or SAT solvers with cardinality constraints). Two case studies are also presented, including a careful performance evaluation to assess the effectiveness of the proposed extension.(undefined

Metodología para la optimización conjunta de la programación del riego y estaciones de bombeos directos

Se describe una nueva metodología para reducción de los costes energéticos de operación del riego en redes de riego con bombeo directo, contemplando la optimización conjunta de la organización de los riegos y la modulación de las presiones de la estación de bombeo a lo largo de diferentes periodos tarifarios. Se describe el funcionamiento del método de optimización investigado, que es una extensión y mejora del algoritmo inicial existente desarrollado en (Faci E., 2014) destacando las diferencias y mejoras. Por último, se muestran los resultados en el caso de la red de la CR Callén (Huesca), y se comparan con los obtenidos en un estudio para la optimización energética utilizando el algoritmo inicial.A new methodology to reduce energy cost in irrigation networks is developed in this paper. Its goal is to optimize simultaneously both pumping station and hydrant operation by setting different discharge pressure on the pumping station and distributing adequately hydrant irrigation during different tariff periods. methodology is an extension an existing one described in Faci E., (2014) which is only capable of optimize hydrant operation. Advantages and differences between them are described and they are compared in the case study of CR Callén network (Huesca) which shows the new methodology is capable to save an additional 10% of the annual electricity costs

Generalized Totalizer Encoding for Pseudo-Boolean Constraints

Pseudo-Boolean constraints, also known as 0-1 Integer Linear Constraints, are used to model many real-world problems. A common approach to solve these constraints is to encode them into a SAT formula. The runtime of the SAT solver on such formula is sensitive to the manner in which the given pseudo-Boolean constraints are encoded. In this paper, we propose generalized Totalizer encoding (GTE), which is an arc-consistency preserving extension of the Totalizer encoding to pseudo-Boolean constraints. Unlike some other encodings, the number of auxiliary variables required for GTE does not depend on the magnitudes of the coefficients. Instead, it depends on the number of distinct combinations of these coefficients. We show the superiority of GTE with respect to other encodings when large pseudo-Boolean constraints have low number of distinct coefficients. Our experimental results also show that GTE remains competitive even when the pseudo-Boolean constraints do not have this characteristic.Comment: 10 pages, 2 figures, 2 tables. To be published in 21st International Conference on Principles and Practice of Constraint Programming 201

Hispania, la leyenda: The Myth of Viriatus’ Struggle Transfigured for Television

“Hispania, la leyenda” is the first Spanish attempt to represent on screen the Roman occupation of the Iberian Peninsula and the resistance led by Viriatus. This paper analyzes the TV series in terms of two key features that define it as a historical recreation that repackages the foundational myth as an adventure story with patriotic overtones: 1) the appropriation of a key figure in Portuguese culture to build a notion of Hispanic identity; and 2) the analogy with the Napoleonic occupation and War of Independence, amply evoked in the film and television of the dictatorship and early democracy as well as in the productions made for the recent bicentennial commemorations. -------------------------------------------------------------------------------------- Hispania, la leyenda constituye el primer intento español de llevar a la pantalla la ocupación romana de la Península Ibérica y la resistencia liderada por Viriato. Nuestro trabajo analiza la serie televisiva atendiendo a dos elementos que la determinan como proyecto de recreación histórica, finalmente fallido, que aprovecha el mito fundacional en una estructura de ficción de aventuras con tintes patrióticos: 1) la apropiación de una figura con mayor raigambre en la cultura portuguesa para, eludiendo este factor, elaborar una idea de identidad de lo hispano; y 2) la analogía con la ocupación napoleónica y Guerra de la Independencia, que sí cuentan con tradición en el cine y la televisión tanto de la dictadura como de la era constitucional, y cuyo segundo centenario se conmemora en los mismos años de producción del programa

Epithelial–Mesenchymal Transition in a Case of Metastatic Thyroid Carcinoma in a Brown Bear (Ursus arctos)

A 20-year-old male brown bear (Ursus arctos) with a 20 × 25 cm necrotic mass adjacent to the trachea was diagnosed as having an anaplastic thyroid carcinoma. Metastases were observed in the lungs and one adrenal gland and, histologically, these had anaplastic and follicular carcinoma patterns, respectively. E-cadherin labelling was observed in the adrenal mass only, while N-cadherin immunolabelling was detected in the thyroid gland and lung masses. Thyroid-specific markers (thyroid transcription factor-1, thyroglobulin) were expressed in the adrenal gland metastasis. This case illustrates an example of a primary epithelial–mesenchymal transition (EMT) enabling metastasis to distant organ sites, followed by a mesenchymal–epithelial transition within the adrenal gland microenvironment, allowing invasion and reacquisition of thyroid epithelial cell features. EMTs help to understand the phenomenon of carcinoma cell plasticity in enabling colonization and growth of metastases