Estados excitados del antiinflamatorio no esteroideo flurbiprofeno como sondas para la interacción con proteínas

Las proteínas son macromoléculas muy abundantes en los organismos vivos. En concreto, la importancia de las proteínas transportadoras (como albúmina sérica humana y bovina) radica en que actúan como vehículo para la distribución de una amplia variedad de sustancias endógenas y exógenas en la sangre. El estudio de la interacción fármaco/proteína es importante para conocer la biodistribución, el metabolismo, la eliminación y el efecto farmacológico del fármaco en el organismo. El número de técnicas utilizadas para la realización de este tipo de estudios es muy amplio y variado. En esta tesis, se ha desarrollado una nueva metodología haciendo uso de la técnica de fotólisis de destello láser para estudiar las interacciones que tienen lugar entre el flurbiprofeno (fármaco de la familia de los ácidos 2-arilpropiónicos) y las proteínas mencionadas. Se estudiaron las especies transitorias generadas tras absorción de luz, utilizándose las propiedades de los estados excitados del FBP como parámetros cuantitativos sensibles a las características del medio. En primer lugar, se realizó la caracterización de los primeros estados excitados singlete y triplete del flurbiprofeno, identificándose sus principales procesos de desactivación. Conocidas las propiedades fotofísicas del FBP, se procedió a estudiar una serie de sistemas modelo con el fin de simular el complejo no covalente que interviene en la situación real. En ellos, el FBP quedaba covalentemente unido a los aminoácidos del centro activo de la proteína más directamente implicados en la interacción con el fármaco. Con el propósito de avanzar en el estudio de las interacciones fármaco/proteína, se procedió a estudiar sistemas donde ambos componentes se encontrasen en el mismo medio. Así pues, se llevaron a cabo estudios de sistemas intermoleculares FBPMe/AS y FBP/AS. En ellos, el primer estado excitado triplete resultó ser altamente sensible a la interacción con la proteína. Se observó que el tiempo de vida de triplete de FBVayá Pérez, I. (2007). Estados excitados del antiinflamatorio no esteroideo flurbiprofeno como sondas para la interacción con proteínas [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/1945Palanci

Energy‐aware strategies for task‐parallel sparse linear system solvers

This is the pre-peer reviewed version of the following article: Energy‐aware strategies for task‐parallel sparse linear system solvers, which has been published in final form at https://doi.org/10.1002/cpe.4633. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.We present several energy‐aware strategies to improve the energy efficiency of a task‐parallel preconditioned Conjugate Gradient (PCG) iterative solver on a Haswell‐EP Intel Xeon. These techniques leverage the power‐saving states of the processor, promoting the hardware into a more energy‐efficient C‐state and modifying the CPU frequency (P‐states of the processors) of some operations of the PCG. We demonstrate that the application of these strategies during the main operations of the iterative solver can reduce its energy consumption considerably, especially for memory‐bound computations

Influence of the linking bridge on the photoreactivity of benzophenone-thymine conjugates

[EN] Benzophenone (BP) is present in a variety of bioactive molecules. This chromophore is able to photosensitize DNA damage, where one of the most relevant BP/ DNA interactions occurs with thymine (Thy). In view of the complex photoreactivity previously observed for dyads containing BP covalently linked to thymidine, the aim of this work is to investigate whether appropriate changes in the nature of the spacer could modulate the intramolecular BP/Thy photoreactivity, resulting in an enhanced selectivity. Accordingly, the photobehavior of a series of dyads derived from BP and Thy, separated by linear linkers of different length, has been investigated by steady-state photolysis, as well as femtosecond and nanosecond transient absorption spectroscopy. Irradiation of the dyads led to photoproducts arising from formal hydrogen abstraction or Paterno-Buchi (PB) photoreaction, with a chemoselectivity that was clearly dependent on the nature of the linking bridge; moreover, the PB process occurred with complete regio- and stereoselectivity. The overall photoreactivity increased with the length of the spacer and correlated well with the rate constants estimated from the BP triplet lifetimes. A reaction mechanism explaining these results is proposed, where the key features are the strain associated with the reactive conformations and the participation of triplet exciplexes.Financial support from the Spanish Government (RYC-2015-17737 and CTQ2017-89416-R) and from the Conselleria d'Educació Cultura i Esport (PROMETEO/2017/075 and GRISOLIAP/2017/005) is gratefully acknowledged. The authors would like to thank the use of RIAIDT-USC analytical facilities for the X-ray crystallography analysis.Blasco-Brusola, A.; Vayá Pérez, I.; Miranda Alonso, MÁ. (2020). Influence of the linking bridge on the photoreactivity of benzophenone-thymine conjugates. The Journal of Organic Chemistry. 85(21):14068-14076. https://doi.org/10.1021/acs.joc.0c02088S14068140768521Kraemer, K. H. (1997). Sunlight and skin cancer: Another link revealed. Proceedings of the National Academy of Sciences, 94(1), 11-14. doi:10.1073/pnas.94.1.11Cadet, J., Mouret, S., Ravanat, J.-L., & Douki, T. (2012). Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions†. Photochemistry and Photobiology, 88(5), 1048-1065. doi:10.1111/j.1751-1097.2012.01200.xRastogi, R. P., Richa, Kumar, A., Tyagi, M. B., & Sinha, R. P. (2010). Molecular Mechanisms of Ultraviolet Radiation-Induced DNA Damage and Repair. Journal of Nucleic Acids, 2010, 1-32. doi:10.4061/2010/592980Sinha, R. P., & Häder, D.-P. (2002). UV-induced DNA damage and repair: a review. Photochemical & Photobiological Sciences, 1(4), 225-236. doi:10.1039/b201230hChatterjee, N., & Walker, G. C. (2017). Mechanisms of DNA damage, repair, and mutagenesis. Environmental and Molecular Mutagenesis, 58(5), 235-263. doi:10.1002/em.22087Brash, D. E., & Haseltine, W. A. (1982). UV-induced mutation hotspots occur at DNA damage hotspots. Nature, 298(5870), 189-192. doi:10.1038/298189a0Taylor, J. S., & Cohrs, M. P. (1987). DNA, light, and Dewar pyrimidinones: the structure and biological significance to TpT3. Journal of the American Chemical Society, 109(9), 2834-2835. doi:10.1021/ja00243a052Taylor, J. S., Garrett, D. S., & Cohrs, M. P. (1988). Solution-state structure of the Dewar pyrimidinone photoproduct of thymidylyl-(3’ .fwdarw. 5’)-thymidine. Biochemistry, 27(19), 7206-7215. doi:10.1021/bi00419a007Kim, S. T., Malhotra, K., Smith, C. A., Taylor, J. S., & Sancar, A. (1994). Characterization of (6-4) photoproduct DNA photolyase. Journal of Biological Chemistry, 269(11), 8535-8540. doi:10.1016/s0021-9258(17)37228-9Li, J., Liu, Z., Tan, C., Guo, X., Wang, L., Sancar, A., & Zhong, D. (2010). Dynamics and mechanism of repair of ultraviolet-induced (6–4) photoproduct by photolyase. Nature, 466(7308), 887-890. doi:10.1038/nature09192Todo, T., Ryo, H., Yamamoto, K., Toh, H., Inui, T., Ayaki, H., … Ikenaga, M. (1996). Similarity Among the Drosophila (6-4)Photolyase, a Human Photolyase Homolog, and the DNA Photolyase-Blue-Light Photoreceptor Family. Science, 272(5258), 109-112. doi:10.1126/science.272.5258.109Todo, T., Takemori, H., Ryo, H., lhara, M., Matsunaga, T., Nikaido, O., … Nomura, T. (1993). A new photoreactivating enzyme that specifically repairs ultraviolet light-induced (6-4)photoproducts. Nature, 361(6410), 371-374. doi:10.1038/361371a0Todo, T., Tsuji, H., Otoshi, E., Hitomi, K., Sang-Tae Kim, & Ikenaga, M. (1997). Characterization of a human homolog of (6-4)photolyase. Mutation Research/DNA Repair, 384(3), 195-204. doi:10.1016/s0921-8777(97)00032-3Epe, B., Pflaum, M., & Boiteux, S. (1993). DNA damage induced by photosensitizers in cellular and cell-free systems. Mutation Research/Genetic Toxicology, 299(3-4), 135-145. doi:10.1016/0165-1218(93)90091-qMichaud, S., Hajj, V., Latapie, L., Noirot, A., Sartor, V., Fabre, P.-L., & Chouini-Lalanne, N. (2012). Correlations between electrochemical behaviors and DNA photooxidative properties of non-steroïdal anti-inflammatory drugs and their photoproducts. Journal of Photochemistry and Photobiology B: Biology, 110, 34-42. doi:10.1016/j.jphotobiol.2012.02.007Marguery, M. C., Chouini-Lalanne, N., Ader, J. C., & Paillous, N. (1998). Comparison of the DNA Damage Photoinduced by Fenofibrate and Ketoprofen, Two Phototoxic Drugs of Parent Structure. Photochemistry and Photobiology, 68(5), 679-684. doi:10.1111/j.1751-1097.1998.tb02529.xVinette, A. L., McNamee, J. P., Bellier, P. V., McLean, J. R. N., & Scaiano, J. C. (2003). Prompt and Delayed Nonsteroidal Anti-inflammatory Drug–photoinduced DNA Damage in Peripheral Blood Mononuclear Cells Measured with the Comet Assay¶. Photochemistry and Photobiology, 77(4), 390. doi:10.1562/0031-8655(2003)0772.0.co;2Lhiaubet, V., Gutierrez, F., Penaud–Berruyer, F., Amouyal, E., Daudey, J.-P., Poteau, R., … Paillous, N. (2000). Spectroscopic and theoretical studies of the excited states of fenofibric acid and ketoprofen in relation with their photosensitizing properties. New Journal of Chemistry, 24(6), 403-410. doi:10.1039/a909539jLhiaubet, V., Paillous, N., & Chouini-Lalanne, N. (2001). Comparison of DNA Damage Photoinduced by Ketoprofen, Fenofibric Acid and Benzophenone via Electron and Energy Transfer¶. Photochemistry and Photobiology, 74(5), 670. doi:10.1562/0031-8655(2001)0742.0.co;2Cuquerella, M. C., Lhiaubet-Vallet, V., Cadet, J., & Miranda, M. A. (2012). Benzophenone Photosensitized DNA Damage. Accounts of Chemical Research, 45(9), 1558-1570. doi:10.1021/ar300054eBignon, E., Marazzi, M., Besancenot, V., Gattuso, H., Drouot, G., Morell, C., … Monari, A. (2017). Ibuprofen and ketoprofen potentiate UVA-induced cell death by a photosensitization process. Scientific Reports, 7(1). doi:10.1038/s41598-017-09406-8Boscá, F., & Miranda, M. A. (1998). New Trends in Photobiology (Invited Review) Photosensitizing drugs containing the benzophenone chromophore. Journal of Photochemistry and Photobiology B: Biology, 43(1), 1-26. doi:10.1016/s1011-1344(98)00062-1Rogers, J. E., & Kelly, L. A. (1999). Nucleic Acid Oxidation Mediated by Naphthalene and Benzophenone Imide and Diimide Derivatives:  Consequences for DNA Redox Chemistry. Journal of the American Chemical Society, 121(16), 3854-3861. doi:10.1021/ja9841299Surana, K., Chaudhary, B., Diwaker, M., & Sharma, S. (2018). Benzophenone: a ubiquitous scaffold in medicinal chemistry. MedChemComm, 9(11), 1803-1817. doi:10.1039/c8md00300aCuquerella, M. C., Lhiaubet-Vallet, V., Bosca, F., & Miranda, M. A. (2011). Photosensitised pyrimidine dimerisation in DNA. Chemical Science, 2(7), 1219. doi:10.1039/c1sc00088hBlasco-Brusola, A., Navarrete-Miguel, M., Giussani, A., Roca-Sanjuán, D., Vayá, I., & Miranda, M. A. (2020). Regiochemical memory in the adiabatic photolysis of thymine-derived oxetanes. A combined ultrafast spectroscopic and CASSCF/CASPT2 computational study. Physical Chemistry Chemical Physics, 22(35), 20037-20042. doi:10.1039/d0cp03084hBurrows, C. J., & Muller, J. G. (1998). Oxidative Nucleobase Modifications Leading to Strand Scission. Chemical Reviews, 98(3), 1109-1152. doi:10.1021/cr960421sBelmadoui, N., Climent, M. J., & Miranda, M. A. (2006). Photochemistry of a naphthalene–thymine dyad in the presence of acetone. Tetrahedron, 62(7), 1372-1377. doi:10.1016/j.tet.2005.11.035Bonancía, P., Vayá, I., Climent, M. J., Gustavsson, T., Markovitsi, D., Jiménez, M. C., & Miranda, M. A. (2012). Excited-State Interactions in Diastereomeric Flurbiprofen–Thymine Dyads. The Journal of Physical Chemistry A, 116(35), 8807-8814. doi:10.1021/jp3063838Encinas, S., Climent, M. J., Gil, S., Abrahamsson, U. O., Davidsson, J., & Miranda, M. A. (2004). Singlet Excited-State Interactions in Naphthalene-Thymine Dyads. ChemPhysChem, 5(11), 1704-1709. doi:10.1002/cphc.200400262Belmadoui, N., Encinas, S., Climent, M. J., Gil, S., & Miranda, M. A. (2006). Intramolecular Interactions in the Triplet Excited States of Benzophenone–Thymine Dyads. Chemistry - A European Journal, 12(2), 553-561. doi:10.1002/chem.200500345Dumont, E., Wibowo, M., Roca-Sanjuán, D., Garavelli, M., Assfeld, X., & Monari, A. (2015). Resolving the Benzophenone DNA-Photosensitization Mechanism at QM/MM Level. The Journal of Physical Chemistry Letters, 6(4), 576-580. doi:10.1021/jz502562dDelatour, T., Douki, T., D’Ham, C., & Cadet, J. (1998). Photosensitization of thymine nucleobase by benzophenone through energy transfer, hydrogen abstraction and one-electron oxidation. Journal of Photochemistry and Photobiology B: Biology, 44(3), 191-198. doi:10.1016/s1011-1344(98)00142-0Tamai, N., Asahi, T., & Masuhara, H. (1992). Intersystem crossing of benzophenone by femtosecond transient grating spectroscopy. Chemical Physics Letters, 198(3-4), 413-418. doi:10.1016/0009-2614(92)85074-kGut, I. G., Wood, P. D., & Redmond, R. W. (1996). Interaction of Triplet Photosensitizers with Nucleotides and DNA in Aqueous Solution at Room Temperature. Journal of the American Chemical Society, 118(10), 2366-2373. doi:10.1021/ja9519344Miro, P., Gomez‐Mendoza, M., Sastre, G., Cuquerella, M. C., Miranda, M. A., & Marin, M. L. (2019). Generation of the Thymine Triplet State by Through‐Bond Energy Transfer. Chemistry – A European Journal, 25(28), 7004-7011. doi:10.1002/chem.201900830Joseph, A., Prakash, G., & Falvey, D. E. (2000). Model Studies of the (6−4) Photoproduct Photolyase Enzyme:  Laser Flash Photolysis Experiments Confirm Radical Ion Intermediates in the Sensitized Repair of Thymine Oxetane Adducts. Journal of the American Chemical Society, 122(45), 11219-11225. doi:10.1021/ja002541uMartínez, L. J., & Scaiano, J. C. (1997). Transient Intermediates in the Laser Flash Photolysis of Ketoprofen in Aqueous Solutions:  Unusual Photochemistry for the Benzophenone Chromophore. Journal of the American Chemical Society, 119(45), 11066-11070. doi:10.1021/ja970818tPerez-Ruiz, R., Groeneveld, M., van Stokkum, I. H. M., Tormos, R., Williams, R. M., & Miranda, M. A. (2006). Fast transient absorption spectroscopy of the early events in photoexcited chiral benzophenone–naphthalene dyads. Chemical Physics Letters, 429(1-3), 276-281. doi:10.1016/j.cplett.2006.07.077Martens, J.; Maison, W.; Schlemminger, I.; Westerhoff, O.; Groger, H. Preparation of Precursors for PNA monomers. WO20000028642000

Characterization of Multicore Architectures using Task-Parallel ILU-type Preconditioned CG Solvers

Ponència presentada al 2nd Workshop on Power-Aware Computing (PACO 2017) Ringberg Castle, Germany, July, 5-8 2017We investigate the eficiency of state-of-the-art multicore processors using a multi-threaded task-parallel implementation of the Conjugate Gradient (CG) method, accelerated with an incomplete LU (ILU) preconditioner. Concretely, we analyze multicore architectures with distinct designs and market targets to compare their parallel performance and energy eficiency

Regioselectivity in the adiabatic photocleavage of DNA-based oxetanes

[EN] Direct absorption of UVB light by DNA may induce formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone (6-4) photoproducts. The latter arise from the rearrangement of unstable oxetane intermediates, which have also been proposed to be the electron acceptor species in the photoenzymatic repair of this type of DNA damage. In the present work, direct photolysis of oxetanes composed of substituted uracil (Ura) or thymine (Thy) derivatives and benzophenone (BP) have been investigated by means of transient absorption spectroscopy from the femtosecond to the microsecond time-scales. The results showed that photoinduced oxetane cleavage takes place through an adiabatic process leading to the triplet excited BP and the ground state nucleobase. This process was markedly affected by the oxetane regiochemistry (head-to-head, HH, vs. head-to-tail, HT) and by the nucleobase substitution; it was nearly quantitative for all investigated HH-oxetanes while it became strongly influenced by the substitution at positions 1 and 5 for the HT-isomers. The obtained results clearly confirm the generality of the adiabatic photoinduced cleavage of BP/Ura or Thy oxetanes, as well as its dependence on the regiochemistry, supporting the involvement of triplet exciplexes. As a matter of fact, when formation of this species was favored by keeping together the Thy and BP units after splitting by means of a linear linker, a transient absorption at similar to 400 nm, ascribed to the exciplex, was detected.Financial support from the Spanish Government (RYC-2015-17737 and CTQ2017-89416-R) and from the Conselleria d'Educacio Cultura i Esport (PROMETEO/2017/075 and GRISOLIAP/2017/005) is gratefully acknowledged.Blasco-Brusola, A.; Vayá Pérez, I.; Miranda Alonso, MÁ. (2020). Regioselectivity in the adiabatic photocleavage of DNA-based oxetanes. Organic & Biomolecular Chemistry. 18(44):9117-9123. https://doi.org/10.1039/D0OB01974GS91179123184

Triplet excited states as chiral reporter for the binding of drugs to transport proteins

[EN] The triplet excited state of flurbiprofen methyl ester (FBPMe) has been used as a chiral reporter for the two binding sites of human serum albumin (HSA). The occupation level of the binding sites has been estimated from regression analysis of the triplet decays at several [FBPMe]/[HSA] ratios. The data agree with two high affinity binding sites (I and II) that are populated to a different extent. A remarkable stereodifferentiation has been found in the drug triplet lifetimes within the protein microenvironment.The UPV (Grant PI 2003-0522 and fellowship to I.V.), the MEC (Grant CTQ2004-03811), and Generalitat Valenciana (Grant GV2004-0536 and Grupos03/082) are gratefully acknowledged for financial support.Jiménez Molero, MC.; Miranda Alonso, MÁ.; Vayá Pérez, I. (2005). Triplet excited states as chiral reporter for the binding of drugs to transport proteins. Journal of the American Chemical Society. 127(29):10134-10135. https://doi.org/10.1021/ja0514489S10134101351272

Harvesting Energy in ILUPACK via Slack Elimination

Ponència presentada al 2nd Workshop on Power-Aware Computing (PACO 2017) Ringberg Castle, Germany, July, 5-8 2017We develop a new energy-aware methodology to improve the energy consumption of a task-parallel preconditioned Conjugate Gradient iter- ative solver on a Haswell-EP Intel Xeon. This technique leverages the power-saving modes of the processor and the frequency range of the userspace Linux governor, modifying the CPU frequency for some oper- ations. We demonstrate that its application during the main operations of the PCG solver can reduce its energy consumption

Stereodifferentiation in the fluorescence of naproxen-arginine salts in the solid state

[EN] Three stereoisomeric salts of naproxen (NPX) with arginine (Arg), namely (S)-NPX/(S)-Arg, (R)-NPX/(S)-Arg and (S)NPX/(R)-Arg, have been prepared, and their fluorescence spectra recorded in solution and in the solid state. While the emission properties in solution did not show significant differences with lambda(max) = 355 nm, tau(F) (MeOH) ca. 11.5 ns and tau(F) (H2O) ca. 9 ns (as NPX/Na), the (R)-NPX/(S)-Arg and (S)-NPX/(R)-Arg solid salts displayed red-shifted fluorescence spectra With maxima at 375 mn and tau(F) = 1.1 ns. By contrast, the behaviour of solid (S)-NPX/(S)-Arg was similar to that of NPX/Na With; ax = 355 nm and tau(F) ca. 5.5 ns. These results are explained based on the X-ray crystal structures and attributed to formation of NPX excimers emitting at longer wavelengths. Accordingly, such excimer emission was also observed in the fluorescence spectrum of a model NPX dyad in solution.The UPV (PI 2003-0522 and predoctoral fellowship to I.V.), the MYCT (Grant CTQ2004-03811) the Generalitat Valenciana (Grupos03/082 and GV04B-468) are gratefully acknowledged for financial support. We also thank our colleague Dr. M. L. Marin for providing a gift of (2-methoxynaphthalen-6-yl)acetic acid and Dr. A. Llamas (Unidade de Raios X de la Universidade de Santiago de Compostela) for the X-ray measurements.Vayá Pérez, I.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2005). Stereodifferentiation in the fluorescence of naproxen-arginine salts in the solid state. Tetrahedron Asymmetry. 16(12):2167-2171. https://doi.org/10.1016/j.tetasy.2005.05.018S21672171161

Transient absorption spectroscopy for determining multiple site occupancy in drug-protein conjugates. A comparison between human and bovine serum albumins using flurbiprofen methyl ester as probe

This document is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of Physical Chemistry B, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/jp076960q[EN] Laser flash photolysis (LFP) has been used to determine the degree of binding of (S)- or (R)-flurbiprofen methyl ester (FBPMe) to human and bovine serum albumins (HSA and BSA, respectively). Regression analysis of the triplet decay of the drug (lambda = 360 nm) in the presence of the proteins led to a satisfactory fitting when considering a set of three lifetimes; the corresponding A(free), A(I) and A(II) preexponential coefficients can be correlated with the presence of FBPMe in the bulk solution and within the two known binding sites. The most remarkable differences between HSA and BSA were found under nonsaturating conditions; thus, when the [FBPMe]/[SA] ratio was 1: 1, all the drug was bound to HSA, whereas 20-30% of it remained free in the bulk solution in the presence of BSA. The UP approach was also applicable to the study of more complex FBPMe/HSA/BSA mixtures; the obtained results were in good agreement with the previous findings in FBPMe/HSA and FBPMe/BSA systems. This suggests the possibility of making use of the transient triplet-triplet absorption for investigating the distribution of a drug between several compartments in different host biomolecules.Financial support from the MCYT (CTQ2004-03811 and CTQ2007-67010) and the Generalitat Valenciana (GV06/099) is gratefully acknowledged. I.V. thanks MEC for a fellowship.Vayá Pérez, I.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2008). Transient absorption spectroscopy for determining multiple site occupancy in drug-protein conjugates. A comparison between human and bovine serum albumins using flurbiprofen methyl ester as probe. The Journal of Physical Chemistry B. 112(9):2694-2699. doi:10.1021/jp076960qS26942699112

Iteration-fusing conjugate gradient for sparse linear systems with MPI + OmpSs

In this paper, we target the parallel solution of sparse linear systems via iterative Krylov subspace-based method enhanced with a block-Jacobi preconditioner on a cluster of multicore processors. In order to tackle large-scale problems, we develop task-parallel implementations of the preconditioned conjugate gradient method that improve the interoperability between the message-passing interface and OmpSs programming models. Specifically, we progressively integrate several communication-reduction and iteration-fusing strategies into the initial code, obtaining more efficient versions of the method. For all these implementations, we analyze the communication patterns and perform a comparative analysis of their performance and scalability on a cluster consisting of 32 nodes with 24 cores each. The experimental analysis shows that the techniques described in the paper outperform the classical method by a margin that varies between 6 and 48%, depending on the evaluation