Novel metaheuristic for parameter estimation in nonlinear dynamic biological systems

BACKGROUND: We consider the problem of parameter estimation (model calibration) in nonlinear dynamic models of biological systems. Due to the frequent ill-conditioning and multi-modality of many of these problems, traditional local methods usually fail (unless initialized with very good guesses of the parameter vector). In order to surmount these difficulties, global optimization (GO) methods have been suggested as robust alternatives. Currently, deterministic GO methods can not solve problems of realistic size within this class in reasonable computation times. In contrast, certain types of stochastic GO methods have shown promising results, although the computational cost remains large. Rodriguez-Fernandez and coworkers have presented hybrid stochastic-deterministic GO methods which could reduce computation time by one order of magnitude while guaranteeing robustness. Our goal here was to further reduce the computational effort without loosing robustness. RESULTS: We have developed a new procedure based on the scatter search methodology for nonlinear optimization of dynamic models of arbitrary (or even unknown) structure (i.e. black-box models). In this contribution, we describe and apply this novel metaheuristic, inspired by recent developments in the field of operations research, to a set of complex identification problems and we make a critical comparison with respect to the previous (above mentioned) successful methods. CONCLUSION: Robust and efficient methods for parameter estimation are of key importance in systems biology and related areas. The new metaheuristic presented in this paper aims to ensure the proper solution of these problems by adopting a global optimization approach, while keeping the computational effort under reasonable values. This new metaheuristic was applied to a set of three challenging parameter estimation problems of nonlinear dynamic biological systems, outperforming very significantly all the methods previously used for these benchmark problems

Parameter estimation in large-scale systems biology models: a parallel and self-adaptive cooperative strategy

[Abstract] Background The development of large-scale kinetic models is one of the current key issues in computational systems biology and bioinformatics. Here we consider the problem of parameter estimation in nonlinear dynamic models. Global optimization methods can be used to solve this type of problems but the associated computational cost is very large. Moreover, many of these methods need the tuning of a number of adjustable search parameters, requiring a number of initial exploratory runs and therefore further increasing the computation times. Here we present a novel parallel method, self-adaptive cooperative enhanced scatter search (saCeSS), to accelerate the solution of this class of problems. The method is based on the scatter search optimization metaheuristic and incorporates several key new mechanisms: (i) asynchronous cooperation between parallel processes, (ii) coarse and fine-grained parallelism, and (iii) self-tuning strategies. Results The performance and robustness of saCeSS is illustrated by solving a set of challenging parameter estimation problems, including medium and large-scale kinetic models of the bacterium E. coli, bakerés yeast S. cerevisiae, the vinegar fly D. melanogaster, Chinese Hamster Ovary cells, and a generic signal transduction network. The results consistently show that saCeSS is a robust and efficient method, allowing very significant reduction of computation times with respect to several previous state of the art methods (from days to minutes, in several cases) even when only a small number of processors is used. Conclusions The new parallel cooperative method presented here allows the solution of medium and large scale parameter estimation problems in reasonable computation times and with small hardware requirements. Further, the method includes self-tuning mechanisms which facilitate its use by non-experts. We believe that this new method can play a key role in the development of large-scale and even whole-cell dynamic models.Ministerio de Economía y Competitividad; DPI2011-28112-C04-03Ministerio de Economía y Competitividad; DPI2011-28112-C04-04Ministerio de Economía y Competitividad; DPI2014-55276-C5-2-RMinisterio de Economía y Competitividad; TIN2013-42148-PMinisterio de Economía y Competitividad; TIN2016-75845-PGalicia. Consellería de Cultura, Educación e Ordenación Universitaria; R2014/041Galicia. Consellería de Cultura, Educación e Ordenación Universitaria; R2016/045Galicia. Consellería de Cultura, Educación e Ordenación Universitaria; GRC2013/05

ABA inhibits myristoylation and induces shuttling of the RGLG1 E3 ligase to promote nuclear degradation of PP2CA

[EN] Hormone- and stress-induced shuttling of signaling or regulatory proteins is an important cellular mechanism to modulate hormone signaling and cope with abiotic stress. Hormone-induced ubiquitination plays a crucial role to determine half-life of key negative regulators of hormone signaling. For ABA signaling, degradation of clade A PP2Cs, such as PP2CA or ABI1, is a complementary mechanism to PYR/PYL/RCAR-mediated inhibition of PP2C activity. ABA promotes the degradation of PP2CA through the RGLG1 E3 ligase, although it is not known how ABA enhances the interaction of RGLG1 with PP2CA given they are predominantly found in plasma membrane and nucleus, respectively. We demonstrate that ABA modifies the subcellular localization of RGLG1 and promotes nuclear interaction with PP2CA. We found RGLG1 is myristoylated in vivo, which facilitates its attachment to plasma membrane. ABA inhibits myristoylation of RGLG1 through downregulation of Nmyristoyltransferase1 (NMT1) and promotes nuclear translocation of RGLG1 in a cycloheximide-insensitive manner. Enhanced nuclear recruitment of the E3 ligase was also promoted by increasing PP2CA protein levels and the formation of RGLG1-receptor-phosphatase complexes. We show that RGLG1Gly2Ala -mutated in the Nterminal myristoylation site- shows constitutive nuclear localization and causes enhanced response to ABA and salt/osmotic stress. RGLG1/5 can interact with certain monomeric ABA receptors, which facilitates the formation of nuclear complexes such as RGLG1-PP2CA-PYL8. In summary, we provide evidence that an E3 ligase can dynamically re-localize in response to both ABA and increased levels of its target, which reveals a mechanism to explain how ABA enhances RGLG1-PP2CA interaction and hence PP2CA degradation.Work in P.L.R.'s laboratory was supported by the Ministerio de Ciencia e Innovacion, Fondo Europeo de Desarrollo Regional and Consejo Superior de Investigaciones Cientificas through grants BIO2014-52537-R and BIO2017-82503-R. This work was also funded by grants from the Deutsche Forschungsgemeinschaft (DFG) Ku931/4-1 to J. K., and BA4742/1-2 to O.B. B.B. was funded by Programa VALi+ d GVA APOSTD/2017/039. J.J. was supported by an FPI contract from MINECOBelda Palazón, B.; Julian, J.; Coego, A.; Wu, Q.; Zhang, X.; Batistic, O.; Alquraishi, SA.... (2019). ABA inhibits myristoylation and induces shuttling of the RGLG1 E3 ligase to promote nuclear degradation of PP2CA. The Plant Journal. 98(5):813-825. https://doi.org/10.1111/tpj.14274S813825985Antoni, R., Gonzalez-Guzman, M., Rodriguez, L., Rodrigues, A., Pizzio, G. A., & Rodriguez, P. L. (2011). Selective Inhibition of Clade A Phosphatases Type 2C by PYR/PYL/RCAR Abscisic Acid Receptors    . Plant Physiology, 158(2), 970-980. doi:10.1104/pp.111.188623Antoni, R., Gonzalez-Guzman, M., Rodriguez, L., Peirats-Llobet, M., Pizzio, G. A., Fernandez, M. A., … Rodriguez, P. L. (2012). PYRABACTIN RESISTANCE1-LIKE8 Plays an Important Role for the Regulation of Abscisic Acid Signaling in Root      . Plant Physiology, 161(2), 931-941. doi:10.1104/pp.112.208678Belda-Palazon, B., Gonzalez-Garcia, M.-P., Lozano-Juste, J., Coego, A., Antoni, R., Julian, J., … Rodriguez, P. L. (2018). PYL8 mediates ABA perception in the root through non-cell-autonomous and ligand-stabilization–based mechanisms. Proceedings of the National Academy of Sciences, 115(50), E11857-E11863. doi:10.1073/pnas.1815410115Bhaskara, G. B., Nguyen, T. T., & Verslues, P. E. (2012). Unique Drought Resistance Functions of the Highly ABA-Induced Clade A Protein Phosphatase 2Cs    . Plant Physiology, 160(1), 379-395. doi:10.1104/pp.112.202408Bigeard, J., & Hirt, H. (2018). Nuclear Signaling of Plant MAPKs. Frontiers in Plant Science, 9. doi:10.3389/fpls.2018.00469Boisson, B., Giglione, C., & Meinnel, T. (2003). Unexpected Protein Families Including Cell Defense Components Feature in the N-Myristoylome of a Higher Eukaryote. Journal of Biological Chemistry, 278(44), 43418-43429. doi:10.1074/jbc.m307321200Burnaevskiy, N., Fox, T. G., Plymire, D. A., Ertelt, J. M., Weigele, B. A., Selyunin, A. S., … Alto, N. M. (2013). Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ. Nature, 496(7443), 106-109. doi:10.1038/nature12004Burnaevskiy, N., Peng, T., Reddick, L. E., Hang, H. C., & Alto, N. M. (2015). 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Degradation of the ABA co-receptor ABI1 by PUB12/13 U-box E3 ligases. Nature Communications, 6(1). doi:10.1038/ncomms9630Kuhn, J. M., Boisson-Dernier, A., Dizon, M. B., Maktabi, M. H., & Schroeder, J. I. (2005). The Protein Phosphatase AtPP2CA Negatively Regulates Abscisic Acid Signal Transduction in Arabidopsis, and Effects of abh1 on AtPP2CA mRNA  . Plant Physiology, 140(1), 127-139. doi:10.1104/pp.105.070318Lee, S. C., Lan, W., Buchanan, B. B., & Luan, S. (2009). A protein kinase-phosphatase pair interacts with an ion channel to regulate ABA signaling in plant guard cells. Proceedings of the National Academy of Sciences, 106(50), 21419-21424. doi:10.1073/pnas.0910601106Lee, H.-J., Park, Y.-J., Seo, P. J., Kim, J.-H., Sim, H.-J., Kim, S.-G., & Park, C.-M. (2015). Systemic Immunity Requires SnRK2.8-Mediated Nuclear Import of NPR1 in Arabidopsis. The Plant Cell, 27(12), 3425-3438. doi:10.1105/tpc.15.00371Leitner, J., Petrasek, J., Tomanov, K., Retzer, K., Parezova, M., Korbei, B., … Luschnig, C. (2012). Lysine63-linked ubiquitylation of PIN2 auxin carrier protein governs hormonally controlled adaptation of Arabidopsis root growth. Proceedings of the National Academy of Sciences, 109(21), 8322-8327. doi:10.1073/pnas.1200824109Li, W., & Schmidt, W. (2010). A lysine-63-linked ubiquitin chain-forming conjugase, UBC13, promotes the developmental responses to iron deficiency in Arabidopsis roots. The Plant Journal, 62(2), 330-343. doi:10.1111/j.1365-313x.2010.04150.xLumba, S., Cutler, S., & McCourt, P. (2010). Plant Nuclear Hormone Receptors: A Role for Small Molecules in Protein-Protein Interactions. Annual Review of Cell and Developmental Biology, 26(1), 445-469. doi:10.1146/annurev-cellbio-100109-103956Lynch, T., Erickson, B. J., & Finkelstein, R. R. (2012). Direct interactions of ABA-insensitive(ABI)-clade protein phosphatase(PP)2Cs with calcium-dependent protein kinases and ABA response element-binding bZIPs may contribute to turning off ABA response. Plant Molecular Biology, 80(6), 647-658. doi:10.1007/s11103-012-9973-3Majeran, W., Le Caer, J.-P., Ponnala, L., Meinnel, T., & Giglione, C. (2018). Targeted Profiling of Arabidopsis thaliana Subproteomes Illuminates Co- and Posttranslationally N-Terminal Myristoylated Proteins. The Plant Cell, 30(3), 543-562. doi:10.1105/tpc.17.00523Moes, D., Himmelbach, A., Korte, A., Haberer, G., & Grill, E. (2008). Nuclear localization of the mutant protein phosphatase abi1 is required for insensitivity towards ABA responses in Arabidopsis. The Plant Journal, 54(5), 806-819. doi:10.1111/j.1365-313x.2008.03454.xMoreno-Alvero, M., Yunta, C., Gonzalez-Guzman, M., Lozano-Juste, J., Benavente, J. L., Arbona, V., … Albert, A. (2017). Structure of Ligand-Bound Intermediates of Crop ABA Receptors Highlights PP2C as Necessary ABA Co-receptor. Molecular Plant, 10(9), 1250-1253. doi:10.1016/j.molp.2017.07.004NAKAGAWA, T., SUZUKI, T., MURATA, S., NAKAMURA, S., HINO, T., MAEO, K., … ISHIGURO, S. (2007). Improved Gateway Binary Vectors: High-Performance Vectors for Creation of Fusion Constructs in Transgenic Analysis of Plants. Bioscience, Biotechnology, and Biochemistry, 71(8), 2095-2100. doi:10.1271/bbb.70216Peirats-Llobet, M., Han, S.-K., Gonzalez-Guzman, M., Jeong, C. W., Rodriguez, L., Belda-Palazon, B., … Rodriguez, P. L. (2016). A Direct Link between Abscisic Acid Sensing and the Chromatin-Remodeling ATPase BRAHMA via Core ABA Signaling Pathway Components. Molecular Plant, 9(1), 136-147. doi:10.1016/j.molp.2015.10.003Pierre, M., Traverso, J. A., Boisson, B., Domenichini, S., Bouchez, D., Giglione, C., & Meinnel, T. (2007). N-Myristoylation Regulates the SnRK1 Pathway inArabidopsis. The Plant Cell, 19(9), 2804-2821. doi:10.1105/tpc.107.051870Pizzio, G. A., Rodriguez, L., Antoni, R., Gonzalez-Guzman, M., Yunta, C., Merilo, E., … Rodriguez, P. L. (2013). The PYL4 A194T Mutant Uncovers a Key Role of PYR1-LIKE4/PROTEIN PHOSPHATASE 2CA Interaction for Abscisic Acid Signaling and Plant Drought Resistance      . Plant Physiology, 163(1), 441-455. doi:10.1104/pp.113.224162Rodriguez, L., Gonzalez-Guzman, M., Diaz, M., Rodrigues, A., Izquierdo-Garcia, A. C., Peirats-Llobet, M., … Rodriguez, P. L. (2014). C2-Domain Abscisic Acid-Related Proteins Mediate the Interaction of PYR/PYL/RCAR Abscisic Acid Receptors with the Plasma Membrane and Regulate Abscisic Acid Sensitivity in Arabidopsis. The Plant Cell, 26(12), 4802-4820. doi:10.1105/tpc.114.129973Romero-Barrios, N., & Vert, G. (2017). Proteasome-independent functions of lysine-63 polyubiquitination in plants. New Phytologist, 217(3), 995-1011. doi:10.1111/nph.14915Rubio, S., Rodrigues, A., Saez, A., Dizon, M. B., Galle, A., Kim, T.-H., … Rodriguez, P. L. (2009). Triple Loss of Function of Protein Phosphatases Type 2C Leads to Partial Constitutive Response to Endogenous Abscisic Acid      . Plant Physiology, 150(3), 1345-1355. doi:10.1104/pp.109.137174Saez, A., Rodrigues, A., Santiago, J., Rubio, S., & Rodriguez, P. L. (2008). HAB1–SWI3B Interaction Reveals a Link between Abscisic Acid Signaling and Putative SWI/SNF Chromatin-Remodeling Complexes in Arabidopsis. The Plant Cell, 20(11), 2972-2988. doi:10.1105/tpc.107.056705Santiago, J., Rodrigues, A., Saez, A., Rubio, S., Antoni, R., Dupeux, F., … Rodriguez, P. L. (2009). Modulation of drought resistance by the abscisic acid receptor PYL5 through inhibition of clade A PP2Cs. The Plant Journal, 60(4), 575-588. doi:10.1111/j.1365-313x.2009.03981.xSantiago, J., Dupeux, F., Round, A., Antoni, R., Park, S.-Y., Jamin, M., … Márquez, J. A. (2009). The abscisic acid receptor PYR1 in complex with abscisic acid. 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Current Opinion in Plant Biology, 40, 63-70. doi:10.1016/j.pbi.2017.07.007Umezawa, T., Sugiyama, N., Mizoguchi, M., Hayashi, S., Myouga, F., Yamaguchi-Shinozaki, K., … Shinozaki, K. (2009). Type 2C protein phosphatases directly regulate abscisic acid-activated protein kinases in Arabidopsis. Proceedings of the National Academy of Sciences, 106(41), 17588-17593. doi:10.1073/pnas.0907095106Vlad, F., Rubio, S., Rodrigues, A., Sirichandra, C., Belin, C., Robert, N., … Merlot, S. (2009). Protein Phosphatases 2C Regulate the Activation of the Snf1-Related Kinase OST1 by Abscisic Acid inArabidopsis . The Plant Cell, 21(10), 3170-3184. doi:10.1105/tpc.109.069179Wu, C., Feng, J., Wang, R., Liu, H., Yang, H., Rodriguez, P. L., … Wang, D. (2012). HRS1 Acts as a Negative Regulator of Abscisic Acid Signaling to Promote Timely Germination of Arabidopsis Seeds. 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Two Novel RING-Type Ubiquitin Ligases, RGLG3 and RGLG4, Are Essential for Jasmonate-Mediated Responses in Arabidopsis      . Plant Physiology, 160(2), 808-822. doi:10.1104/pp.112.20342

Conceptual design of the early implementation of the NEutron Detector Array (NEDA) with AGATA

The NEutron Detector Array (NEDA) project aims at the construction of a new high-efficiency compact neutron detector array to be coupled with large (Formula presented.) -ray arrays such as AGATA. The application of NEDA ranges from its use as selective neutron multiplicity filter for fusion-evaporation reaction to a large solid angle neutron tagging device. In the present work, possible configurations for the NEDA coupled with the Neutron Wall for the early implementation with AGATA has been simulated, using Monte Carlo techniques, in order to evaluate their performance figures. The goal of this early NEDA implementation is to improve, with respect to previous instruments, efficiency and capability to select multiplicity for fusion-evaporation reaction channels in which 1, 2 or 3 neutrons are emitted. Each NEDA detector unit has the shape of a regular hexagonal prism with a volume of about 3.23l and it is filled with the EJ301 liquid scintillator, that presents good neutron- (Formula presented.) discrimination properties. The simulations have been performed using a fusion-evaporation event generator that has been validated with a set of experimental data obtained in the 58Ni + 56Fe reaction measured with the Neutron Wall detector array

Quality changes and shelf-life prediction of a fresh fruit and vegetables purple smoothie

The sensory, microbial and bioactive quality changes of untreated (CTRL) and mild heat−treated (HT; 90 ºC/45 s) smoothies were studied and modelled throughout storage (5, 15 and 25 ºC). The overall acceptability was better preserved in HT samples being highly correlated (hierarchical clustering) with the flavour. The sensory quality data estimated smoothie shelf−life (CTRL/HT) of 18/55 (at 5 ºC), 4.5/12 (at 15 ºC), 2.4/5.8 (at 25 ºC) days. The yeast and moulds growth rate was lower in HT compared to CTRL while a lag phase for mesophiles/psychrophiles was observed in HT−5/15 ºC. HT and 5 ºC−storage stabilized the phenolics content. FRAP reported the best correlation (R2=0.94) with the studied bioactive compounds, followed by ABTS (R2=0.81) while DPPH was the total antioxidant capacity method with the lowest adjustment (R2=0.49). Conclusively, modelling was used to estimate the shelf−life of a smoothie based on quality retention after a short time−high temperature heat treatment that better preserved microbial and nutritional quality during storage.The financial support of this research was provided by the Ministerio Español de Economía y Competitividad MINECO (Projects AGL2013−48830−C2−1−R and AGL2013−48993−C2−1−R) and by FEDER funds. G.A. González−Tejedor thanks to Panamá Government for the scholarship to carry out his PhD Thesis. A. Garre (BES−2014−070946) is grateful to the MINECO for awarding him a pre−doctoral grant. We are also grateful to E. Esposito and N. Castillejo for their skilful technical assistance

A mechanism of growth inhibition by abscisic acid in germinating seeds of Arabidopsis thaliana based on inhibition of plasma membrane H+-ATPase and decreased cytosolic pH, K+, and anions

[EN] The stress hormone abscisic acid (ABA) induces expression of defence genes in many organs, modulates ion homeostasis and metabolism in guard cells, and inhibits germination and seedling growth. Concerning the latter effect, several mutants of Arabidopsis thaliana with improved capability for H+ efflux (wat1-1D, overexpression of AKT1 and ost2-1D) are less sensitive to inhibition by ABA than the wild type. This suggested that ABA could inhibit H+ efflux (H+ -ATPase) and induce cytosolic acidification as a mechanism of growth inhibition. Measurements to test this hypothesis could not be done in germinating seeds and we used roots as the most convenient system. ABA inhibited the root plasma-membrane H+ -ATPase measured in vitro (ATP hydrolysis by isolated vesicles) and in vivo (H+ efflux from seedling roots). This inhibition involved the core ABA signalling elements: PYR/PYL/RCAR ABA receptors, ABA-inhibited protein phosphatases (HAB1), and ABA-activated protein kinases (SnRK2.2 and SnRK2.3). Electrophysiological measurements in root epidermal cells indicated that ABA, acting through the PYR/PYL/RCAR receptors, induced membrane hyperpolarization (due to K+ efflux through the GORK channel) and cytosolic acidification. This acidification was not observed in the wat1-1D mutant. The mechanism of inhibition of the H+ -ATPase by ABA and its effects on cytosolic pH and membrane potential in roots were different from those in guard cells. ABA did not affect the in vivo phosphorylation level of the known activating site (penultimate threonine) of H+ -ATPase in roots, and SnRK2.2 phosphorylated in vitro the C-terminal regulatory domain of H+ -ATPase while the guard-cell kinase SnRK2.6/OST1 did not.This work was funded by grants BFU2011-22526 (to RS) and BIO2011-23446 (to PLR) of the Spanish 'Ministerio de Economia y Competitividad', Madrid, Spain, and grant PROMETEO/2010/038 (to RS) of the 'Generalitat Valenciana', Valencia, Spain. MGG was funded by a JAE-DOC contract of the Spanish 'Consejo Superior de Investigaciones Cientificas', Madrid, Spain. We thank Dr Toshinori Kinoshita (Nagoya University, Nagoya, Japan) for the rabbit antibody against the last 9 aa of AHA2 H+-ATPase with the penultimate Thr947 phosphorylated. We also thank the Proteomics Facility of the 'Centro Nacional de Biotecnologia', Madrid, Spain, for the attempts to identify the phosphorylation site of the H+-ATPase.Planes Ferrer, MD.; Niñoles Rodenes, R.; Rubio, L.; Bissoli, G.; Bueso Ródenas, E.; Garcia-Sanchez, MJ.; Alejandro Martínez, S.... (2015). A mechanism of growth inhibition by abscisic acid in germinating seeds of Arabidopsis thaliana based on inhibition of plasma membrane H+-ATPase and decreased cytosolic pH, K+, and anions. Journal of Experimental Botany. 66(3):813-825. https://doi.org/10.1093/jxb/eru442S81382566

Impact of Deep Coalescence on the Reliability of Species Tree Inference from Different Types of DNA Markers in Mammals

An important challenge for phylogenetic studies of closely related species is the existence of deep coalescence and gene tree heterogeneity. However, their effects can vary between species and they are often neglected in phylogenetic analyses. In addition, a practical problem in the reconstruction of shallow phylogenies is to determine the most efficient set of DNA markers for a reliable estimation. To address these questions, we conducted a multilocus simulation study using empirical values of nucleotide diversity and substitution rates obtained from a wide range of mammals and evaluated the performance of both gene tree and species tree approaches to recover the known speciation times and topological relationships. We first show that deep coalescence can be a serious problem, more than usually assumed, for the estimation of speciation times in mammals using traditional gene trees. Furthermore, we tested the performance of different sets of DNA markers in the determination of species trees using a coalescent approach. Although the best estimates of speciation times were obtained, as expected, with the use of an increasing number of nuclear loci, our results show that similar estimations can be obtained with a much lower number of genes and the incorporation of a mitochondrial marker, with its high information content. Thus, the use of the combined information of both nuclear and mitochondrial markers in a species tree framework is the most efficient option to estimate recent speciation times and, consequently, the underlying species tree