Stochastic models for CD4+ T cells

In this thesis, we study the mechanisms involved in CD4+ T cell activation focusing on the crucial role of costimulation for an effective immune response. For this purpose, interactions between receptors from T cells and ligands on the APCs, as well as the trafficking of these molecules, need to be analysed. At the same time, population models are developed to study their homeostatic behaviour and the role of IL-2, as well as quorum-sensing mechanisms in CD4+ T cell maintenance. A multidisciplinary approach that combines statistical analysis of experimental data and mathematical models that describe the experiments, has been used that take into account the stochastic nature of these processes. We have combined deterministic methods when appropriate with stochastic ones, as well as made us of numerical simulations

Acercando los recursos de la Biblioteca Universitaria de Córdoba al usuario: unificación y acceso remoto

Comunicación presentada a las XV Jornadas Bibliotecarias de Andalucía: Bibliotecas, rompiendo barreras, tejiendo redes. Córdoba, 15-17, Octubre, 2009.Desde el ámbito de la cooperación tanto a nivel nacional como a nivel regional, se definen las herramientas que cuenta la Biblioteca Universitaria de Córdoba para la integración de fuentes y accesos, destacando entre ellas el Catálogo de la Biblioteca. Se expone la trayectoria y perspectivas de futuro de las distintos métodos de autenticación que ofrece la BUC a fin de garantizar el acceso remoto a los recursos y servicios que proporciona: VPN, Proxy PAPI, WAM, federaciones de identidad

Effect of water contamination on the shear bond strength of five orthodontic adhesives

Objectives: To evaluate the shear bond strength and site of failure of brackets bonded to dry and wet enamel. Study design: 50 teeth were divided into ten groups of 5 teeth each (10 surfaces). In half the groups enamel was kept dry before bonding, and in the other half distilled water was applied to wet the surface after etching. The following groups were established: 1)Acid/Transbond-XT (dry/wet) XT; 2) Transbond Plus Self Etching Primer (TSEP)/Transbond-XT paste (dry/wet); 3) Concise (dry), Transbond MIP/Concise (wet), 4) FujiOrtho-LC (dry/wet); 5) SmartBond (dry/wet). Brackets were bonded to both buccal and lingual surfaces. Specimens were stored in distilled water (24 hours at 37ºC) and thermocycled. Brackets were debonded using a Universal testing machine (cross-head speed 1 mm/min). Failure sites were classified using a stereomicroscope. Results: No significant differences in bond strength were detected between the adhesives under wet and dry conditions except for Smart- Bond, whose bond strength was significantly lower under dry conditions. For all the adhesives most bond failures were of mixed site location except for Smartbond, which failed at the adhesive-bracket interface. Conclusions: Under wet conditions the bonding capacity of the adhesives tested was similar than under dry conditions, with the exception of SmartBond which improved under wet condition

Efficiency of water service management alternatives in Spain considering environmental factors

The main aim of this study is to identify the most efficient forms of management for municipal water supply services, taking into account exogenous factors. The study is based on a sample of 1518 Spanish municipalities, all with 1000 to 50,000 inhabitants, for the year 2019. The study method consists of analysing order-m partial frontiers subjected to environmental factors. The main results obtained indicate that mixed management forms achieve the highest levels of efficiency.Andalusian Regional Government, Grant Number: P20.00605University of Granada (FEDER funding), Grant Number: A.SEJ.351.UGR18Ministry of Science and Innovation, Grant Number: PID2021- 128713OB-I0University of Granada "AYUDAS DEL PLAN PROPIO UGR 2022", Grant Number: PPJIA2022-5

Effect of water contamination on the shear bond strength of five orthodontic adhesives

Objectives: To evaluate the shear bond strength and site of failure of brackets bonded to dry and wet enamel. Study design: 50 teeth were divided into ten groups of 5 teeth each (10 surfaces). In half the groups enamel was kept dry before bonding, and in the other half distilled water was applied to wet the surface after etching. The following groups were established: 1)Acid/Transbond-XT (dry/wet) XT; 2) Transbond Plus Self Etching Primer (TSEP)/Transbond-XT paste (dry/wet); 3) Concise (dry), Transbond MIP/Concise (wet), 4) FujiOrtho-LC (dry/ wet); 5) SmartBond (dry/wet). Brackets were bonded to both buccal and lingual surfaces. Specimens were stored in distilled water (24 hours at 37ºC) and thermocycled. Brackets were debonded using a Universal testing machine (cross-head speed 1 mm/min). Failure sites were classified using a stereomicroscope. Results: No significant differences in bond strength were detected between the adhesives under wet and dry conditions except for SmartBond, whose bond strength was significantly lower under dry conditions. For all the adhesives most bond failures were of mixed site location except for Smartbond, which failed at the adhesive-bracket interface. Conclusions: Under wet conditions the bonding capacity of the adhesives tested was similar than under dry conditions, with the exception of SmartBond which improved under wet conditions

Fate of a Naive T Cell: A Stochastic Journey

The homeostasis of T cell populations depends on migration, division and death of individual cells (1). T cells migrate between spatial compartments (spleen, lymph nodes, lung, liver, etc.), where they may divide or differentiate, and eventually die (2). The kinetics of recirculation influences the speed at which local infections are detected and controlled (3). New experimental techniques have been developed to measure the lifespan of cells, and their migration dynamics; for example, fluorescence-activated cell sorting (4), in vitro time-lapse microscopy (5), or in vivo stable isotope labeling (e.g., deuterium) (6). When combined with mathematical and computational models, they allow estimation of rates of migration, division, differentiation and death (6, 7). In this work, we develop a stochastic model of a single cell migrating between spatial compartments, dividing and eventually dying. We calculate the number of division events during a T cell's journey, its lifespan, the probability of dying in each compartment and the number of progeny cells. A fast-migration approximation allows us to compute these quantities when migration rates are larger than division and death rates. Making use of published rates: (i) we analyse how perturbations in a given spatial compartment impact the dynamics of a T cell, (ii) we study the accuracy of the fast-migration approximation, and (iii) we quantify the role played by direct migration (not via the blood) between some compartments

Gold Nanoparticle-Assisted Virus Formation by Means of the Delivery of an Oncolytic Adenovirus Genome

[EN] Oncolytic adenoviruses are a therapeutic alternative to treat cancer based on their ability to replicate selectively in tumor cells. However, their use is limited mainly by the neutralizing antibody (Nab) immune response that prevents repeated dosing. An alternative to facilitate the DNA access to the tumor even in the presence of anti-viral Nabs could be gold nanoparticles able to transfer DNA molecules. However, the ability of these nanoparticles to carry large DNA molecules, such as an oncolytic adenovirus genome, has not been studied. In this work, gold nanoparticles were functionalized with different amounts of polyethylenimine to transfer in a safe and efficient manner a large oncolytic virus genome. Their transfer efficacy and final effect of the oncolytic virus in cancer cells are studied. For each synthesized nanoparticle, (a) DNA loading capacity, (b) complex size, (c) DNA protection ability, (d) transfection efficacy and (e) cytotoxic effect were studied. We observed that small gold nanoparticles (70-80 nm in diameter) protected DNA against nucleases and were able to transfect the ICOVIR-15 oncolytic virus genome encoded in pLR1 plasmid. In the present work, efficient transgene RNA expression, luciferase activity and viral cytopathic effect on cancer cells are reported. These results suggest gold nanoparticles to be an efficient and safe vector for oncolytic adenovirus genome transfer.This research was supported by University of Valencia 'Ayuda a la Investigacion', Asociacion Pablo Ugarte and European Regional Development Fund (VLC-CAMPUS).Sendra, L.; Miguel, A.; Navarro-Plaza, MC.; Herrero, MJ.; De La Higuera, J.; Cháfer-Pericás, C.; Aznar, E.... (2020). Gold Nanoparticle-Assisted Virus Formation by Means of the Delivery of an Oncolytic Adenovirus Genome. Nanomaterials. 10(6):1-16. https://doi.org/10.3390/nano10061183S116106Cebrián, V., Martín-Saavedra, F., Yagüe, C., Arruebo, M., Santamaría, J., & Vilaboa, N. (2011). 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Bioconjugate Chemistry, 13(1), 3-6. doi:10.1021/bc015545cThomas, M., & Klibanov, A. M. (2003). Conjugation to gold nanoparticles enhances polyethylenimine’s transfer of plasmid DNA into mammalian cells. Proceedings of the National Academy of Sciences, 100(16), 9138-9143. doi:10.1073/pnas.1233634100Noh, S. M., Kim, W.-K., Kim, S. J., Kim, J. M., Baek, K.-H., & Oh, Y.-K. (2007). Enhanced cellular delivery and transfection efficiency of plasmid DNA using positively charged biocompatible colloidal gold nanoparticles. Biochimica et Biophysica Acta (BBA) - General Subjects, 1770(5), 747-752. doi:10.1016/j.bbagen.2007.01.012Chan, T. G., Morse, S. V., Copping, M. J., Choi, J. J., & Vilar, R. (2018). Targeted Delivery of DNA-Au Nanoparticles across the Blood-Brain Barrier Using Focused Ultrasound. ChemMedChem, 13(13), 1311-1314. doi:10.1002/cmdc.201800262Mbatha, L. S., & Singh, M. (2019). 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In Vitro Gene Delivery in Retinal Pigment Epithelium Cells by Plasmid DNA-Wrapped Gold Nanoparticles. Genes, 10(4), 289. doi:10.3390/genes10040289Munsell, E. V., Fang, B., & Sullivan, M. O. (2018). Histone-Mimetic Gold Nanoparticles as Versatile Scaffolds for Gene Transfer and Chromatin Analysis. Bioconjugate Chemistry, 29(11), 3691-3704. doi:10.1021/acs.bioconjchem.8b00611Dhanya, G. R., Caroline, D. S., Rekha, M. R., & Sreenivasan, K. (2018). Histidine and arginine conjugated starch-PEI and its corresponding gold nanoparticles for gene delivery. International Journal of Biological Macromolecules, 120, 999-1008. doi:10.1016/j.ijbiomac.2018.08.142Hersey, P., & Gallagher, S. (2013). Intralesional immunotherapy for melanoma. Journal of Surgical Oncology, 109(4), 320-326. doi:10.1002/jso.23494Mastrangelo, M. J., Maguire, H. C., Eisenlohr, L. C., Laughlin, C. E., Monken, C. E., McCue, P. A., … Lattime, E. C. (1999). Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Therapy, 6(5), 409-422. doi:10.1038/sj.cgt.7700066Senzer, N. N., Kaufman, H. L., Amatruda, T., Nemunaitis, M., Reid, T., Daniels, G., … Nemunaitis, J. J. (2009). Phase II Clinical Trial of a Granulocyte-Macrophage Colony-Stimulating Factor–Encoding, Second-Generation Oncolytic Herpesvirus in Patients With Unresectable Metastatic Melanoma. Journal of Clinical Oncology, 27(34), 5763-5771. doi:10.1200/jco.2009.24.3675Goins, W. F., Huang, S., Cohen, J. B., & Glorioso, J. C. (2014). Engineering HSV-1 Vectors for Gene Therapy. Herpes Simplex Virus, 63-79. doi:10.1007/978-1-4939-0428-0_5Dummer, R., Rochlitz, C., Velu, T., Acres, B., Limacher, J.-M., Bleuzen, P., … Urosevic, M. (2008). Intralesional Adenovirus-mediated Interleukin-2 Gene Transfer for Advanced Solid Cancers and Melanoma. Molecular Therapy, 16(5), 985-994. doi:10.1038/mt.2008.32GUPTA, P., SU, Z., LEBEDEVA, I., SARKAR, D., SAUANE, M., EMDAD, L., … DENT, P. (2006). mda-7/IL-24: Multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacology & Therapeutics, 111(3), 596-628. doi:10.1016/j.pharmthera.2005.11.005Abbink, P., Lemckert, A. A. C., Ewald, B. A., Lynch, D. M., Denholtz, M., Smits, S., … Barouch, D. H. (2007). Comparative Seroprevalence and Immunogenicity of Six Rare Serotype Recombinant Adenovirus Vaccine Vectors from Subgroups B and D. Journal of Virology, 81(9), 4654-4663. doi:10.1128/jvi.02696-06Mast, T. C., Kierstead, L., Gupta, S. B., Nikas, A. A., Kallas, E. G., Novitsky, V., … Shiver, J. W. (2010). International epidemiology of human pre-existing adenovirus (Ad) type-5, type-6, type-26 and type-36 neutralizing antibodies: Correlates of high Ad5 titers and implications for potential HIV vaccine trials. Vaccine, 28(4), 950-957. doi:10.1016/j.vaccine.2009.10.145Barouch, D. H., Kik, S. V., Weverling, G. J., Dilan, R., King, S. L., Maxfield, L. F., … Goudsmit, J. (2011). International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations. Vaccine, 29(32), 5203-5209. doi:10.1016/j.vaccine.2011.05.025Na, Y., Nam, J.-P., Hong, J., Oh, E., Shin, H. C., Kim, H. S., … Yun, C.-O. (2019). Systemic administration of human mesenchymal stromal cells infected with polymer-coated oncolytic adenovirus induces efficient pancreatic tumor homing and infiltration. Journal of Controlled Release, 305, 75-88. doi:10.1016/j.jconrel.2019.04.040Kasala, D., Yoon, A.-R., Hong, J., Kim, S. W., & Yun, C.-O. (2016). Evolving lessons on nanomaterial-coated viral vectors for local and systemic gene therapy. Nanomedicine, 11(13), 1689-1713. doi:10.2217/nnm-2016-0060Kwon, O.-J., Kang, E., Kim, S., & Yun, C.-O. (2011). Viral genome DNA/lipoplexes elicit in situ oncolytic viral replication and potent antitumor efficacy via systemic delivery. 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Gold Nanoparticle-Assisted Virus Formation by Means of the Delivery of an Oncolytic Adenovirus Genome

Oncolytic adenoviruses are a therapeutic alternative to treat cancer based on their ability to replicate selectively in tumor cells. However, their use is limited mainly by the neutralizing antibody (Nab) immune response that prevents repeated dosing. An alternative to facilitate the DNA access to the tumor even in the presence of anti-viral Nabs could be gold nanoparticles able to transfer DNA molecules. However, the ability of these nanoparticles to carry large DNA molecules, such as an oncolytic adenovirus genome, has not been studied. In this work, gold nanoparticles were functionalized with different amounts of polyethylenimine to transfer in a safe and efficient manner a large oncolytic virus genome. Their transfer efficacy and final effect of the oncolytic virus in cancer cells are studied. For each synthesized nanoparticle, (a) DNA loading capacity, (b) complex size, (c) DNA protection ability, (d) transfection efficacy and (e) cytotoxic effect were studied. We observed that small gold nanoparticles (70-80 nm in diameter) protected DNA against nucleases and were able to transfect the ICOVIR-15 oncolytic virus genome encoded in pLR1 plasmid. In the present work, efficient transgene RNA expression, luciferase activity and viral cytopathic effect on cancer cells are reported. These results suggest gold nanoparticles to be an efficient and safe vector for oncolytic adenovirus genome transfer

Core-Shell Palladium/MOF Platforms as Diffusion-Controlled Nanoreactors in Living Cells and Tissue Models

Translating the potential of transition metal catalysis to biological and living environments promises to have a profound impact in chemical biology and biomedicine. A major challenge in the field is the creation of metal-based catalysts that remain active over time. Here, we demonstrate that embedding a reactive metallic core within a microporous metal-organic framework-based cloak preserves the catalytic site from passivation and deactivation, while allowing a suitable diffusion of the reactants. Specifically, we report the fabrication of nanoreactors composed of a palladium nanocube core and a nanometric imidazolate framework, which behave as robust, long-lasting nanoreactors capable of removing propargylic groups from phenol-derived pro-fluorophores in biological milieu and inside living cells. These heterogeneous catalysts can be reused within the same cells, promoting the chemical transformation of recurrent batches of reactants. We also report the assembly of tissue-like 3D spheroids containing the nanoreactors and demonstrate that they can perform the reactions in a repeated mannerThe authors thank the financial support of the MINECO ( CTQ2017-89588-R , SAF2016-76689-R , CTQ2017-84767-P , RYC-2014-16962 , and RYC-2017-23457 ), the Xunta de Galicia ( ED431F 2017/02 , 2015-CP082 , ED431C 2017/19 , and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03 ), the European Union (European Regional Development Fund [ERDF]; H2020-MSCA-IF-2016 grant agreement no. 749667 ; and INTERREG V-A Spain-Portugal [POCTEP] 2014-2020, project 0624_2IQBIONEURO_6_E ), and the European Research Council (advanced grant no. 340055 ). Support of the orfeo-cinqa network ( CTQ2016-81797-REDC ) is also kindly acknowledgedS