Extracellular Vesicle-Mediated Immune Regulation of Tissue Remodeling and Angiogenesis After Myocardial Infarction

Myocardial ischemia-related disorders constitute a major health problem, being a leading cause of death in the world. Upon ischemia, tissue remodeling processes come into play, comprising a series of inter-dependent stages, including inflammation, cell proliferation and repair. Neovessel formation during late phases of remodeling provides oxygen supply, together with cellular and soluble components necessary for an efficient myocardial reconstruction. Immune system plays a central role in processes aimed at repairing ischemic myocardium, mainly in inflammatory and angiogenesis phases. In addition to cellular components and soluble mediators as chemokines and cytokines, the immune system acts in a paracrine fashion through small extracellular vesicles (EVs) release. These vesicular structures participate in multiple biological processes, and transmit information through bioactive cargoes from one cell to another. Cell therapy has been employed in an attempt to improve the outcome of these patients, through the promotion of tissue regeneration and angiogenesis. However, clinical trials have shown variable results, which put into question the actual applicability of cell-based therapies. Paracrine factors secreted by engrafted cells partially mediate tissue repair, and this knowledge has led to the hypothesis that small EVs may become a useful tool for cell-free myocardial infarction therapy. Current small EVs engineering strategies allow delivery of specific content to selected cell types, thus revealing the singular properties of these vesicles for myocardial ischemia treatment.This work was supported by grants to AA-S (FIS PI15/01491) and to FS-M (grants SAF2014-55579-R and SAF2017-82886-R to FS-M), BIOIMID PIE13/041 and CIBER CARDIOVASCULAR from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria del Instituto de Salud Carlos III with co-funding from the Fondo Europeo de Desarrollo Regional; FEDER), Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to FS-M, and ERC2011-AdG294340-GENTRIS to FS-M, and Fundació La Marató TV3 (20152330 31). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the ProCNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).S

Influence of cracking on oxygen transport in UHPFRC using stainless steel sensors

[EN] Reinforced concrete elements frequently suffer small cracks that are not relevant from the mechanical point of view, but they can be an entrance point for aggressive agents, such as oxygen, which could initiate the degradation processes. Fiber-Reinforced Concrete and especially Ultra High Performance Concrete increase the multi-cracking behavior, reducing the crack width and spacing. In this work, the oxygen availability of three types of concrete was compared at similar strain levels to evaluate the benefit of multi-cracking in the transport of oxygen. The types of concrete studied include traditional, High-Performance, and Ultra-High-Performance Fiber-Reinforced Concrete with and without nanofibers. To this purpose, reinforced concrete beams sized 150 x 100 x 750 mm(3) were prepared with embedded stainless steel sensors that were located at three heights, which have also been validated through this work. These beams were pre-cracked in bending up to fixed strain levels. The results indicate that the sensors used were able to detect oxygen availability due to the presence of cracks and the detected differences between the studied concretes. Ultra High Performance Concrete in the cracked state displayed lower oxygen availability than the uncracked High Performance Concrete, demonstrating its potential higher durability, even when working in cracked state, thanks to the increased multi-cracking response.The authors would like to express their gratitude to the Spanish Ministry of Science and Innovation for the pre-doctoral scholarship granted to Ana Martinez Ibernon (FPU 16/00723), to the Universitat Politecnica de Valencia for the pre-doctoral scholarship granted to Josep Ramon Lliso Ferrando (FPI-UPV-2018), and the European Union's Horizon 2020 ReSHEALience project (Grant Agreement No. 760824).Martínez-Ibernón, A.; Roig-Flores, M.; Lliso-Ferrando, JR.; Mezquida-Alcaraz, EJ.; Valcuende Payá, MO.; Serna Ros, P. (2020). Influence of cracking on oxygen transport in UHPFRC using stainless steel sensors. Applied Sciences. 10(1):1-17. https://doi.org/10.3390/app10010239S117101Front Matter. (2013). fib Model Code for Concrete Structures 2010, I-XXXIII. doi:10.1002/9783433604090.fmatterYoo, D.-Y., & Banthia, N. (2016). Mechanical properties of ultra-high-performance fiber-reinforced concrete: A review. Cement and Concrete Composites, 73, 267-280. doi:10.1016/j.cemconcomp.2016.08.001Wittmann, F., & Van Zijl, G. (Eds.). (2011). Durability of Strain-Hardening Fibre-Reinforced Cement-Based Composites (SHCC). doi:10.1007/978-94-007-0338-4Li, V. C. (2003). On Engineered Cementitious Composites (ECC). Journal of Advanced Concrete Technology, 1(3), 215-230. doi:10.3151/jact.1.215Asgari, M. A., Mastali, M., Dalvand, A., & Abdollahnejad, Z. (2017). Development of deflection hardening cementitious composites using glass fibres for flexural repairing/strengthening concrete beams: experimental and numerical studies. European Journal of Environmental and Civil Engineering, 23(8), 916-944. doi:10.1080/19648189.2017.1327888Ravindrarajah, R. S., & Swamy, R. N. (1989). Load effects on fracture of concrete. Materials and Structures, 22(1), 15-22. doi:10.1007/bf02472690Bascoul, A. (1996). State of the art report—Part 2: Mechanical micro-cracking of concrete. Materials and Structures, 29(2), 67-78. doi:10.1007/bf02486196Damgaard Jensen, A., & Chatterji, S. (1996). State of the art report on micro-cracking and lifetime of concrete—Part 1. Materials and Structures, 29(1), 3-8. doi:10.1007/bf02486001Berrocal, C. G., Löfgren, I., Lundgren, K., Görander, N., & Halldén, C. (2016). Characterisation of bending cracks in R/FRC using image analysis. Cement and Concrete Research, 90, 104-116. doi:10.1016/j.cemconres.2016.09.016Correia, M. J., Pereira, E. V., Salta, M. M., & Fonseca, I. T. E. (2006). Sensor for oxygen evaluation in concrete. Cement and Concrete Composites, 28(3), 226-232. doi:10.1016/j.cemconcomp.2006.01.006Yoon, I.-S. (2018). Comprehensive Approach to Calculate Oxygen Diffusivity of Cementitious Materials Considering Carbonation. International Journal of Concrete Structures and Materials, 12(1). doi:10.1186/s40069-018-0242-yBanthia, N., Zanotti, C., & Sappakittipakorn, M. (2014). Sustainable fiber reinforced concrete for repair applications. Construction and Building Materials, 67, 405-412. doi:10.1016/j.conbuildmat.2013.12.073Berrocal, C. G., Löfgren, I., & Lundgren, K. (2018). The effect of fibres on steel bar corrosion and flexural behaviour of corroded RC beams. Engineering Structures, 163, 409-425. doi:10.1016/j.engstruct.2018.02.068Sisomphon, K., Copuroglu, O., & Koenders, E. A. B. (2012). Self-healing of surface cracks in mortars with expansive additive and crystalline additive. Cement and Concrete Composites, 34(4), 566-574. doi:10.1016/j.cemconcomp.2012.01.005Ferrara, L., Krelani, V., & Carsana, M. (2014). A «fracture testing» based approach to assess crack healing of concrete with and without crystalline admixtures. Construction and Building Materials, 68, 535-551. doi:10.1016/j.conbuildmat.2014.07.008Roig-Flores, M., Pirritano, F., Serna, P., & Ferrara, L. (2016). Effect of crystalline admixtures on the self-healing capability of early-age concrete studied by means of permeability and crack closing tests. Construction and Building Materials, 114, 447-457. doi:10.1016/j.conbuildmat.2016.03.196López, J. Á., Serna, P., Navarro-Gregori, J., & Camacho, E. (2014). An inverse analysis method based on deflection to curvature transformation to determine the tensile properties of UHPFRC. Materials and Structures, 48(11), 3703-3718. doi:10.1617/s11527-014-0434-0Lopez, J. A., Serna, P., Camacho, E., Coll, H., & Navarro-Gregori, J. (2014). First Ultra-High-Performance Fibre-Reinforced Concrete Footbridge in Spain: Design and Construction. Structural Engineering International, 24(1), 101-104. doi:10.2749/101686614x13830788505793Negrini, A., Roig-Flores, M., Mezquida-Alcaraz, E. J., Ferrara, L., & Serna, P. (2019). Effect of crack pattern on the self-healing capability in traditional, HPC and UHPFRC concretes measured by water and chloride permeability. MATEC Web of Conferences, 289, 01006. doi:10.1051/matecconf/20192890100

Extracellular Vesicle-Mediated Immune Regulation of Tissue Remodeling and Angiogenesis After Myocardial Infarction

Myocardial ischemia-related disorders constitute a major health problem, being a leading cause of death in the world. Upon ischemia, tissue remodeling processes come into play, comprising a series of inter-dependent stages, including inflammation, cell proliferation and repair. Neovessel formation during late phases of remodeling provides oxygen supply, together with cellular and soluble components necessary for an efficient myocardial reconstruction. Immune system plays a central role in processes aimed at repairing ischemic myocardium, mainly in inflammatory and angiogenesis phases. In addition to cellular components and soluble mediators as chemokines and cytokines, the immune system acts in a paracrine fashion through small extracellular vesicles (EVs) release. These vesicular structures participate in multiple biological processes, and transmit information through bioactive cargoes from one cell to another. Cell therapy has been employed in an attempt to improve the outcome of these patients, through the promotion of tissue regeneration and angiogenesis. However, clinical trials have shown variable results, which put into question the actual applicability of cell-based therapies. Paracrine factors secreted by engrafted cells partially mediate tissue repair, and this knowledge has led to the hypothesis that small EVs may become a useful tool for cell-free myocardial infarction therapy. Current small EVs engineering strategies allow delivery of specific content to selected cell types, thus revealing the singular properties of these vesicles for myocardial ischemia treatment

Immune synapse instructs epigenomic and transcriptomic functional reprogramming in dendritic cells.

Understanding the fate of dendritic cells (DCs) after productive immune synapses (postsynaptic DCs) with T cells during antigen presentation has been largely neglected in favor of deciphering the nuances of T cell activation and memory generation. Here, we describe that postsynaptic DCs switch their transcriptomic signature, correlating with epigenomic changes including DNA accessibility and histone methylation. We focus on the chemokine receptor Ccr7 as a proof-of-concept gene that is increased in postsynaptic DCs. Consistent with our epigenomic observations, postsynaptic DCs migrate more efficiently toward CCL19 in vitro and display enhanced homing to draining lymph nodes in vivo. This work describes a previously unknown DC population whose transcriptomics, epigenomics, and migratory capacity change in response to their cognate contact with T cells.This study was supported by grant SAF2017-82886-R from the Spanish Ministry of Economy and Competitiveness (MINECO), grant S2017/BMD-3671-INFLAMUNE-CM from the Comunidad de Madrid, a grant from the Ramon Areces Foundation “Ciencias de la Vida y la Salud” (XIX Concurso-2018), a grant from Ayudas Fundacion BBVA a Equipos de Investigacion Cientifica (BIOMEDICINA-2018), the Fundacio Marato TV3 (grant 122/C/2015), “la Caixa” Banking Foundation (HR17-00016), BIOIMID (PIE13/041) from Instituto de Salud Carlos III, CIBER Cardiovascular (CB16/11/00272), and Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo Regional FEDER). D.C.-F. is supported by a Fellowship from “la Caixa” Foundation (LCF/BQ/DR19/11740010). I.F.-D. is supported by a Fellowship from the Spanish Ministry of Science, Innovation, and Universities (FPU15/02539). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015- 0505). Funding agencies did not intervene in the design of the studies, with no copyright over the study.S

Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 patients

SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID-19. We investigated whether the specific immune responses in the peripheral blood of 276 patients were associated with the severity and progression of COVID-19. At admission, dramatic lymphopenia of T, B, and NK cells is associated with severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56–CD16+ NK-cells increased. Regarding humoral immunity, levels of IgM, IgA, and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless of their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes, and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID-19 patients, associating severity with an imbalanced humoral response, and identifying new targets for therapeutic interventionThe study was funded by grants SAF2017- 82886-R to FS-M from the Ministerio de Economía y Competitividad, and from “La Caixa Banking Foundation” (HR17-00016) to FS-M. Grant PI018/01163 to CMC and grant PI19/00549 to AA were funded by Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo, Spain. SAF2017-82886-R, PI018/01163 and PI19/00549 grants were also co-funded by European Regional Development Fund, ERDF/FEDER. This work has been funded by grants Fondo Supera COVID (CRUE-Banco de Santander) to FSM, and “Ayuda Covid 2019” from Comunidad de Madri

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Mechanical Behavior of Calcium Sulphate Modified with Citric Acid and with Added Carbon Fibers

The study and subsequent analysis of the interaction of calcium sulfate with added citric acid and with two additional proportions of carbon fibers of different lengths has been based on the IMR and D Method for its realization. The purpose of this work is the study of the physical and mechanical behavior of the resulting material between the intimate mixture of calcium sulfate with additives and carbon fibers, justifying said work with a link to the Sustainable Development Goals (SDG) regarding the benefits that the Calcium sulfate has contributed to civil society since times dating back to ancient Egypt. We find ourselves with a material of which the energy used in its manufacture is far from that required by steel or cement, and construction with this new compound is in a much higher stage than construction with adobe. Therefore, this is a compound that can be developed for a wide variety of applications. The novelty of this study is the inclusion of polymeric fibers in a material used over the centuries to improve its mechanical properties. With these improvements we will be able to reduce thicknesses in manufacturing, which implies a reduction in manufacturing energy and weight structures in buildings, which should be studied and analyzed in the future. The kneading of calcium sulfate with long fibers at high percentages complicates not only the results, but also the manufacturing process. As representative results of the study, we can indicate that a composite material with high mechanical capacity has been achieved, with maximum values of flexural strength of 8.12 N/mm2 and compression strength of 17.58 N/mm2

Mechanical Behavior of Calcium Sulphate Modified with Citric Acid and with Added Carbon Fibers

The study and subsequent analysis of the interaction of calcium sulfate with added citric acid and with two additional proportions of carbon fibers of different lengths has been based on the IMR and D Method for its realization. The purpose of this work is the study of the physical and mechanical behavior of the resulting material between the intimate mixture of calcium sulfate with additives and carbon fibers, justifying said work with a link to the Sustainable Development Goals (SDG) regarding the benefits that the Calcium sulfate has contributed to civil society since times dating back to ancient Egypt. We find ourselves with a material of which the energy used in its manufacture is far from that required by steel or cement, and construction with this new compound is in a much higher stage than construction with adobe. Therefore, this is a compound that can be developed for a wide variety of applications. The novelty of this study is the inclusion of polymeric fibers in a material used over the centuries to improve its mechanical properties. With these improvements we will be able to reduce thicknesses in manufacturing, which implies a reduction in manufacturing energy and weight structures in buildings, which should be studied and analyzed in the future. The kneading of calcium sulfate with long fibers at high percentages complicates not only the results, but also the manufacturing process. As representative results of the study, we can indicate that a composite material with high mechanical capacity has been achieved, with maximum values of flexural strength of 8.12 N/mm2 and compression strength of 17.58 N/mm2

Monoclonal Antibody Therapies for Hematological Malignancies: Not Just Lineage-Specific Targets

Today, monoclonal antibodies (mAbs) are a widespread and necessary tool for biomedical science. In the hematological cancer field, since rituximab became the first mAb approved by the Food and Drug Administration for the treatment of B-cell malignancies, a number of effective mAbs targeting lineage-specific antigens (LSAs) have been successfully developed. Non-LSAs (NLSAs) are molecules that are not restricted to specific leukocyte subsets or tissues but play relevant pathogenic roles in blood cancers including the development, proliferation, survival, and refractoriness to therapy of tumor cells. In consequence, efforts to target NLSAs have resulted in a plethora of mAbs—marketed or in development—to achieve different goals like neutralizing oncogenic pathways, blocking tumor-related chemotactic pathways, mobilizing malignant cells from tumor microenvironment to peripheral blood, modulating immune-checkpoints, or delivering cytotoxic drugs into tumor cells. Here, we extensively review several novel mAbs directed against NLSAs undergoing clinical evaluation for treating hematological malignancies. The review focuses on the structure of these antibodies, proposed mechanisms of action, efficacy and safety profile in clinical studies, and their potential applications in the treatment of hematological malignancies

Aurora A controls CD8+ T cell cytotoxic activity and antiviral response

Aurora A is a serine/threonine kinase whose role in cell cycle progression and tumour generation has been widely studied. Recent work has revealed an unexpected function for Aurora A during CD4+ T cell activation and, also, in graft versus host disease development. However, it remains unknown whether Aurora A is involved in CD8+ T cell effector function and in cytotoxic T lymphocyte-mediated antiviral response. Here, we show that Aurora A chemical inhibition leads to an impairment of both the peptide-specific cytotoxicity and the degranulation activity of CD8+ T cells. This finding was similarly proven for both mice and human CD8+ CTL activity. As a result of Aurora A blockade, we detected a reduction in the expression induced by T cell activation of genes classically related to the effector function of cytotoxic T lymphocytes such as granzyme B or perforin1. Finally, we have found that Aurora A is necessary for CD8+ T cell-mediated antiviral response, in an in vivo model of vaccinia virus infection. Thus, we can conclude that Aurora A activity is, indeed, needed for the proper effector function of cytotoxic T lymphocytes and for their activity against viral threats.This study was supported by grants SAF2017/82886-R and BIO2012-37926 from the Spanish Ministry of Economy and Competitiveness, INFLAMUNE-CAMS2017/BMD-3671 from the Comunidad de Madrid and ERC-2011-AdG 294340-GENTRIS. Red Cardiovascular RD 12-0042-0056 from Instituto Salud Carlos III (ISCIII) and also CIBER Cardiovascular. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and it is a Severo Ochoa Centre of Excellence (SEV-2015-0505).S