Bex3 dimerization regulates NGF-dependent neuronal survival and differentiation by enhancing trkA gene transcription

The development of the nervous system is a temporally and spatially coordinated process that relies on the proper regulation of the genes involved. Neurotrophins and their receptors are directly responsible for the survival and differentiation of sensory and sympathetic neurons; however, it is not fully understood how genes encoding Trk neurotrophin receptors are regulated. Here, we show that rat Bex3 protein specifically regulates TrkA expression by acting at the trkA gene promoter level. Bex3 dimerization and shuttling to the nucleus regulate the transcription of the trkA promoter under basal conditions and also enhance nerve growth factor (NGF)-mediated trkA promoter activation. Moreover, qChIP assays indicate that Bex3 associates with the trkA promoter within a 150 bp sequence, immediately upstream from the transcription start site, which is sufficient to mediate the effects of Bex3. Consequently, the downregulation of Bex3 using shRNA increases neuronal apoptosis in NGF-dependent sensory neurons deprived of NGF and compromises PC12 cell differentiation in response to NGF. Our results support an important role for Bex3 in the regulation of TrkA expression and in NGF-mediated functions through modulation of the trkA promoter.This work was supported by Ministerio de Ciencia e Innovación Grant BFU2008-00162, by Ministerio de Economía y Competitividad Grant (BFU2011-22898 to J.C.A. and BFU2013-39394-P to P.P.), by a Marie Curie International Reintegration Grant within the European Community 7th Framework Programme, by the Consejería de Educación Grant SA074A08, and by a Consejería de Sanidad de Junta Castilla y León grant to J.C.A. This work was in part supported by the FP7-PAINCAGE integrative project. D.M.-Z. is funded by a grant from the Spanish “Instituto de Saludo Carlos III” PI1202847. L.C. has been the recipient of a Predoctoral Fellowship from the University of Salamanca. J.C.A. was a “Ramón y Cajal” Investigator from the University of Salamanca and a NARSAD 2009 Young Investigator Awardee.Peer Reviewe

AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins

The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression. We modulated the abundance of specific AKT isoforms in IBH-6 and T47D human breast cancer cell lines and showed that AKT1 promoted cell proliferation, through S6 and cyclin D1 upregulation, but it inhibited cell migration and invasion through β1-integrin and focal adhesion kinase (FAK) downregulation. In contrast, AKT2 promoted cell migration and invasion through F-actin and vimentin induction. Thus, while overexpression of AKT1 promoted local tumor growth, downregulation of AKT1 or overexpression of AKT2 promoted peritumoral invasion and lung metastasis. Furthermore, we evaluated The Cancer Genome Atlas (TCGA) dataset for invasive breast carcinomas and found that increased AKT2 but not AKT1 mRNA levels correlated with a worse clinical outcome. We conclude that AKT isoforms play specific roles in different steps of breast cancer progression, with AKT1 involved in the local tumor growth and AKT2 involved in the distant tumor dissemination, having AKT2 a poorer prognostic value and consequently being a worthwhile target for therapy.Fil: Riggio, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Perrone, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Polo, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rodriguez, Maria Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: May, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Abba, Martín Carlos. Universidad Nacional de La Plata; ArgentinaFil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Novaro, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Role of Curing Temperature of Poly(Glycerol Sebacate) Substrates on Protein-Cell Interaction and Early Cell Adhesion

[EN] A novel procedure to obtain smooth, continuous polymeric surfaces from poly(glycerol sebacate) (PGS) has been developed with the spin-coating technique. This method proves useful for separating the effect of the chemistry and morphology of the networks (that can be obtained by varying the synthesis parameters) on cell-protein-substrate interactions from that of structural variables. Solutions of the PGS pre-polymer can be spin-coated, to then be cured. Curing under variable temperatures has been shown to lead to PGS networks with different chemical properties and topographies, conditioning their use as a biomaterial. Particularly, higher synthesis temperatures yield denser networks with fewer polar terminal groups available on the surface. Material-protein interactions were characterised by using extracellular matrix proteins such as fibronectin (Fn) and collagen type I (Col I), to unveil the biological interface profile of PGS substrates. To that end, atomic force microscopy (AFM) images and quantification of protein adsorbed in single, sequential and competitive protein incubations were used. Results reveal that Fn is adsorbed in the form of clusters, while Col I forms a characteristic fibrillar network. Fn has an inhibitory effect when incubated prior to Col I. Human umbilical endothelial cells (HUVECs) were also cultured on PGS surfaces to reveal the effect of synthesis temperature on cell behaviour. To this effect, early focal adhesions (FAs) were analysed using immunofluorescence techniques. In light of the results, 130 degrees C seems to be the optimal curing temperature since a preliminary treatment with Col I or a Fn:Col I solution facilitates the formation of early focal adhesions and growth of HUVECs.This research was funded by the Spanish Ministerio de Economia y Competitividad, grant number DPI2015-65401-C3-2-R. A. Valles acknowledges the support of the Generalitat Valenciana, Conselleria de Educacion, Investigacion, Cultura y Deporte through project AEST/2020/052.Martín-Cabezuelo, R.; Rodriguez-Hernandez, J.; Vilariño, G.; Vallés Lluch, A. (2021). Role of Curing Temperature of Poly(Glycerol Sebacate) Substrates on Protein-Cell Interaction and Early Cell Adhesion. Polymers. 13(3):1-14. https://doi.org/10.3390/polym13030382S11413

Evaluación técnica y económica para el mejoramiento de suelos finos con fines de cimentación, por medio de compactación dinámica e inclusiones rígidas

El presente trabajo de tesis tuvo como finalidad evaluar de manera técnica y económica los mejoramientos de suelos finos a través de los métodos de compactación dinámica e inclusiones rígidas. Estas técnicas mejoran de manera significativa las propiedades geotécnicas de los suelos en su estado natural, como es la capacidad portante, reducir su nivel de asentamiento y evitar el fenómeno de licuación. La Compactación Dinámica (C.D.) es una técnica desarrollada en Europa y que se está aplicando en Sudamérica con buenos resultados, consiste en aplicar impactos continuos de una masa a cierta altura, que comprime el suelo con una determinada energía de impacto, logrando mejorar las propiedades mecánicas del suelo. Detallaremos un caso práctico de C.D. realizado en el Perú y como fue el proceso de mejoramiento de suelo. Se analizaron las características antes durante y después, a través de ensayos de campo y de laboratorio, bajo el soporte de la normativa técnica vigente (N.T.E. 050), estos suelos al ser finos y colapsables presentaron una capacidad portante inicial de 0.80 Kg/cm2, con esta técnica evaluaremos como se logró mejorar dicho valor y reducir el asentamiento de manera significativa. De las inclusiones rígidas se efectúa un modelo teórico para evaluar las propiedades del suelo del caso práctico. Con los resultados obtenidos en ambos casos, se ha procedido a evaluar y comparar de manera técnica, considerando el tiempo y el costo, con la finalidad de obtener conclusiones y recomendaciones que ratifiquen los objetivos del presente trabajo.Tesi

Selection and publication of network interface cards in multihomed pervasive computing devices

Proceedings of the 8th IEEE International Workshop on Middleware and system support for pervasive computing, march 21-25, 2011, Seattle, USAMany modern devices come with several, heterogeneous, network interface cards (NICs). However, simple operations like transferring data flows to the cheapest NIC or to one with enough Quality of Service (QoS) are awkward tasks on most Operating Systems. In this paper, we discuss the criteria to select the proper NIC for a given data flow. We also present a new Operating System service, called netqos, to publish data and figures of merit for these criteria. The main objective of netqos is providing relevant information to applications and middleware about NIC selection criteria, isolating them from the idiosyncrasies of the many QoS gathering tools and allowing to choose the proper NIC to fit their needs. We have built this new service as a synthetic file system for the Linux kernel. We describe our experiences in using it in a real-world scenario and the practical and inherent limitations of this approachProyecto CCG10-UC3M/TIC-4992 de la Comunidad Autónoma de Madrid y la Universidad Carlos III de Madri

Il-15 enhances the persistence and function of bcma-targeting car-t cells compared to il-2 or il-15/il-7 by limiting car-t cell dysfunction and differentiation

Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the treatment of B-lymphoid malignancies. For multiple myeloma (MM), B-cell maturation antigen (BCMA)-targeted CAR-T cells have achieved outstanding complete response rates, but unfortunately, patients often relapse within a year of receiving the therapy. Increased persistence and reduced dysfunction are crucial features that enhance the durability of CAR-T cell responses. One of the factors that influence CAR-T cell in vivo longevity and loss of function, but which has not yet been extensively studied for BCMA-directed CAR-T cells, are the cytokines used during their production. We here compared the impact of IL-2, IL-15 and a combination of IL-15/IL-7 on the phenotype and function of ARI2h, an academic BCMA-directed CAR-T cell that is currently being administered to MM patients. For this study, flow cytometry, in vitro cytotoxicity assays and analysis of cytokine release were performed. In addition, ARI2h cells expanded with IL-2, IL-15, or IL-15/IL-7 were injected into MM tumor-bearing mice to assess their in vivo efficacy. We demonstrated that each of the cytokine conditions was suitable for the expansion of ARI2h cells, with clear in vitro activity. Strikingly, however, IL-15-produced ARI2h cells had improved in vivo efficacy and persistence. When explored further, it was found that IL-15 drove a less-differentiated ARI2h phenotype, ameliorated parameters related to CAR-T cell dysfunction, and lowered the release of cytokines potentially involved in cytokine release syndrome and MM progression. Moreover, we observed that IL-15 was less potent in inducing T cell senescence and DNA damage accumulation, both of which may contribute to an unfavorable CAR-T cell phenotype. These findings show the superiority of IL-15 to IL-2 and IL-15/IL-7 in the quality of anti-BCMA CAR-T cells, particularly their efficacy and persistence, and as such, could improve the duration of responses if applied to the clinical production of CAR-T cells for patients

Deletion Syndrome 22q11.2: A Systematic Review

DiGeorge syndrome; Congenital anomalies; Velocardiofacial syndromeSíndrome de DiGeorge; Anomalías congénitas; Síndrome velocardiofacialSíndrome de DiGeorge; Anomalies congènites; Síndrome velocardiofacial22q11.2 deletion syndrome (DS 22q11.2) is a rare disease of genetic origin, caused by the loss of the q11.2 region of chromosome 22. It affects one in 4000 live newborns, and among the clinical manifestations that can occur in this syndrome are abnormalities in the parathyroid glands (producing calcium deficits), the palate, the heart and the thymus. It is also known as DiGeorge syndrome or velocardiofacial syndrome, among other names, depending on the clinical presentation of each individual. The main objective of the review was to update information on DS 22q11.2 from publications in the scientific literature. The daily activities of these patients are seriously impaired, due to the impact of the clinical manifestations. Interventions can be performed to improve their social, cognitive and emotional skills, thus increasing their ability to perform different daily activities

Analysis of location prediction performance of LZ algorithms using GSM Cell-based location data

Proceedings of the 5th International Symposium of Ubiquitous Computing and Ambient Intelligence (UCAMI 2011), December 5-8th, 2011, Riviera Maya, MexicoPredictions about users' next locations allow bringing forward their future context, thus having additional time to react. To make such predictions, algorithms capable of learning mobility patterns and estimating the next location are needed. This work is focused on making the predictions on mobile terminals, thus resource consumption being an important constraint. Among the predictors with low resource consumption, the family of LZ algorithms has been chosen to study their performance, analyzing the results drawn from processing location records of 95 users. The main contribution is to divide the algorithms into two phases, thus being possible to use the best combination to obtain better prediction accuracy or lower resource consumption.Proyecto CCG10-UC3M/TIC-4992 de la Comunidad Autónoma de Madrid y la Universidad Carlos III de Madri

Telemedicine approach for patient follow-up after total knee and reverse total shoulder arthroplasty: a pilot study

Arthroplasty; Internet-based intervention; TelehealthArtroplàstia; Intervenció basada en Internet; TelesalutArtroplastia; Intervención basada en Internet; TelesaludPurpose: The study aimed to demonstrate the reduction in postoperative follow-up visit time for patients receiving total knee arthroplasty (TKA) or reverse total shoulder arthroplasty (RTSA) by implementing a novel asynchronous telemedicine system compared to face-to-face visits. The range of motion interobserver agreement and patient satisfaction were evaluated in the telemedicine group. Methods: A randomized controlled trial was conducted with a total of 28 patients with a mean age of 71 years (range 13.3). Patients were distributed into two study groups, TKA (n = 14) and RTSA (n = 14), and each group was randomly allocated into a face-to-face or virtual follow-up visit group. For the virtual group, software was designed including patient-specific model items (X-ray, range of motion and functional scores) for each arthroplasty. Functional assessment was conducted using the International Knee Documentation Committee (IKDC) score for TKA and American Shoulder and Elbow score (ASES) and Simple Shoulder Test (SST) for RTSA. The range of motion interobserver concordance was conducted in the virtual follow-up groups via an intraclass correlation coefficient. Finally, a satisfaction survey was performed in the virtual follow-up groups. Mann-Whitney U test was used for statistical analysis. Results: Mean time differences between face-to-face and virtual follow-ups were 502.5 s (95% CI 387.8-617.1; p < 0.002) in the RTSA group and 710 s (95% CI 597.91-822; p < 0. 002) in the TKA group. The range of motion interobserver concordance in the virtual group was 0.974 for TKA and 0.804 for RTSA. Finally, virtual follow-up satisfaction using the telematic method was 8.9 out of 10. Conclusion: The results of this study showed that a virtual follow-up using asynchronous telemedicine systems could reduce visit times, allow a correct articular range of motion evaluation and maintain satisfaction perception for patients. Asynchronous telemedicine could be an efficient method to conduct postoperative follow-up after knee and shoulder arthroplasty

Pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in bipolar disorder: A systematic review

Background: The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic symptomatology of bipolar disorder (BD). Among a broad range of mechanisms implicated, immune dysregulation may contribute to the increased inflammation that influences the course of BD. Inflammatory, neurotrophic and oxidative stress factors may be identified as promising peripheral biomarkers in brain functioning, perhaps serving as predictors of an effective response to treatment for BD. The present systematic review aimed to examine the evidence supporting the pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in BD. Methods: PubMed, PsychINFO, Scopus and Web of Science were searched from inception to May 2024 by two independent reviewers. A total of 40 studies with 3371 patients with diagnosis and intervention of BD were selected. Results: Inconsistencies in the effects of pharmacological treatments on the connection between the expected anti- inflammatory response and symptomatologic improvement were identified. Mood stabilizers (lithium), antipsychotics (quetiapine), antidepressants (ketamine) or their combination were described to increase both pro- inflammatory (TNFα, IL-6) and anti-inflammatory (IL-4, IL-8) factors. Other medications, such as memantine and dextromethorphan, autoimmune (infliximab) non-steroidal anti-inflammatory (aspirin, celecoxib) drugs, antidiabetics (pioglitazone), and even dietary supplementation (omega-3), or their combination, clearly decrease inflammatory factors (TNFα, IL-6, IL-1β, C-reactive protein) and/or increase the neurotrophic factor BDNF in BD patients. Conclusion: Inflammation in BD requires further investigation to understand the underlying immunologic mechanism, to identify predictors of treatment response, and to make informed decisions about the use and development of more effective pharmacological interventions for BD.RICORDS Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación and European Regional Development Funds-European Union (ERDF-EU), grant number RD21/0009/0003; ISCIII, ERDF-EU, grant number PI22/00427; Ministerio de Sanidad, Delegación de Gobierno para el Plan Nacional sobre Drogas (PND), grant numbers 2019I040, 2020I048 and 2022I020; Proyectos de Excelencia I + D + i (PAIDI 2020), Consejería de Universidad, Investigación e Innovación, Junta de Andalucía, grant number PI21/00291. PR-S (CM21/00097), CG-S-L (CM19/00240) and JH-I (CM21/00255) hold “Rio Hortega” research contracts from the National System of Health, ISCIII, ERDF-EU. Patricia Rivera is supported by the research contract “Miguel Servet” (CP19/00068) of the National System of Health, ERDF-EU-ISCIII, cofunded by European Social Fund, “Investing in your future”, Government of Spain. Funding for open access charge: Universidad de Málaga / CBUA. The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in writing of the report; and in the decision to submit the paper for publication