Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180–Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models.Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: González, Nazareno. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ciarlantini, Matias Sebastián. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Gandolfi Donadío, Lucía. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Comin, Maria Julieta. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Two-dimensional plasmons in the random impedance network model of disordered thin-film nanocomposites

Random impedance networks are widely used as a model to describe plasmon resonances in disordered metal-dielectric nanocomposites. In order to study thin films, two-dimensional networks are often used despite the fact that such networks correspond to a two-dimensional electrodynamics [J.P. Clerc et al, J. Phys. A 29, 4781 (1996)]. In the present work, we propose a model of two-dimensional systems with three-dimensional Coulomb interaction and show that this model is equivalent to a planar network with long-range capacitive connections between sites. In a case of a metal film, we get a known dispersion $\omega \propto \sqrt{k}$ of plane-wave two-dimensional plasmons. In the framework of the proposed model, we study the evolution of resonances with decreasing of metal filling factor. In the subcritical region with metal filling $p$ lower than the percolation threshold $p_c$, we observe a gap with Lifshitz tails in the spectral density of states (DOS). In the supercritical region $p>p_c$, the DOS demonstrates a crossover between plane-wave two-dimensional plasmons and resonances associated with small clusters.Comment: 8 pages, 3 figures, revtex; references adde

Turbulent electromagnetic fields at sub-proton scales: Two-fluid and full-kinetic plasma simulations

Plasma dynamics is a multi-scale problem that involves many spatial and temporal scales. Turbulence connects the disparate scales in this system through a cascade that is established by nonlinear interactions. Most astrophysical plasma systems are weakly collisional, making a fully kinetic Vlasov description of the system essential. The use of reduced models to study such systems is computationally desirable, but careful benchmarking of physics in different models is needed. We perform one such comparison here between the fully kinetic Particle-In-Cell model and a two-fluid model that includes Hall physics and electron inertia, with a particular focus on the sub-proton scale electric field. We show that in general, the two fluid model captures large scale dynamics reasonably well. At smaller scales, the Hall physics is also captured reasonably well by the fluid code, but electron features show departures from the fully kinetic model. Implications for the use of such fluid models are discussed.Fil: González, C. A.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; ArgentinaFil: Parashar, T.. University of Delaware; Estados UnidosFil: Gomez, Daniel Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio(i); ArgentinaFil: Matthaeus, W. H.. University of Delaware; Estados UnidosFil: Dmitruk, Pablo Ariel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Long-term dynamics of somatosensory activity in a stroke model of distal middle cerebral artery oclussion

A constant challenge in experimental stroke is the use of appropriate tests to identify signs of recovery and adverse effects linked to a particular therapy. In this study, we used a long-term longitudinal approach to examine the functional brain changes associated with cortical infarction in a mouse model induced by permanent ligation of the middle cerebral artery (MCA). Sensorimotor function and somatosensory cortical activity were evaluated with fault-foot and forelimb asymmetry tests in combination with somatosensory evoked potentials. The stroke mice exhibited both long-term deficits in the functional tests and impaired responses in the infarcted and intact hemispheres after contralateral and ipsilateral forepaw stimulation. In the infarcted hemisphere, reductions in the amplitudes of evoked responses were detected after contralateral and ipsilateral stimulation. In the intact hemisphere, and similar to cortical stroke patients, a gradual hyperexcitability was observed after contralateral stimulation but no parallel evidence of a response was detected after ipsilateral stimulation. Our results suggest the existence of profound and persistent changes in the somatosensory cortex in this specific mouse cortical stroke model. The study of evoked potentials constitutes a feasible and excellent tool for evaluating the fitness of the somatosensory cortex in relation to functional recovery after preclinical therapeutic intervention

Temporal variability of waves at the proton cyclotron frequency upstream from Mars: Implications for Mars distant hydrogen exosphere

We report on the temporal variability of the occurrence of waves at the local proton cyclotron frequency upstream from the Martian bow shock from Mars Global Surveyor observations during the first aerobraking and science phasing orbit periods. Observations at high southern latitudes during minimum-to-mean solar activity show that the wave occurrence rate is significantly higher around perihelion/ southern summer solstice than around the spring and autumn equinoxes. A similar trend is observed in the hydrogen (H) exospheric density profiles over the Martian dayside and South Pole obtained from a model including UV thermospheric heating effects. In spite of the complexity in the ion pickup and plasma wave generation and evolution processes, these results support the idea that variations in the occurrence of waves could be used to study the temporal evolution of the distant Martian H corona and its coupling with the thermosphere at altitudes currently inaccessible to direct measurements.Fil: Bertucci, Cesar. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Romanelli, Norberto Julio. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Chaufray, J. Y.. LATMOS; FranciaFil: Gomez, Daniel Osvaldo. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Mazelle, C.. IRAP; FranciaFil: Delva, M.. IWF-ÖAW; AustriaFil: Modolo, R.. LATMOS; FranciaFil: González Galindo, F.. Instituto de Astrofísica de Andalucía; EspañaFil: Brain, D. A.. University of Colorado Boulder; Estados Unido

Global Emergence of Resistance to Fluconazole and Voriconazole in Candida parapsilosis in Tertiary Hospitals in Spain During the COVID-19 Pandemic

Candida parapsilosis; Antifungal resistance; OutbreaksCandida parapsilosis; Resistencia antifúngica; BrotesCandida parapsilosis; Resistència antifúngica; BrotsBackground Candida parapsilosis is a frequent cause of candidemia worldwide. Its incidence is associated with the use of medical implants, such as central venous catheters or parenteral nutrition. This species has reduced susceptibility to echinocandins, and it is susceptible to polyenes and azoles. Multiple outbreaks caused by fluconazole-nonsusceptible strains have been reported recently. A similar trend has been observed among the C. parapsilosis isolates received in the last 2 years at the Spanish Mycology Reference Laboratory. Methods Yeast were identified by molecular biology, and antifungal susceptibility testing was performed using the European Committee on Antimicrobial Susceptibility Testing protocol. The ERG11 gene was sequenced to identify resistance mechanisms, and strain typing was carried out by microsatellite analysis. Results We examined the susceptibility profile of 1315 C. parapsilosis isolates available at our reference laboratory between 2000 and 2021, noticing an increase in the number of isolates with acquired resistance to fluconazole, and voriconazole has increased in at least 8 different Spanish hospitals in 2020–2021. From 121 recorded clones, 3 were identified as the most prevalent in Spain (clone 10 in Catalonia and clone 96 in Castilla-Leon and Madrid, whereas clone 67 was found in 2 geographically unrelated regions, Cantabria and the Balearic Islands). Conclusions Our data suggest that concurrently with the coronavirus disease 2019 pandemic, a selection of fluconazole-resistant C. parapsilosis isolates has occurred in Spain, and the expansion of specific clones has been noted across centers. Further research is needed to determine the factors that underlie the successful expansion of these clones and their potential genetic relatedness.O.Z. was funded by grants SAF2017–86912-R and PID2020–114546RB-I00 from the Spanish Ministry for Science and Innovation. This work was also funded by the National Centre for Microbiology (Instituto de Salud Carlos III) through the Surveillance Program of Antifungal Resistance and the Center for Biomedical Research in Network of Infectious Diseases CIBERINFECTCB21/13/00105 (O.Z. and L.A.F.), CIBERINFEC-CB21/13/00009 (M.P.-A.), CIBERES-CB06/06/0037 (C.A.-T.), and CIBERES-CB06/06/0058 (J.G). L.A.-F. was supported by Fondo de Investigación Sanitaria (MPY 117/18 and MPY 305/20). We thank Dr. David Campany Herrero (Vall d’Hebron Hospital), Noelia Garrido Peño (Móstoles Hospital), David Gómez Gómez y Aitziber Illaro Uranga (Marqués de Valdecilla Hospital), María Ángeles Machín Morón (Burgos Hospital), Jose Manuel Caro Teller (Doce de Octubre Hospital), Marina Calvo (Puerta de Hierro Hospital), and Ariadna Padulles (Bellvitge Hospital) for providing the data on antifungal consumption from their hospitals. We also thank Ángel Zaballos and Pilar Jiménez from the Genomics Core Facility from Instituto de Salud Carlos III for their technical help with the microsatellite analysis technique

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A116 is also able to inhibit the oncogenic Rac1P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development.Fil: González, Nazareno. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chinestrad, Patricio Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; ArgentinaFil: Robles Valero, Javier. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Rodríguez Fdez, Sonia. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Lorenzo Martín, L. Francisco. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Bustelo, Xosé R.. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Farmacología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Integración de un amplificador de RF de alto rendimiento con un amplificador de envolvente con red de cancelación de rizado mediante la técnica de EER

En este artículo se presenta la integración de un amplificador de envolvente de una etapa con un amplificador de clase E mediante la técnica de Kahn o Eliminación y restauración de envolvente (EER). Esta técnica se basa en la combinación de un amplificador de potencia conmutado de alto rendimiento alimentado por una fuente de alimentación modulada. El amplificador de envolvente se ha implementado con un convertidor reductor síncrono con red de cancelación de rizado, lo cual permite reducir la relación entre la frecuencia de conmutación y el ancho de banda de gran señal del amplificador de envolvente, que es uno de los factores de diseño más limitantes en esta aplicación. Para la mejora de la linealidad se ha usado la técnica de predistorsión realizándose una validación experimental. El amplificador de envolvente conmuta a 4MHz y el amplificador de clase E a 100MHz. El rendimiento total obtenido para una modulación de amplitud en cuadratura (QAM) es del 68%, con un relación de potencia del canal adyacente (ACPR) de 40dB. Para una modulación por multiplexación por división de frecuencias ortogonales (OFDM), se ha obtenido un rendimiento total del 57% y un ACPR de 32dB.

Tecnologías aplicadas al sector agrícola.

El desperdicio de alimentos, la escasez de recursos naturales, el cambio climático y el crecimiento de la población son las cuatro piezas del rompecabezas que, cuando se juntan, nos dan una imagen general del papel que la agricultura juega y jugará en nuestras sociedades en el futuro (Figura 1). Los modelos demográficos predicen que en 2050 habrá que alimentar a casi 10,000 millones de personas en la Tierra. Los retos agrícolas y alimentarios son, por tanto, numerosos. Muchos empresarios famosos están invirtiendo fuertemente en la agricultura, con la esperanza de aprovechar estas oportunidades o con el deseo de perturbar los mercados. La agricultura inteligente es la nueva frontera del sector en respuesta a los retos que afronta nuestro planeta. Aunque todavía existe un verdadero escepticismo y una escasa inversión económica entre el mundo de los agricultores y el de la digitalización y la genómica, la agricultura de precisión (AP) está dando sus frutos en forma de técnicas optimizadas e innovadoras de producción de alimentos en muchas partes del mundo. En este libro, los autores buscaron facilitar las herramientas necesarias a la implementación de prácticas de AP. En el primer capítulo, se trató definir los conceptos claves de la AP y plantear sus contextos, características y aplicaciones. En el segundo capítulo, se desarrolló las particularidades de la inteligencia artificial y del machine learning, incluyendo un histórico, los diferentes tipos de aprendizaje y los aspectos de programación. El tercer capítulo se enfocó en la aplicación de estos métodos a la agricultura, particularmente detallando las especificaciones y diferencias entre la agricultura de precisión y la agricultura inteligente, el uso de las plataformas adecuadas de manera accesible a cualquier usuario interesado en desarrollar este tipo de tecnología. El cuarto capítulo expuso el caso particular de las enfermedades en plantas y de cómo la AP permite anticiparlas y/o detectarlas a tiempo. El quinto capítulo representa una apertura al mundo tecnológico de la AP, describiendo las evoluciones y las diferentes herramientas de la AP, sus usos y niveles de adopción a través de una amplia pero no exhaustiva presentación de casos internacionales

Riparian zones - from policy neglected to policy integrated

[EN] 1. Riparian zones are vital areas of interaction between land and rivers and are often degraded by several pressures such as urbanisation, intensive agriculture and river engineering works. 2. This policy brief provides five key policy messages and recommendations to be considered by policy-makers, scientists, managers, and stakeholders to enhance riparian zone management. 3. Adopting an integrated socio-economic and environmentally dynamic view will ensure the sustainable management of riparian zones. 4. In light of climate change, it is critically important to conserve and/or restore the ecological integrity of riparian zones. 5. European Union Directives and national-scale legislation and regulations need updating to ensure coordinated implementation of riparian zone-related policies. 6. Stakeholder knowledge exchange, policy co-creation and adaptive management are key to enhancing riparian zone functions.Funding was provided by COST Action CONVERGES (CA16208) and by the Horizon 2020 Framework Programme of the European Union. GU was partially supported by the Slovenian Research Agency. PR-G was supported by the Portuguese Foundation for Science and Technology (FCT) through the CEEC Individual Programme (2020.03356. CEECIND), and Forest Research Centre was supported through the FCT UIDB/00239/2020. Portuguese Foundation for Science and Technology (FCT) funded Inês Gomes Marques through a PhD scholarship (SFRH/BD/133162/2017). AA was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No. 451-03-68/2022-14/200010).Urbanic, G.; Politti, E.; Rodríguez-González, PM.; Payne, R.; Schook, D.; Alves, MH.; Andelkovic, A.... (2022). Riparian zones - from policy neglected to policy integrated. Frontiers in Environmental Science. 9(5):1-8. https://doi.org/10.3389/fenvs.2022.868527189