Apuntes para el análisis diplomático de las Cartas Credenciales

Letters of Credence have been, since the origin of civilizations, the formal instrument with which diplomatic activity begins. Despite the importance of their issuance, there is currently very little scientific work devoted to their examination. This article applies the principles of diplomatic documentary analysis to establish a pattern that allows us to study not only the letters, but also the documents derived from the state's external action, in order to ensure their continuity in a context marked by the absence of references.Las Cartas Credenciales constituyen, desde el origen de las civilizaciones, el instrumento formal con el que da comienzo la actividad diplomática. Pese a la relevancia que su emisión comporta, en la actualidad existen muy pocos trabajos científicos destinados a su examen. El presente artículo aplica los principios del análisis documental diplomático para establecer un patrón que permita, no solo estudiar las misivas, sino también los escritos derivados de la acción exterior del Estado, con el fin de asegurar su continuidad, en un contexto marcado por la ausencia de referencias

Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells

Recent evidences indicate that triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype show a basal activation of the unfolded protein response (UPR) that increases their sensitivity to endoplasmic reticulum (ER) stress although the underlying cell death mechanism remains largely unexplored. Here we show that both caspase-8-dependent and -independent apoptotic mechanisms are activated in TNBC cells undergoing sustained ER stress. Activation of the extrinsic apoptotic pathway by ER stress involves ATF4-dependent upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5). In addition, accumulation of BH3-only protein Noxa at the mitochondria further contributes to apoptosis following ER stress in TNBC cells. Accordingly, simultaneous abrogation of both extrinsic and intrinsic apoptotic pathways is required to inhibit ER stress-induced apoptosis in these cells. Importantly, persistent FLICE-inhibitory protein (FLIP) expression plays an adaptive role to prevent early activation of the extrinsic pathway of apoptosis upon ER stress. Overall, our data show that ER stress induces cell death through a pleiotropic mechanism in TNBC cells and suggest that targeting FLIP expression may be an effective approach to sensitize these tumor cells to ER stress-inducing agents

Functional characterization of the human mariner transposon Hsmar2

DNA transposons are mobile elements with the ability to mobilize and transport genetic information between different chromosomal loci. Unfortunately, most transposons copies are currently inactivated, little is known about mariner elements in humans despite their role in the evolution of the human genome, even though the Hsmar2 transposon is associated to hotspots for homologous recombination involved in human genetic disorders as Charcot-Marie-Tooth, Prader-Willi/Angelman, and Williams syndromes. This manuscript describes the functional characterization of the human HSMAR2 transposase generated from fossil sequences and shows that the native HSMAR2 is active in human cells, but also in bacteria, with an efficiency similar to other mariner elements. We observe that the sub-cellular localization of HSMAR2 is dependent on the host cell type, and is cytotoxic when overexpressed in HeLa cells. Finally, we also demonstrate that the binding of HSMAR2 to its own ITRs is specific, and that the excision reaction leaves non-canonical footprints both in bacteria and eukaryotic cells

Futuro y viabilidad de la nuevas energías: La fusión nuclear y las energías renovables

En las páginas siguientes se recoge el contenido que desarrollaron los ponentes del Seminario-Debate multidisciplinar, organizado por esta revista, sobre el Futuro y viabilidad de las nuevas energías, celebrado el pasado 5 de Mayo en la Universidad Autónoma de Madrid. El texto corresponde fundamentalmente al contenido íntegro de las intervenciones de tales ponentes, así como también al de algunos otros participantes que intervinieron en dicho debate. Los citados ponentes fueron (por orden de intervención): Vicente Gil Sordo (Director Programa Interuniversitario de Economía Energética); J. Emilio Menéndez Pérez (Subdirector de Investigación y Desarrollo. ENDESA); Carlos Alejaldre Losilla (Director del Laboratorio Nacional de Fusión. CIEMAT); Jesús Fernández González (Catedrático de Agroenergética. U.P.M.); Enrique García Camarero (Profesor Titular de Física Aplicada. U.A.M.); Jesús Rodríguez Pomeda (Profesor de Organización de Empresas. U.A.M.); Rosa Sáez Angulo (Estudios Socioeconómicos Energía y Medioambiente. CIEMAT); El Seminario-Debate fue moderado por D. Jesús Lizcano Alvarez (Director de esta revista, y Catedrático de la UAM

El SCIB aplicado a la sistematización del derecho

En el marco del Primer Encuentro Universitario de Informática Jurídica organizado por la Universidad Pontificia Bolivariana del 27 al 30 de noviembre de 1985

ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress

ERK5 kinase; Antitumor drug; ApoptosisKinasa ERK5; Medicament antitumoral; ApoptosiQuinasa ERK5; Medicamento antitumoral; ApoptosisAutophagy is a highly conserved intracellular process that preserves cellular homeostasis by mediating the lysosomal degradation of virtually any component of the cytoplasm. Autophagy is a key instrument of cellular response to several stresses, including endoplasmic reticulum (ER) stress. Cancer cells have developed high dependency on autophagy to overcome the hostile tumor microenvironment. Thus, pharmacological activation or inhibition of autophagy is emerging as a novel antitumor strategy. ERK5 is a novel member of the MAP kinase family that is activated in response to growth factors and different forms of stress. Recent work has pointed ERK5 as a major player controlling cancer cell proliferation and survival. Therefore small-molecule inhibitors of ERK5 have shown promising therapeutic potential in different cancer models. Here, we report for the first time ERK5 as a negative regulator of autophagy. Thus, ERK5 inhibition or silencing induced autophagy in a panel of human cancer cell lines with different mutation patterns. As reported previously, ERK5 inhibitors (ERK5i) induced apoptotic cancer cell death. Importantly, we found that autophagy mediates the cytotoxic effect of ERK5i, since ATG5ˉ/ˉ autophagy-deficient cells viability was not affected by these compounds. Mechanistically, ERK5i stimulated autophagic flux independently of the canonical regulators AMPK or mTORC1. Moreover, ERK5 inhibition resulted in ER stress and activation of the Unfolded Protein Response (UPR) pathways. Specifically, ERK5i induced expression of the ER luminal chaperone BiP (a hallmark of ER stress), the UPR markers CHOP and ATF4, and the spliced form of XBP1. Pharmacological inhibition of UPR with chemical chaperone TUDC, or ATF4 silencing, resulted in impaired ERK5i-mediated UPR, autophagy and cytotoxicity. Overall, our results suggest that ERK5 inhibition induces autophagy-mediated cancer cell death by activating ER stress. Since ERK5 inhibition sensitizes cancer cells and tumors to chemotherapy, future work will determine the relevance of UPR and autophagy in the combined use of chemotherapy and ERK5i to tackle Cancer.This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2015-64237-R), the Spanish Ministry of Science and Innovation (Grant PID2019-107561RB-I00), and cofounded by the European Regional Development Fund (ERDF)

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Apoptosis; Endometrial cancer; Map kinaseApoptosis; Cáncer endometrial; Mapa quinasaApoptosi; Càncer d'endometri; Mapa quinasaEndometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.Open Access Funding provided by Universitat Autonoma de Barcelona. The JM Lizcano research group was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2015-64237-R), and the Spanish Ministry of Science and Innovation (grant PID2019-107561RB-I00), and co-funded by the European Regional Development Fund (ERDF)

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed altera- tions in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/ IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell prolifera- tion and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.The online version contains supplementary material available at 10.1007/s00018-022-04541-