Análisis de estructuras : texto guía para prácticas

Este texto guía se ha elaborado como apoyo a la realización de las prácticas de Análisis de Estructuras de las titulaciones de Ingeniería y Arquitectura. El avance de las técnicas informáticas en los últimos años ha provocado un aumento de la capacidad de cálculo de los ordenadores. El desarrollo continuado del hardware y del software permite hoy en día el análisis de estructuras de gran tamaño y/o complejidad, impensable hace unos pocos años. La mayor parte del texto está dedicado a las prácticas relacionadas con los métodos de análisis de estructuras con ordenador. Para las estructuras discretas, se proponen prácticas relacionadas con los métodos clásicos de análisis de estructuras, como paso previo a las prácticas relacionadas con los métodos matriciales (más adecuados para su implementación en programas de ordenador, debido al carácter sistemático de los mismos)

Resolvin E1 attenuates doxorubicin-induced cardiac fibroblast senescence: A key role for IL-1β

Cardiac fibroblasts (CFs) undergo senescence in reaction to different stressors, leading to a poor prognosis of cardiac disease. Doxorubicin (Doxo) is an antineoplastic drug with strong cardiotoxic effects, which induces IL-1β secretion and thus, triggers a potent pro-inflammatory response. Doxo induces CFs senescence; however, the mechanisms are not fully understood. Different pharmacological strategies have been used to eliminate senescent cells by inducing their apoptosis or modifying their secretome. However, Resolvin E1 (RvE1), a lipid derivative resolutive mediator with potent anti-inflammatory effects has not been used before to prevent CFs senescence. CFs were isolated from adult male C57BL/6J mice and subsequently stimulated with Doxo, in the presence or absence of RvE1. Senescence-associated β-galactosidase activity (SA-β-gal), γ-H2A.X, p53, p21, and senescence-associated secretory phenotype (SASP) were evaluated. The involvement of the NLRP3 inflammasome/interleukin-1 receptor (IL-1R) signaling pathway on CFs senescence was studied using an NLRP3 inhibitor (MCC950) and an endogenous IL-1R antagonist (IR1A). Doxo is able to trigger CFs senescence, as evidenced by an increase of γ-H2A.X, p53, p21, and SA-β-gal, and changes in the SASP profile. These Doxo effects were prevented by RvE1. Doxo triggers IL-1β secretion, which was dependent on NLRP3 activation. Doxo-induced CFs senescence was partially blocked by MCC950 and IR1A. In addition, IL-1β also triggered CFs senescence, as evidenced by the increase of γ-H2A.X, p53, p21, SA-β-gal activity, and SASP. All these effects were also prevented by RvE1 treatment. Conclusion: These data show the anti-senescent role of RvE1 in Doxo-induced CFs senescence, which could be mediated by reducing IL-1β secretion.This study was supported by PID2020-115590RB-100/AEI/ 10.13039/501100011033 and FONDECYT 1210627 to C.P., C.F.S.F., and G.D.A., respectively. L.S. and J.A.E.C. are the recipients of FPI Universidad Autonoma ´ de Madrid (SFPI/2020-00053) and Beca Doctorado Nacional Ano ˜ 2017 ANID (21170233) fellowships, respectivel

La ciudad como experiencia de conocimiento: Nuevas metodologías de aprendizaje, iniciación de la investigación y extensión universitaria a partir de la historia urbana

Depto. de GeografíaDepto. de Historia Moderna y ContemporáneaDepto. de Historia del ArteFac. de Geografía e HistoriaFALSEsubmitte

Determinantes estructurales del procesamiento y la actividad catalítica de tirosinasa

La melanogénesis es la ruta responsable de la biosíntesis de melaninas. Tirosinasa, la enzima limitante, presenta una alta homología con otras metaloenzimas implicadas, pero capacidades catalíticas diferentes (entre ellas y entre especies). Se han estudiado las relaciones estructura-función de estas proteínas. Las conclusiones más importantes han sido: -En humanos, tirosinasa es la enzima responsable de la actividad DHICA oxidasa de la ruta, en oposición a la enzima de ratón. -Se ha caracterizado el papel de dos importantes aminoácidos del centro activo de tirosinasa de ratón: His390 como tercer ligando del cobre en una región de unión a metal e His389 como responsable de la interacción enantioespecífica enzima-difenoles, pero no con monofenoles, introduciendo relevantes aportaciones al mecanismo del ciclo catalítico de tirosinasa. -La unión del cobre es un evento posterior en la maduración post-traduccional de la enzima, que además presenta dos sitios de glicosilación cuya ocupación es dependientes de conformación. ABSTRACT: Melanogenesis is the biochemical pathway responsible for melanin synthesis. Tyrosinase, the rate-limiting enzyme, shows high homology with other metalloenzymes involved. However, they differ in their enzymatic capabilities (also among species). In our attempt to characterize the structure-function relationships in mammalian melanogenic enzymes, we showed that: -In human, tyrosinase accounts for the DHICA oxidase activity prior to melanin formation, while the murine enzyme is unable to catalyze DHICA consumption. -Two important residues in the active site of the protein have been characterized: His390 as the third copper ligand in the metal-binding region and His389 as the amino acid responsible for the stereospecific interaction enzyme-diphenolic substrates, but not monophenols. This conclusion allowed for the modification of several aspects of the classical catalytic mechanism of the enzyme. -Neither glycosylation of all the potential sequons nor copper binding are sine qua non requirements for maturation of tyrosinase and processing beyond the endoplasmic reticulum

Thr40 and Met122 are new partial loss-of-function natural mutations of the human melanocortin 1 receptor

AbstractActivation by melanocortins of the melanocortin 1 receptor (MC1R), expressed in epidermal melanocytes, stimulates melanogenesis. Human MC1R gene loss-of-function mutations are associated with fair skin, poor tanning and increased skin cancer risk. We identified two natural alleles: Ile40Thr, probably associated with skin types I–II, and Val122Met. Val122Met bound [125I][Nle4, D-Phe7]-α-melanocyte stimulating hormone with lower affinity than the wild-type. Dose–response curves of cAMP accumulation were right-shifted for both forms. The Val122Met form failed to achieve maximal cAMP responses comparable to the wild-type or Ile40Thr receptors. Thus, the Ile40Thr and Val122Met variants are partial loss-of-function natural mutations of MC1R

Loss-of-function variants of the human melanocortin-1 receptor gene in melanoma cells define structural determinants of receptor function.

The alpha-melanocyte-stimulating hormone (alphaMSH) receptor (MC1R) is a major determinant of mammalian skin and hair pigmentation. Binding of alphaMSH to MC1R in human melanocytes stimulates cell proliferation and synthesis of photoprotective eumelanin pigments. Certain MC1R alleles have been associated with increased risk of melanoma. This can be theoretically considered on two grounds. First, gain-of-function mutations may stimulate proliferation, thus promoting dysplastic lesions. Second, and opposite, loss-of-function mutations may decrease eumelanin contents, and impair protection against the carcinogenic effects of UV light, thus predisposing to skin cancers. To test these possibilities, we sequenced the MC1R gene from seven human melanoma cell (HMC) lines and three giant congenital nevus cell (GCNC) cultures. Four HMC lines and two GCNC cultures contained MC1R allelic variants. These were the known loss-of-function Arg142His and Arg151Cys alleles and a new variant, Leu93Arg. Moreover, impaired response to a superpotent alphaMSH analog was demonstrated for the cell line carrying the Leu93Arg allele and for a HMC line homozygous for wild-type MC1R. Functional analysis in heterologous cells stably or transiently expressing this variant demonstrated that Leu93Arg is a loss-of-function mutation abolishing agonist binding. These results, together with site-directed mutagenesis of the vicinal Glu94, demonstrate that the MC1R second transmembrane fragment is critical for agonist binding and maintenance of a resting conformation, whereas the second intracellular loop is essential for coupling to the cAMP system. Therefore, loss-of-function, but not activating MC1R mutations are common in HMC. Their study provides important clues to understand MC1R structure-function relationships.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Heparan sulfate potentiates leukocyte adhesion on cardiac fibroblast by enhancing Vcam-1 and Icam-1 expression

Cardiac fibroblasts (CF) act as sentinel cells responding to chemokines, cytokines and growth factors released in cardiac tissue in cardiac injury events, such as myocardial infarction (MI). Cardiac injury involves the release of various damage-associated molecular patterns (DAMPs) including heparan sulfate (HS), a constituent of the extracellular matrix (ECM), through the TLR4 receptor activation triggering a strong inflammatory response, inducing leukocytes recruitment. This latter cells are responsible of clearing cell debris and releasing cytokines that promote CF differentiation to myofibroblast (CMF), thus initiating scar formation. CF were isolated from adult male rats and subsequently stimulated with HS or LPS, in the presence or absence of chemical inhibitors, to evaluate signaling pathways involved in ICAM-1 and VCAM-1 expression. siRNA against ICAM-1 and VCAM-1 were used to evaluate participation of these adhesion molecules on leukocytes recruitment. HS through TLR4, PI3K/Ala and NF-KB increased ICAM-1 and VCAM-1 expression, which favored the adhesion of spleen mononuclear cells (SMC) and bone marrow granulocytes (PMN) to CF. These effects were prevented by siRNA against ICAM-1 and VCAM-1. Co-culture of CF with SMC increased alpha-SMA expression, skewing CF towards a pro-fibrotic phenotype, while CF pretreatment with HS partially reverted this effect. Conclusion: These data show the dual role of HS during the initial stages of wound healing. Initially, HS enhance the pro-inflammatory role of CF increasing cytokines secretion; and later, by increasing protein adhesion molecules allows the adhesion of SMC on CF, which trigger CF-to-CMF differentiation.FONDECYT 1170425 FONDAP ACCDiS 15130011 CEAL-AL/2017-02

Centro de Recursos de Matemáticas II

El grupo de trabajo de matemáticas del C.P. Victoria Kent ha realizado este libro dentro del curso destinado al estudio 'manipulativo' de las matemáticas. El objetivo es adecuar materiales y recursos al Proyecto Curricular de Centro, y ponerlos en común con los distintos profesores del grupo. Parte de una serie de estrategias pedagógicas tratadas en otro curso anterior y desarrolla en grupos pequeños el conocimiento de útiles y herramientas básicas en matemáticas (compás, regla, cartabón, etc) y su aplicación en experiencias creativas que inviten al alumno a la exploración y la investigación dentro del área estudiada. El material didáctico en el que se apoya la obra se refleja en los capítulos dedicados a los policubos, ábaco, multiplicación y la calculadora donde se incluyen ejercicios prácticos..MadridES

Contribution a l´etude des premiers peuplements de l´Europe occidental: l´apport des reserches sur le Plio-leistocene d´Orce et Cueva Victoria (Espagne).

Danslesud-estdel'Espagne,del'industrie lithique et des restes humains dates du Pliocene superieur et du Pleistocene inferieur ont ete trouves dans des Sediments lacustres de la region d'Orce(Granada)