Neurodinamia del plexo braquial en el cáncer de mama

Antecedentes: La cirugía axilar y el tratamiento coadyuvante del cáncer de mama pueden ocasionar daño en el tejido neural del miembro superior. La presente Tesis pretende conocer si el tejido neural está implicado en los síntomas de las mujeres tratadas de cáncer de mama, así como estudiar el comportamiento muscular durante la realización del test neurodinámico del nervio mediano (ULNT1) mediante el registro de la actividad mioeléctrica de los músculos circundantes a este nervio. Sujetos y metodología: Se ha realizado un estudio descriptivo transversal en el que han participado 125 mujeres del Hospital de Torrejón, de las cuales 30 fueron intervenidas de cáncer de mama unilateral con linfadenectomía (LA), 32 fueron intervenidas de cáncer de mama unilateral con biopsia del ganglio centinela (BGC), y 63 eran mujeres sanas (C). Se realizó el ULNT1 así como una maniobra de sensibilización neural para determinar si el test era positivo. Se registró la actividad mioeléctrica de los músculos bíceps braquial y tríceps braquial y se tomaron medidas goniométricas del rango de movimiento de abducción, rotación externa de hombro y del déficit de extensión de codo en los tres tiempos de medida durante la realización del ULNT1: 1) aparición de la tensión; 2) aumento la amplitud de la actividad muscular; y 3) máxima resistencia muscular. Se estudió la normalidad de la muestra mediante los tests de Kolmogorov-Smirnov y Shapiro-Wilk, y se utilizaron la prueba de chicuadrado de Pearson y el test de ANOVA de una vía para observar las diferencias inter-grupos. Las comparaciones múltiples de las variables cuantitativas se estudiaron con el test de Bonferroni. Resultados: El 100% de las mujeres de los grupos de cáncer de mama presentaron un ULNT1 positivo. Los grupos de cáncer de mama presentaron un incremento de la actividad mioeléctrica del músculo bíceps braquial en comparación con el grupo control, de un 39% en el grupo LA y un 49% en el grupo BGC en el tiempo de aparición de la tensión. Sin embargo, en el músculo tríceps braquial el incremento fue significativo sólo en el grupo BGC, que en comparación con el grupo C fue de un 15% y en comparación con el grupo LA de un 11,5% en el tiempo de aparición de la tensión. Conclusiones: El tejido neural está implicado en los síntomas de las mujeres tratadas de cáncer de mama y la mecanosensibilidad neural del plexo braquial está incrementada, mostrando un incremento de la respuesta protectora muscular del músculo bíceps braquial en comparación con mujeres sanas. La respuesta protectora del músculo tríceps braquial parece verse influida por el tipo de cirugía axilar, ya que las mujeres intervenidas con BGC han presentado una mayor actividad mioeléctrica

Cytochrome c signalosome in mitochondria

Cytochrome c delicately tilts the balance between cell life (respiration) and cell death (apoptosis). Whereas cell life is governed by transient electron transfer interactions of cytochrome c inside the mitochondria, the cytoplasmic adducts of cytochrome c that lead to cell death are amazingly stable. Interestingly, the contacts of cytochrome c with its counterparts shift from the area surrounding the heme crevice for the redox complexes to the opposite molecule side when the electron flow is not necessary. The cytochrome c signalosome shows a higher level of regulation by post-translational modifications—nitration and phosphorylation—of the hemeprotein. Understanding protein interfaces, as well as protein modifications, would puzzle the mitochondrial cytochrome c-controlled pathways out and enable the design of novel drugs to silence the action of pro-survival and pro-apoptotic partners of cytochrome c.Spanish Ministry of Science and Innovation BFU2009-07190Andalusian Government BIO198 P08-CVI-387

Cytochrome c: Surfing Off of the Mitochondrial Membrane on the Tops of Complexes III and IV

The proper arrangement of protein components within the respiratory electron transport chain is nowadays a matter of intense debate, since altering it leads to cell aging and other related pathologies. Here, we discuss three current views-the so-called solid, fluid and plasticity models-which describe the organization of the main membrane-embedded mitochondrial protein complexes and the key elements that regulate and/or facilitate supercomplex assembly. The soluble electron carrier cytochrome c has recently emerged as an essential factor in the assembly and function of respiratory supercomplexes. In fact, a 'restricted diffusion pathway' mechanism for electron transfer between complexes III and IV has been proposed based on the secondary, distal binding sites for cytochrome c at its two membrane partners recently discovered. This channeling pathway facilitates the surfing of cytochrome c on both respiratory complexes, thereby tuning the efficiency of oxidative phosphorylation and diminishing the production of reactive oxygen species. The well-documented post-translational modifications of cytochrome c could further contribute to the rapid adjustment of electron flow in response to changing cellular conditions.Spanish Ministry of Economy and Competitiveness (BFU2015-71017/BMC MINECO/FEDER and PGC2018-096049-B-I00 BIO/BMC MICINN/FEDER, EU

Structural and functional characterization of phosphomimetic mutants of cytochrome c at threonine 28 and serine 47

Protein function is frequently modulated by post-translational modifications of specific residues. Cytochrome c, in particular, is phosphorylated in vivo at threonine 28 and serine 47. However, the effect of such modifications on the physiological functions of cytochrome c – namely, the transfer of electrons in the respiratory electron transport chain and the triggering of programmed cell death – is still unknown. Here we replace each of these two residues by aspartate, in order to mimic phosphorylation, and report the structural and functional changes in the resulting cytochrome c variants. We find that the T28D mutant causes a 30-mV decrease on the midpoint redox potential and lowers the affinity for the distal site of Arabidopsis thaliana cytochrome c1 in complex III. Both the T28D and S47D variants display a higher efficiency as electron donors for the cytochrome c oxidase activity of complex IV. In both protein mutants, the peroxidase activity is significantly higher, which is related to the ability of cytochrome c to leave the mitochondria and reach the cytoplasm. We also find that both mutations at serine 47 (S47D and S47A) impair the ability of cytoplasmic cytochrome c to activate the caspases cascade, which is essential for triggering programmed cell death.Peer reviewe

Long distance electron transfer through the aqueous solution between redox partner proteins

Despite the importance of electron transfer between redox proteins in photosynthesis and respiration, the inter-protein electron transfer rate between redox partner proteins has never been measured as a function of their separation in aqueous solution. Here, we use electrochemical tunneling spectroscopy to show that the current between two protein partners decays along more than 10 nm in the solution. Molecular dynamics simulations reveal a reduced ionic density and extended electric field in the volume confined between the proteins. The distance-decay factor and the calculated local barrier for electron transfer are regulated by the electrochemical potential applied to the proteins. Redox partners could use electrochemically gated, long distance electron transfer through the solution in order to conciliate high specificity with weak binding, thus keeping high turnover rates in the crowded environment of cells.España, MINECO BFU2015-71017-P/España, Gobierno de Andalucía (BIO198)Comisión de Universidades e Investigación del Departamento de Innovación, Universidades y Empresa de la Generalitat de Catalunya.(2017 SGR 1442, 2014 SGR 1442, and 2017 SGR 1189

Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria

Respiratory cytochrome c has been found to be phosphorylated at tyrosine 97 in the postischemic brain upon neuroprotective insulin treatment, but how such posttranslational modification affects mitochondrial metabolism is unclear. Here, we report the structural features and functional behavior of a phosphomimetic cytochrome c mutant, which was generated by site-specific incorporation at position 97 of p-carboxymethyl-l-phenylalanine using the evolved tRNA synthetase method. We found that the point mutation does not alter the overall folding and heme environment of cytochrome c, but significantly affects the entire oxidative phosphorylation process. In fact, the electron donation rate of the mutant heme protein to cytochrome c oxidase, or complex IV, within respiratory supercomplexes was higher than that of the wild-type species, in agreement with the observed decrease in reactive oxygen species production. Direct contact of cytochrome c with the respiratory supercomplex factor HIGD1A (hypoxia-inducible domain family member 1A) is reported here, with the mutant heme protein exhibiting a lower affinity than the wild-type species. Interestingly, phosphomimetic cytochrome c also exhibited a lower caspase-3 activation activity. Altogether, these findings yield a better understanding of the molecular basis for mitochondrial metabolism in acute diseases, such as brain ischemia, and thus could allow the use of phosphomimetic cytochrome c as a neuroprotector with therapeutic applications.España, Junta de Andalucía BIO-198España MINECO BFU2015-71017/BM

The cytochrome f–plastocyanin complex as a model to study transient interactions between redox proteins

AbstractTransient complexes, with a lifetime ranging between microseconds and seconds, are essential for biochemical reactions requiring a fast turnover. That is the case of the interactions between proteins engaged in electron transfer reactions, which are involved in relevant physiological processes such as respiration and photosynthesis. In the latter, the copper protein plastocyanin acts as a soluble carrier transferring electrons between the two membrane-embedded complexes cytochrome b6f and photosystem I. Here we review the combination of experimental efforts in the literature to unveil the functional and structural features of the complex between cytochrome f and plastocyanin, which have widely been used as a suitable model for analyzing transient redox interactions

Evaluación de los aspectos sensoriomotores y cognitivo-afectivos de los pacientes con síndrome post- COVID-19 persistente y las posibles diferencias con los que presentan dolor musculoesquelético asociado

11 p.Introducción: Entre los síntomas más frecuentes que aparecen en pacientes con síndrome de post-COVID persistente destaca la presencia de dolor musculoesquelético, pero actualmente existe una falta de evidencia sobre el impacto de la presencia de este síntoma sobre otras variables cognitivas, afectivas, funcionales y de discapacidad. En base a ello, el objetivo principal del proyecto es comparar la capacidad funcional y el grado de discapacidad entre pacientes con síndrome post-COVID-19 persistente que sufren dolor y pacientes con dicho síndrome que no sufren dolor. Métodos: Se llevará a cabo un estudio descriptivo transversal. Los pacientes serán reclutados y evaluados en el Centro XXXXX de Valladolid, España. Se recogerán datos mediante cuestionarios autoadministrados para determinadas variables de carácter cognitivo o afectivo y se realizarán pruebas de carácter físico/funcional como la prueba del escalón para evaluar la resistencia cardiorrespiratoria o la dinamometría para evaluar la fuerza muscular, entre otras. Para analizar los datos, se empleará la prueba estadística t de student para estudiar la comparación entre las variables continuas. Las relaciones entre las variables de las dimensiones capacidad física, sensorial, cognitiva y afectiva-motivacional, se examinarán mediante el coeficiente de correlación de Pearson. Ética y difusión: El estudio se realizará atendiendo a la legislación nacional para la protección de datos de los voluntarios según la LOPD y la declaración de Helsinki. Una vez se analicen los datos obtenidos, los resultados serán publicados en una revista de impacto y se difundirán en congresos científicos.Colegio Profesional de Fisioterapeutas de la Comunidad de Madri

Histone chaperone activity of Arabidopsis thaliana NRP1 is blocked by cytochrome c

Higher-order plants and mammals use similar mechanisms to repair and tolerate oxidative DNA damage. Most studies on the DNA repair process have focused on yeast and mammals, in which histone chaperone-mediated nucleosome disassembly/reassembly is essential for DNA to be accessible to repair machinery. However, little is known about the specific role and modulation of histone chaperones in the context of DNA damage in plants. Here, the histone chaperone NRP1, which is closely related to human SET/TAF-Iβ, was found to exhibit nucleosome assembly activity in vitro and to accumulate in the chromatin of Arabidopsis thaliana after DNA breaks. In addition, this work establishes that NRP1 binds to cytochrome c, thereby preventing the former from binding to histones. Since NRP1 interacts with cytochrome c at its earmuff domain, that is, its histone-binding domain, cytochrome c thus competes with core histones and hampers the activity of NRP1 as a histone chaperone. Altogether, the results obtained indicate that the underlying molecular mechanisms in nucleosome disassembly/reassembly are highly conserved throughout evolution, as inferred from the similar inhibition of plant NRP1 and human SET/TAF-Iβ by cytochrome c during DNA damage response.Junta de Andalucía BIO198Ministerio de Economía y Competitividad BFU2015-71017 / BMC y BFU2013-4706

RNA Binding Protein Regulation and Cross-Talk in the Control of AU-rich mRNA Fate

mRNA metabolism is tightly orchestrated by highly-regulated RNA Binding Proteins (RBPs) that determine mRNA fate, thereby influencing multiple cellular functions across biological contexts. Here, we review the interplay between six well-known RBPs (TTP, AUF-1, KSRP, HuR, TIA-1, and TIAR) that recognize AU-rich elements (AREs) at the 3′ untranslated regions of mRNAs, namely ARE-RBPs. Examples of the links between their cross-regulations and modulation of their targets are analyzed during mRNA processing, turnover, localization, and translational control. Furthermore, ARE recognition can be self-regulated by several factors that lead to the prevalence of one RBP over another. Consequently, we examine the factors that modulate the dynamics of those protein-RNA transient interactions to better understand the final consequences of the regulation mediated by ARE-RBPs. For instance, factors controlling the RBP isoforms, their conformational state or their post-translational modifications (PTMs) can strongly determine the fate of the protein-RNA complexes. Moreover, mRNA specific sequence and secondary structure or subtle environmental changes are also key determinants to take into account. To sum up, the whole understanding of such a fine tuned regulation is a challenge for future research and requires the integration of all the available structural and functional data by in vivo, in vitro and in silico approaches.España, Ministerio de Economía y Competitividad BFU2015-71017-PEspaña, Ministerio de Educación, Cultura y Deporte FPU013/04373, FPU016/0151