115,120 research outputs found

    Un an√°lisis de la agenda de seguridad Per√ļ-Brasil: los mecanismos de seguridad y confianza mutua (2003-2018)

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    Las relaciones bilaterales entre Per√ļ y Brasil han fluctuado entre el acercamiento y el cordial desinter√©s. Esta inconsistencia en la agenda entre ambos pa√≠ses impidi√≥ que se fortalezcan lazos en materia pol√≠tica, econ√≥mico, cultural, ambiental, seguridad, entre otros temas, por mucho tiempo. No obstante, a inicios del nuevo milenio escenarios como el retorno de la democracia en Per√ļ y la consolidaci√≥n de Brasil como potencia regional (Mindreau 2006:18) permitieron un acercamiento entre ambas naciones. Como consecuencia de ello, se firm√≥ una Asociaci√≥n Estrat√©gica (2003), que iba a suponer una profundizaci√≥n en sus relaciones bilaterales. Sin embargo, una d√©cada m√°s tarde los resultados, a grandes rasgos, muestran lo contrario: esc√°ndalos de corrupci√≥n en torno a la construcci√≥n de megaproyectos licitados a empresas brasile√Īas en Per√ļ y un d√©ficit comercial con Brasil , que ascendi√≥ a 695 millones de d√≥lares, en el a√Īo 2018. Por lo general los estudios acerca de las relaciones peruano-brasile√Īas han sido enfocados en el aspecto comercial. En vista de ello, la presente investigaci√≥n se enfocar√° en la agenda de seguridad de mencionados pa√≠ses. Se tomar√° como caso de estudio los Mecanismos de Seguridad y Confianza Mutua, que son una serie de acuerdos a los cuales dos pa√≠ses se comprometen, con el √ļnico objetivo de incrementar y fomentar la confianza (Galindo 1994). Los Mecanismos de Seguridad y Confianza Mutua entre Per√ļ y Brasil se han caracterizado por presentar dificultades en materia de desarrollo e implementaci√≥n. Por ello, en la presente investigaci√≥n se identificaran cu√°les son los factores que afectan el desempe√Īo de los Mecanismos de Seguridad y Confianza Mutua.Tesi

    Bases moleculares de la interacción de la E3 ubiquitina ligasa TRIM7 con glucogenina-1 y su potencial relevancia en el contexto de la glucogenosis tipo XV

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    Tesis (Doctor en Ciencias Qu√≠micas) - - Universidad Nacional de C√≥rdoba. Facultad de Ciencias Qu√≠micas, 2021Resumen: La ubiquitinaci√≥n es un tipo de modificaci√≥n postraduccional caracter√≠stico de organismos eucariotas, que requiere de la acci√≥n conjunta de las enzimas E1 activadora, E2 conjugadora y E3 ligasa para mediar la transferencia de ubiquitina a una prote√≠na sustrato. TRIM7 es una E3 ligasa que recientemente ha adquirido inter√©s por su rol en diversas patolog√≠as, y pertenece a la familia de prote√≠nas TRIM, caracterizadas por un motivo conservado tripartito (TRIM) N-terminal y una regi√≥n C-terminal variable que puede mediar el reconocimiento de sustratos. Inicialmente, fue identificada como una prote√≠na que interacciona a trav√©s de su dominio C-terminal B30.2 (TRIM7B30.2) con glucogenina-1 (GN1). Dicha prote√≠na es responsable de la iniciaci√≥n de la bios√≠ntesis del gluc√≥geno, por lo que las mutaciones que afectan al gen que la codifica se traducen en un trastorno extremadamente raro denominado glucogenosis tipo XV. El presente trabajo se centr√≥ en caracterizar a TRIM7B30.2 por cristalograf√≠a de rayos X, y describir detalles sobre las regiones relevantes para la interacci√≥n con GN1. La estructura de TRIM7B30.2 revel√≥ un plegamiento de tipo s√°ndwich-ő≤ formado por dos l√°minas ő≤ antiparalelas caracter√≠stico de este tipo de dominios, adem√°s de presentar una cavidad con carga positiva en la cara c√≥ncava de dicho plegamiento. Adicionalmente, se logr√≥ identificar a residuos clave que delimitan la zona involucrada en la interacci√≥n con GN1, adem√°s de obtener indicios de que el extremo C-terminal de esta √ļltima es necesario para su reconocimiento por TRIM7B30.2 y la prote√≠na TRIM7 entera. Otra parte de este estudio se dedic√≥ a conocer el impacto de la mutaci√≥n patol√≥gica Ala16Pro sobre GN1 de conejo, que presenta una alta homolog√≠a con la prote√≠na humana, mediante el uso de un amplio conjunto de t√©cnicas bioqu√≠micas y biof√≠sicas. El an√°lisis revel√≥ un cambio estructural significativo que ocasion√≥ una disminuci√≥n de la afinidad por su sustrato y, en consecuencia, de la actividad de la prote√≠na; adem√°s de una marcada p√©rdida de estabilidad. Por √ļltimo, se busc√≥ conocer si GN1 y sus mutantes patol√≥gicas Ala16Pro y Thr83Met, son sustrato de su actividad E3 ligasa; y si esto podr√≠a tener un rol relevante en la glucogenosis tipo XV. Los resultados de la reacci√≥n in vitro mostraron que la transferencia de ubiquitina no ocurre bajo las condiciones empleadas, sin embargo, se encontr√≥ que TRIM7 interacciona con la mutante patol√≥gica GN1 Ala16Pro pese al cambio estructural de la prote√≠na, lo que podr√≠a implicar a TRIM7 en la v√≠a de degradaci√≥n de esta mutante, y por ello el estudio ser√° continuado en cultivos celulares.Abstract : Ubiquitination is a common post translational modification in eukaryotes, which involves an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase enzyme; in a process that mediates the transfer of ubiquitin to a substrate protein. TRIM7 is an E3 ligase member of the TRIM protein family, characterized by an N-terminal tripartite motif (TRIM) and a variable C-terminal region that can mediate substrate recognition, that has been recently linked to diverse pathological processes. TRIM7 was initially identified as a glycogenin-1 (GN1) interacting protein, and this interaction involves the C-terminal B30.2 domain of TRIM7 (TRIM7B30.2). GN1 is the protein that initiates glycogen biosynthesis, and mutations in the gene that encodes for this enzyme are involved in the onset of an extremely rare disease known as type XV glycogen storage disease. This work was mainly focused on the characterization of TRIM7B30.2, through the use of X-ray crystallography, and the details of the region involved in the interaction with GN1. The structure of TRIM7B30.2 revealed the characteristic B30.2 domain fold consisting of two ő≤-sheets arranged as a distorted ő≤-sandwich, and a positively charged cavity in the hypervariable region of this domain. Besides, key residues that define the zone of interaction with GN1 were identified, and evidence for the requirement of the latter‚Äôs C-terminal region in the binding was found. This study was also focused on the effect of the pathogenic Ala16Pro mutation on rabbit GN1, which displays a high sequence homology with the human protein; and to this end, a wide range of biophysical and biochemical techniques were applied. The analysis revealed a significant structural change which resulted in a decrease in substrate affinity and protein activity, besides a considerable loss of stability. Finally, the thesis was oriented towards analyzing the potential E3 ligase activity of TRIM7 on GN1 and the pathological mutants Ala16Pro and Thr83Met, and its possible functional role on type XV glycogen storage disease. The results have shown that in vitro, TRIM7 does not transfer ubiquitin to GN1 or the mutants in this experimental setup. However, it was found that despite the structural change caused by the mutation, TRIM7 still interacts with the Ala16Pro mutant of human GN1, which might implicate the intervention of TRIM7 in the degradation pathway of this mutant, and for this reason, this study will be continued in cell cultures.2023-08-30Fil: Mu√Īoz Sosa, Christian Javier. Universidad Nacional de C√≥rdoba. Facultad de Ciencias Qu√≠micas; Argentina.Fil: Carrizo Garcia, Mar√≠a Elena. Universidad Nacional de C√≥rdoba. Facultad de Ciencias Qu√≠micas. Departamento de Qu√≠mica Biol√≥gica; Argentina.Fil: Carrizo Garcia, Mar√≠a Elena. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Centro de Investigaciones en Qu√≠mica Biol√≥gica de C√≥rdoba; Argentina.Fil: Genti de Raimondi, Susana Del Valle. Universidad Nacional de C√≥rdoba. Facultad de Ciencias Qu√≠micas. Departamento de Bioqu√≠mica Cl√≠nica; Argentina.Fil: Genti de Raimondi, Susana del Valle. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Centro de Investigaciones en Bioqu√≠mica Cl√≠nica e Inmunolog√≠a; Argentina.Fil: Carbonio, Raul Ernesto. Universidad Nacional de C√≥rdoba. Facultad de Ciencias Qu√≠micas. Departamento de Fisicoqu√≠mica; Argentina.Fil: Carbonio, Raul Ernesto. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Instituto de Investigaciones en Fisicoqu√≠mica de C√≥rdoba; Argentina.Fil: Romero, Jorge Miguel. Universidad Nacional de C√≥rdoba. Facultad de Ciencias Qu√≠micas; Argentina.Fil: Erm√°cora, Mario Roberto. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Instituto Multidisciplinario de Biolog√≠a Celular; Argentina

    Application of lactic acid bacteria for the biopreservation of meat products: A systematic review

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    .The increasing concern of consumers about food quality and safety and their rejection of chemical additives has promoted the breakthrough of the biopreservation field and the development of studies on the use of beneficial bacteria and their metabolites as potential natural antimicrobials for shelf life extension and enhanced food safety. Control of foodborne pathogens in meat and meat products represents a serious challenge for the food industry which can be addressed through the intelligent use of bio-compounds or biopreservatives. This article aims to systematically review the available knowledge about biological strategies based on the use of lactic acid bacteria to control the proliferation of undesirable microorganisms in different meat products. The outcome of the literature search evidenced the potential of several strains of lactic acid bacteria and their purified or semi-purified antimicrobial metabolites as biopreservatives in meat products for achieving longer shelf life or inhibiting spoilage and pathogenic bacteria, especially when combined with other technologies to achieve a synergistic effect.S

    Study on the concordance between different SNP‚Äźgenotyping platforms in sheep

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    .Different SNP genotyping technologies are commonly used in multiple studies to perform QTL detection, genotype imputation, and genomic predictions. Therefore, genotyping errors cannot be ignored, as they can reduce the accuracy of different procedures applied in genomic selection, such as genomic imputation, genomic predictions, and false-positive results in genome-wide association studies. Currently, whole-genome resequencing (WGR) also offers the potential for variant calling analysis and high-throughput genotyping. WGR might overshadow array-based genotyping technologies due to the larger amount and precision of the genomic information provided; however, its comparatively higher price per individual still limits its use in larger populations. Thus, the objective of this work was to evaluate the accuracy of the two most popular SNP-chip technologies, namely, Affymetrix and Illumina, for high-throughput genotyping in sheep considering high-coverage WGR datasets as references. Analyses were performed using two reference sheep genome assemblies, the popular Oar_v3.1 reference genome and the latest available version Oar_rambouillet_v1.0. Our results demonstrate that the genotypes from both platforms are suggested to have high concordance rates with the genotypes determined from reference WGR datasets (96.59% and 99.51% for Affymetrix and Illumina technologies, respectively). The concordance results provided in the current study can pinpoint low reproducible markers across multiple platforms used for sheep genotyping data. Comparing results using two reference genome assemblies also informs how genome assembly quality can influence genotype concordance rates among different genotyping platforms. Moreover, we describe an efficient pipeline to test the reliability of markers included in sheep SNP-chip panels against WGR datasets available on public databases. This pipeline may be helpful for discarding low-reliability markers before exploiting genomic information for gene mapping analyses or genomic predictionS

    Identification of Hindbrain Neural Substrates for Motor Initiation in the hatchling Xenopus laevis Tadpole

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    Animal survival profoundly depends on the ability to detect stimuli in the environment, process them and respond accordingly. In this respect, motor responses to a sensory stimulation evolved into a variety of coordinated movements, which involve the control of brain centres over spinal locomotor circuits. The hatchling Xenopus tadpole, even in its embryonic stage, is able to detect external sensory information and to swim away if the stimulus is considered noxious. To do so, the tadpole relies on well-known ascending sensory pathway, which carries the sensory information to the brain. When the stimulus is strong enough, descending interneurons are activated, leading to the excitation of spinal CPG neurons, which causes the undulatory movement of swimming. However, the activation of descending interneurons that marks the initiation of motor response appears after a long delay from the sensory stimulation. Furthermore, the long-latency response is variable in time, as observed in the slow-summating excitation measured in descending interneurons. These two features, i.e. long-latency and variability, cannot be explained by the firing time and pattern of the ascending sensory pathway of the Xenopus tadpole. Therefore, a novel neuronal population has been proposed to lie in the hindbrain of the tadpole, and being able to 'hold' the sensory information, thus accounting for the long and variable delay of swim initiation. In this work, the role of the hindbrain in the maintenance of the long and variable response to trunk skin stimulation is investigated in the Xenopustadpole at developmental stage 37/38. A multifaceted approach has been used to unravel the neuronal mechanisms underlying the delayed motor response, including behavioural experiments, electrophysiology analysis of fictive swimming, hindbrain extracellular recordings and imaging experiments. Two novel neuronal populations have been identified in the tadpole's hindbrain, which exhibit activation patterns compatible with the role of delaying the excitation of the spinal locomotor circuit. Future work on cellular properties and synaptic connections of these newly discovered populations might shed light on the mechanism of descending control active at embryonic stage. Identifying supraspinal neuronal populations in an embryonic organism could aid in understanding mechanisms of descending motor control in more complex vertebrates

    Interactive Sonic Environments: Sonic artwork via gameplay experience

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    The purpose of this study is to investigate the use of video-game technology in the design and implementation of interactive sonic centric artworks, the purpose of which is to create and contribute to the discourse and understanding of its effectiveness in electro-acoustic composition highlighting the creative process. Key research questions include: How can the language of electro-acoustic music be placed in a new framework derived from videogame aesthetics and technology? What new creative processes need to be considered when using this medium? Moreover, what aspects of 'play' should be considered when designing the systems? The findings of this study assert that composers and sonic art practitioners need little or no coding knowledge to create exciting applications and the myriad of options available to the composer when using video-game technology is limited only by imagination. Through a cyclic process of planning, building, testing and playing these applications the project revealed advantages and unique sonic opportunities in comparison to other sonic art installations. A portfolio of selected original compositions, both fixed and open are presented by the author to complement this study. The commentary serves to place the work in context with other practitioners in the field and to provide compositional approaches that have been taken

    Bioinformatic characterization of a triacylglycerol lipase produced by Aspergillus flavus isolated from the decaying seed of Cucumeropsis mannii

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    Lipases are enzymes of industrial importance responsible for the hydrolysis of ester bonds of triglycerides. A lipolytic fungus was isolated and subsequently identified based on the ITS sequence analysis as putative Aspergillus flavus with accession number LC424503. The gene coding for extracellular triacylglycerol lipase was isolated from Aspergillus flavus species, sequenced, and characterised using bioinformatics tools. An open reading frame of 420 amino acid sequence was obtained and designated as Aspergillus flavus lipase (AFL) sequence. Alignment of the amino acid sequence with other lipases revealed the presence GHSLG sequence which is the lipase consensus sequence Gly-X1-Ser-X2-Gly indicating that it a classical lipase. A catalytic active site lid domain composed of TYITDTIIDLS amino acids sequence was also revealed. This lid protects the active site, control the catalytic activity and substrate selectivity in lipases. The 3-Dimensional structural model shared 34.08% sequence identity with a lipase from Yarrowia lipolytica covering 272 amino acid residues of the template model. A search of the lipase engineering database using AFL sequence revealed that it belongs to the class GX-lipase, superfamily abH23 and homologous family abH23.02, molecular weight and isoelectric point values of 46.95‚ÄČKDa and 5.7, respectively. N-glycosylation sites were predicted at residues 164, 236 and 333, with potentials of 0.7250, 0.7037 and 0.7048, respectively. O-glycosylation sites were predicted at residues 355, 358, 360 and 366. A signal sequence of 37 amino acids was revealed at the N-terminal of the polypeptide. This is a short peptide sequence that marks a protein for transport across the cell membrane and indicates that AFL is an extracellular lipase. The findings on the structural and molecular properties of Aspergillus flavus lipase in this work will be crucial in future studies aiming at engineering the enzyme for biotechnology applications

    Structural and Attitudinal Barriers to Bicycle Ownership and Cycle-Based Transport in Gauteng, South Africa

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    Policies that aim to facilitate and promote non-motorised transport (NMT), and in particular cycling, have been developed by many high-income countries facing increasingly congested roads and saturated public transport systems. Such policies are also emerging in many low- and middle-income settings where high rates of urbanisation have led to similar problems with motorised transport. The aim of the present study was to better understand the potential structural and attitudinal barriers to cycle-based transport in one such context: South Africa‚Äôs Gauteng Province, the industrial powerhouse of sub-Saharan Africa that has recently made a firm commitment to NMT. The study focussed on demographic and socioeconomic variation in bicycle and car ownership, and related this to: (1) the reported use of motorised and non-motorised transport (both private and public); and (2) perceived ‚Äėproblems‚Äô with cycling. The analyses drew on interviews with key respondents from n‚ÄČ=‚ÄČ27,490 households conducted in 2013 as part of the third Quality of Life survey undertaken by the Gauteng City Regional Observatory. The survey contained items on three outcomes of interest: household vehicle ownership (bicycles and cars); modes of transport used for the ‚Äútrips‚ÄĚ most often made; and respondents‚Äô ‚Äúsingle biggest problem with‚Ķ cycling‚ÄĚ. Respondent- and household-level demographic and socioeconomic determinants of these outcomes were examined using descriptive and multivariable statistical analyses, the latter after adjustment for measured potential confounders identified using a theoretical causal path diagram (in the form of a directed acyclic graph). Of the n‚ÄČ=‚ÄČ26,469 households providing complete data on all of the variables examined in the present study, only n‚ÄČ=‚ÄČ8722 (32.9%) owned a car and fewer still (n‚ÄČ=‚ÄČ2244; 8.4%) owned a bicycle. The ownership of these assets was commonest amongst wealthier, economically active households; and those that owned a car had over five times the odds of also owning a bicycle, even after adjustment for potential confounding (OR 5.17; 95% CI 4.58, 5.85). Moreover, of household respondents who reported making ‚Äėtrips‚Äô during the preceding month (n‚ÄČ=‚ÄČ18,209), over two-thirds of those whose households owned a car (70.1%) reported private car-based transport for such trips, while only 3.2% of those owning a bicycle reported cycling. Amongst the specific responses given to the item requesting the ‚Äúsingle biggest problem with‚Ķ cycling‚ÄĚ by far the commonest was ‚ÄúDon‚Äôt know how to cycle‚ÄĚ (32.2%), less than half as many citing ‚ÄúVehicle accident risk‚ÄĚ (15.9%), and fewer still: ‚ÄúDestination is too far‚ÄĚ (13.9%); ‚ÄúCrime‚ÄĚ (10.3%); ‚ÄúToo much effort‚ÄĚ (9.2%); or ‚ÄúLack of good paths‚ÄĚ (4.6%). While the first of these reasons was commonest amongst poorer households, concerns about risk and effort were both most common amongst better educated, economically active and wealthier/better serviced households. In contrast, concerns over (cycle) paths were only common amongst those owning bicycles. The low prevalence of household bicycle ownership, and the disproportionate number of households owning bicycles that also owned cars, might explain the very small proportion of the ‚Äėthe trips most often made‚Äô that involved cycle-based transport (0.3%), and the preferential use of cars amongst households owning both bicycles and cars. Low levels of bicycle ownership might also explain why so many respondents cited ‚ÄúDon‚Äôt know how‚ÄĚ as the ‚Äúsingle biggest problem with‚Ķ cycling‚ÄĚ; although risk and effort were also substantial concerns (presumably for many who did, and some who did not, know how to cycle); the lack of suitable cycle lanes being only primarily a concern for those who actually owned bicycles. Structural and attitudinal barriers to cycle-based transport limit the use of cycle-based transport in Gauteng, not only amongst the vast majority of household respondents who lack the means to cycle (and the means to learn how), but also amongst those dissuaded from learning to cycle, purchasing a bicycle and/or using a bicycle they own by: the risks and effort involved; the lack of suitable cycle paths; and/or because they also own a car and prefer to drive than cycle

    The Time Devil runs amok: How I improved my creative practice by adopting a multimodal approach for a specific audience.

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    This research illustrates how teacher-writers can improve their craft and pedagogy by writing for a specific audience, namely school children. It also illustrates why they might do so. It interrogates what was learnt from an innovative collaboration between a university teacher-education department, an inner-city secondary school and the United Kingdom‚Äôs National Maritime Museum (NMM). Multimodality (Barnard 2019) inspired the project: local spaces, institutional settings, historical objects, photographs, pictures, time-travelling films and narratives motivated the teacher-writer and participants to read and respond imaginatively to the world. The author found that the project caused him to ‚Äúremediate‚ÄĚ his own practice: to transfer ‚Äúexisting skills in order to tackle new genres‚ÄĚ (Barnard 2019: 121). This process enabled him to become a more effective writer and teacher. The research shows that the problem of multimodal overload ‚Äď having too much choice regarding what to write about and the many forms writing can take ‚Äď can be circumnavigated if participants are given both autonomy and constraints. It illustrates in some depth how the concept of reciprocity is vital to adopt if writers are to improve their craft

    Uso de las histonas circulantes y sus modificaciones post-traduccionales como biomarcadores en sepsis y shock séptico

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    La sepsis es una afecci√≥n potencialmente mortal causada por una respuesta anormal del hu√©sped a una infecci√≥n, produciendo respuestas fisiol√≥gicas alteradas que da√Īan los propios tejidos del paciente y pueden provocar disfunci√≥n org√°nica e incluso la muerte. Asimismo, algunos pacientes s√©pticos progresan a shock s√©ptico, caracterizado por alteraciones circulatorias, celulares y metab√≥licas sustanciales que aumentan el riesgo de mortalidad. A pesar de que la sepsis se caracteriza por un mal funcionamiento del sistema inmunol√≥gico, lo que a su vez conduce a una respuesta inmune alterada e inmunosupresi√≥n, la alta complejidad de la fisiopatolog√≠a de la sepsis requiere una mayor investigaci√≥n para comprender las respuestas inmunes que ocurren durante la sepsis. Asimismo, las histonas extracelulares circulantes han ganado relevancia como mediadores citot√≥xicos en la sepsis, ya que act√ļan como patrones moleculares asociados a da√Īo, que inducen estr√©s oxidativo y activan el inflamasoma NLRP3. Estos mecanismos median la activaci√≥n de la piroptosis, un mecanismo de muerte celular programada que produce inflamaci√≥n mediante la expresi√≥n de IL-18, IL-1ő≤ and IL-1őĪ. Sin embargo, a pesar de la evidencia de activaci√≥n del inflamasoma en las c√©lulas inmunes durante la sepsis, se desconoce si las histonas extracelulares son capaces de activar los inflamasomas endoteliales y sus consecuencias. En este trabajo destacamos el papel previamente desconocido de las histonas extracelulares, mediando la activaci√≥n del inflamasoma NLRP3 y la piroptosis en las c√©lulas endoteliales, contribuyendo a la disfunci√≥n endotelial y la desregulaci√≥n de la respuesta inmune mediada por el endotelio. Asimismo, tambi√©n demostramos c√≥mo la acetilaci√≥n de histonas disminuye la activaci√≥n de la piroptosis. Adem√°s, demostramos que la piroptosis se produce en pacientes con shock s√©ptico y los niveles de histonas circulantes se correlacionan con la expresi√≥n de citoquinas proinflamatorias y citoquinas piropt√≥ticas, la liberaci√≥n de factores de adhesi√≥n endotelial y la gravedad de la enfermedad. Proponemos la piroptosis mediada por histonas como un nuevo objetivo para desarrollar intervenciones cl√≠nicas. De manera similar, hemos analizado las respuestas inmunorelacionadas que ocurren durante las primeras etapas de la sepsis con el objetivo de proporcionar nuevos datos comparando las cantidades de citoquinas, inmunomoduladores y otros mediadores endoteliales en pacientes cr√≠ticamente enfermos no s√©pticos, s√©pticos y de shock s√©ptico. Nuestro enfoque ayudar√° a caracterizar r√°pidamente las respuestas inmunes alteradas en pacientes s√©pticos y de shock s√©ptico ingresados en la Unidad de Cuidados Intensivos. Finalmente analizamos el papel de la metilaci√≥n del ADN en el control del sistema inmune s√©ptico. Nuestros resultados demostraron el papel central de la metilaci√≥n del ADN modulando la respuesta molecular en los pacientes de shock s√©ptico y contribuyendo a la inmunosupresi√≥n, a trav√©s de la alteraci√≥n de los patrones de metilaci√≥n de los promotores de IL-10 y TREM-2.Sepsis is a life-threatening condition caused by an abnormal host response to an infection that produce altered physiological responses which damages own tissues of the patient and can result in organ dysfunction and in some cases death. Likewise, a subset of septic patients progresses to septic shock, characterized by substantial circulatory, cellular and metabolic abnormalities, which substantially increase the risk of mortality. Sepsis is characterized by a malfunction of the immune system and it can lead to an altered immune response and immunosuppression. Moreover, the high complexity of the pathophysiology of sepsis requires of further investigation to characterize the immune responses in sepsis and septic shock. Likewise, circulating extracellular histones have gained relevance as cytotoxic mediators in sepsis pathophysiology, since they act as damage-associated molecular patterns, which induce oxidative stress and activate NLRP3 inflammasome. Subsequently, inflammasome mediates pyroptosis activation, a programmed cell death mechanism that produces inflammation through the release of IL-18, IL-1ő≤ and IL-1őĪ. However, despite inflammasome activation may occur in immune cells during sepsis, it is unknown if this process also takes place in endothelial cells and particularly whether extracellular histones are capable of activating endothelial inflammasomes and their consequences. In this work we highlight a previously unknown role for extracellular histones, that mediates the activation of NLRP3 inflammasome and pyroptosis in endothelial cells by contributing to endothelial dysfunction and the dysregulation of the immune response mediated by endothelium. Likewise, we demonstrated how histone acetylation decreases pyroptosis activation. Furthermore, we show how pyroptosis occurs in septic shock patients and how circulating histone levels correlate with the expression of pro-inflammatory and pyroptotic cytokines, the release of endothelial adhesion factors and septic shock severity. We propose histone-mediated pyroptosis as a new target to develop clinical interventions. Similarly, we have analyzed the immune-related responses occurring during the early stages of sepsis with the aim of providing new data by comparing the amounts of cytokines, immune modulators and other endothelial mediators in critically-ill non-septic patients, septic and septic shock patients. Our approach will help to rapidly characterize the altered immune responses in septic and septic shock patients admitted in the Intensive Care Unit. Finally, we also analyzed the role of DNA methylation in the control of septic immune system. Our results demonstrated the central role of DNA methylation modulating the molecular response in septic shock patients and contributing to immunosuppression, through the alteration of DNA methylation patterns of IL-10 and TREM2 promoters
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