9,122 research outputs found

    Subsidiary Entrepreneurial Alertness: Antecedents and Outcomes

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    This thesis brings together concepts from both international business and entrepreneurship to develop a framework of the facilitators of subsidiary innovation and performance. This study proposes that Subsidiary Entrepreneurial Alertness (SEA) facilitates the recognition of opportunities (the origin of subsidiary initiatives). First introduced by Kirzner (1979) in the context of the individual, entrepreneurial alertness (EA) is the ability to notice an opportunity without actively searching. Similarly, to entrepreneurial alertness at the individual level, this study argues that SEA enables the subsidiary to best select opportunities based on resources available. The research further develops our conceptualisation of SEA by drawing on work by Tang et al. (2012) identifying three distinct activities of EA: scanning and search (identifying opportunities unseen by others due to their awareness gaps), association and connection of information, and evaluation and judgement to interpret or anticipate future viability of opportunities. This study then hypothesises that SEA leads to opportunity recognition at the subsidiary level and further hypothesises innovation and performance as outcomes of opportunity recognition. This research brings these arguments together to develop and test a comprehensive theoretical model. The theoretical model is tested through a mail survey of the CEOs/MDs of foreign subsidiaries within the Republic of Ireland (an innovative hub for foreign subsidiaries). This method was selected as the best method to reach the targeted respondent, and due to the depth of knowledge the target respondent holds, the survey can answer the desired question more substantially. The results were examined using partial least squares structural equation modelling (PLS-SEM). The study’s findings confirm two critical aspects of subsidiary context, subsidiary brokerage and subsidiary credibility are positively related to SEA. The study establishes a positive link between SEA and both the generation of innovation and the subsidiary’s performance. This thesis makes three significant contributions to the subsidiary literature as it 1) introduces and develops the concept of SEA, 2) identifies the antecedents of SEA, and 3) demonstrates the impact of SEA on subsidiary opportunity recognition. Implications for subsidiaries, headquarters and policy makers are discussed along with the limitations of the study

    Vegetation responses to variations in climate: A combined ordinary differential equation and sequential Monte Carlo estimation approach

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    Vegetation responses to variation in climate are a current research priority in the context of accelerated shifts generated by climate change. However, the interactions between environmental and biological factors still represent one of the largest uncertainties in projections of future scenarios, since the relationship between drivers and ecosystem responses has a complex and nonlinear nature. We aimed to develop a model to study the vegetation’s primary productivity dynamic response to temporal variations in climatic conditions as measured by rainfall, temperature and radiation. Thus, we propose a new way to estimate the vegetation response to climate via a non-autonomous version of a classical growth curve, with a time-varying growth rate and carrying capacity parameters according to climate variables. With a Sequential Monte Carlo Estimation to account for complexities in the climate-vegetation relationship to minimize the number of parameters. The model was applied to six key sites identified in a previous study, consisting of different arid and semiarid rangelands from North Patagonia, Argentina. For each site, we selected the time series of MODIS NDVI, and climate data from ERA5 Copernicus hourly reanalysis from 2000 to 2021. After calculating the time series of the a posteriori distribution of parameters, we analyzed the explained capacity of the model in terms of the linear coefficient of determination and the parameters distribution variation. Results showed that most rangelands recorded changes in their sensitivity over time to climatic factors, but vegetation responses were heterogeneous and influenced by different drivers. Differences in this climate-vegetation relationship were recorded among different cases: (1) a marginal and decreasing sensitivity to temperature and radiation, respectively, but a high sensitivity to water availability; (2) high and increasing sensitivity to temperature and water availability, respectively; and (3) a case with an abrupt shift in vegetation dynamics driven by a progressively decreasing sensitivity to water availability, without any changes in the sensitivity either to temperature or radiation. Finally, we also found that the time scale, in which the ecosystem integrated the rainfall phenomenon in terms of the width of the window function used to convolve the rainfall series into a water availability variable, was also variable in time. This approach allows us to estimate the connection degree between ecosystem productivity and climatic variables. The capacity of the model to identify changes over time in the vegetation-climate relationship might inform decision-makers about ecological transitions and the differential impact of climatic drivers on ecosystems.Estación Experimental Agropecuaria BarilocheFil: Bruzzone, Octavio Augusto. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche; ArgentinaFil: Bruzzone, Octavio Augusto. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; ArgentinaFil: Perri, Daiana Vanesa. Instituto Nacional de Tecnologia Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Área de Recursos Naturales; ArgentinaFil: Perri, Daiana Vanesa. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; ArgentinaFil: Easdale, Marcos Horacio. Instituto Nacional de Tecnologia Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Área de Recursos Naturales; ArgentinaFil: Easdale, Marcos Horacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; Argentin

    Patterns Detection in Glucose Time Series by Domain Transformations and Deep Learning

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    People with diabetes have to manage their blood glucose level to keep it within an appropriate range. Predicting whether future glucose values will be outside the healthy threshold is of vital importance in order to take corrective actions to avoid potential health damage. In this paper we describe our research with the aim of predicting the future behavior of blood glucose levels, so that hypoglycemic events may be anticipated. The approach of this work is the application of transformation functions on glucose time series, and their use in convolutional neural networks. We have tested our proposed method using real data from 4 different diabetes patients with promising results.Comment: 7 pages, 7 figures, 3 table

    Desarrollo de una batería de memoria semántica para pacientes con epilepsia del lóbulo temporal

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    La epilepsia focal más frecuente es aquella epilepsia cuyo foco epileptógeno está localizado en el lóbulo temporal medial y es secundaria a una esclerosis con atrofia de la región amígdalo-hipocámpica, con una red epileptógena que abarca la porción anterior del lóbulo temporal. En ocasiones los pacientes requieren de un tratamiento quirúrgico que incluye la resección unilateral de ambas regiones, tanto del polo anterior, como del complejo amígdala-hipocampo. Estas estructuras han demostrado tener gran importancia para el procesamiento de la memoria semántica (región anterotemporal) y episódica (región amígdalo-hipocámpica), por lo que los pacientes que son sometidos a esta intervención suelen presentar quejas cognitivas relacionadas con ambos tipos de memoria. Sin embargo, parece que las evaluaciones neuropsicológicas que realizamos de forma rutinaria en las diferentes Unidades de Epilepsia no son capaces de detectar todos los problemas cognitivos que ocurren en estos pacientes ya que, a pesar de las dificultades expresadas por estos, las evaluaciones no muestran alteraciones. La hipótesis principal del presente trabajo es que estas quejas se deben a tipos de memoria que no están incluidos en las pruebas neuropsicológicas actuales y, por tanto, no somos capaces de identificar bien sus problemas. En primer lugar, se propone que la memoria semántica está afectada, pero solamente para palabras de baja frecuencia de uso en la vida diaria, no analizadas en las evaluaciones convencionales actuales. En segundo lugar, otros problemas no objetivados se deben a un problema de la memoria de consolidación, medida como olvido a largo plazo acelerado que se detecta cuando se amplia el periodo de evaluación del recuerdo. Además, estas alteraciones van a manifestarse con mayor intensidad en pacientes cuyo foco epileptógeno está localizado en el lóbulo temporal izquierdo. Los objetivos fundamentales de este trabajo son evaluar en pacientes con epilepsia del lóbulo temporal medial intervenidos quirúrgicamente mediante lobectomía temporal anterior con amigdalohipocampectomía la presencia de alteraciones de la memoria verbal tanto semántica como episódica, así como conocer su valor lateralizador según el hemisferio afectado. El estudio se basó en la comparación de pacientes con epilepsia del lóbulo temporal (ELT) tratados con lobectomía temporal anterior con amigdalohipocampectomía con un grupo control de personas sanas, comparables respecto a edad, nivel educativo y coeficiente intelectual (CI). Las pruebas de memoria semántica mostraron que únicamente los pacientes con ELT izquierda tenían alteraciones, especialmente para ítems de baja frecuencia y tanto en tares de expresión como de comprensión verbal. Asimismo, el tiempo de reacción fue mayor en el grupo de pacientes con ELT izquierda para todos los ítems y únicamente para las palabras o conceptos de baja frecuencia en aquellos con ELT derecha. Además, se incluyó una prueba de memoria episódica estándar (RAVLT) que en lugar de restringir la evaluación a 30 minutos, se evaluó a 7 días para medir el olvido a largo plazo. Los resultados mostraron que los dos grupos de pacientes, tanto los de ELT izquierda como aquellos con ELT derecha, desarrollaron olvido a largo plazo. Por último los resultados mostraron que la presencia de crisis epilépticas no afectó a la presencia de olvido a largo plazo acelerado

    Pupillometry and the vigilance decrement: Task‐evoked but not baseline pupil measures reflect declining performance in visual vigilance tasks

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    Baseline and task-evoked pupil measures are known to reflect the activity of the nervous system's central arousal mechanisms. With the increasing availability, affordability and flexibility of video-based eye tracking hardware, these measures may one day find practical application in real-time biobehavioural monitoring systems to assess performance or fitness for duty in tasks requiring vigilant attention. But real-world vigilance tasks are predominantly visual in their nature and most research in this area has taken place in the auditory domain. Here, we explore the relationship between pupil size—both baseline and task-evoked—and behavioural performance measures in two novel vigilance tasks requiring visual target detection: (1) a traditional vigilance task involving prolonged, continuous and uninterrupted performance (n = 28) and (2) a psychomotor vigilance task (n = 25). In both tasks, behavioural performance and task-evoked pupil responses declined as time spent on task increased, corroborating previous reports in the literature of a vigilance decrement with a corresponding reduction in task-evoked pupil measures. Also in line with previous findings, baseline pupil size did not show a consistent relationship with performance measures. Our data offer novel insights into the complex interplay of brain systems involved in vigilant attention and question the validity of the assumption that baseline (prestimulus) pupil size and task-evoked (poststimulus) pupil measures reflect the tonic and phasic firing modes of the locus coeruleus

    Investigating and mitigating the role of neutralisation techniques on information security policies violation in healthcare organisations

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    Healthcare organisations today rely heavily on Electronic Medical Records systems (EMRs), which have become highly crucial IT assets that require significant security efforts to safeguard patients’ information. Individuals who have legitimate access to an organisation’s assets to perform their day-to-day duties but intentionally or unintentionally violate information security policies can jeopardise their organisation’s information security efforts and cause significant legal and financial losses. In the information security (InfoSec) literature, several studies emphasised the necessity to understand why employees behave in ways that contradict information security requirements but have offered widely different solutions. In an effort to respond to this situation, this thesis addressed the gap in the information security academic research by providing a deep understanding of the problem of medical practitioners’ behavioural justifications to violate information security policies and then determining proper solutions to reduce this undesirable behaviour. Neutralisation theory was used as the theoretical basis for the research. This thesis adopted a mixed-method research approach that comprises four consecutive phases, and each phase represents a research study that was conducted in light of the results from the preceding phase. The first phase of the thesis started by investigating the relationship between medical practitioners’ neutralisation techniques and their intention to violate information security policies that protect a patient’s privacy. A quantitative study was conducted to extend the work of Siponen and Vance [1] through a study of the Saudi Arabia healthcare industry. The data was collected via an online questionnaire from 66 Medical Interns (MIs) working in four academic hospitals. The study found that six neutralisation techniques—(1) appeal to higher loyalties, (2) defence of necessity, (3) the metaphor of ledger, (4) denial of responsibility, (5) denial of injury, and (6) condemnation of condemners—significantly contribute to the justifications of the MIs in hypothetically violating information security policies. The second phase of this research used a series of semi-structured interviews with IT security professionals in one of the largest academic hospitals in Saudi Arabia to explore the environmental factors that motivated the medical practitioners to evoke various neutralisation techniques. The results revealed that social, organisational, and emotional factors all stimulated the behavioural justifications to breach information security policies. During these interviews, it became clear that the IT department needed to ensure that security policies fit the daily tasks of the medical practitioners by providing alternative solutions to ensure the effectiveness of those policies. Based on these interviews, the objective of the following two phases was to improve the effectiveness of InfoSec policies against the use of behavioural justification by engaging the end users in the modification of existing policies via a collaborative writing process. Those two phases were conducted in the UK and Saudi Arabia to determine whether the collaborative writing process could produce a more effective security policy that balanced the security requirements with daily business needs, thus leading to a reduction in the use of neutralisation techniques to violate security policies. The overall result confirmed that the involvement of the end users via a collaborative writing process positively improved the effectiveness of the security policy to mitigate the individual behavioural justifications, showing that the process is a promising one to enhance security compliance

    II tüüpi kollageeni neoepitoop C2C uriinis kui põlve osteoartriidi diagnoosimise ja kulu prognoosimise biomarker

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    Väitekirja elektrooniline versioon ei sisalda publikatsiooneOsteoartriit (OA) on sagedasim liigeshaigus, tabades ligi poolt miljardit inimest maailmas. Põlv on üks peamisi kahjustuskohti. Haiguse kaasaegse käsitluse järgi arenevad kahjustused molekulaarsetest muutustest kuni kudede (kõhr, luu, sünoviaalkest, menisk, sidemed) struktuuri muutusteni. OA on aastate jooksul ebaühtlase kiirusega süvenev haigus, mille puhul stabiilsemad perioodid vahelduvad kiiremate muutustega, kulgedes varajases järgus haigustunnusteta. Seetõttu pakuvad kudede ainevahetuse muutusi peegeldavad molekulaarsed markerid varajast hoiatust koekahjustuse tekkest, võimalust hinnata haiguse kulgu ning tulevikus ka ravivastust. Kuna II tüüpi kollageen (Kol2) on kõhre peamine struktuurne komponent, on OA hindamiseks loodud mitmeid Kol2 lammutamist mõõtvaid teste. Käesolevas uurimuses hindasime OA uue biomarkeri, uC2C kasutusvõimalusi põlve OA (pOA) korral. uC2C on Kol2 lõhustumise neoepitoop C2C uriinis. Võrdlesime uC2C väärtusi röntgenleiu, kõhre otsese vaatlusleiu ja patsiendi kliinilise seisundiga, kasutades erinevaid statistilisi mudeleid. Selgus, et uC2C on sobiv kandidaat pOA varajase diagnostilise testi arendamiseks. C2C sisaldus tõuseb juba haiguse varajases järgus ja on seotud haiguse mitme põhiprotsessiga: kõhre lammutamise ja luukasviste tekkega põlveliigese eri osades. uC2C on hea progressioonimarker naistel: uC2C kõrgem algväärtus ennustab naistel väga hästi (>90%) pOA teket või süvenemist järgneva 3 aasta jooksul. uC2C tase on kõrgem suuremate röntgenmuutuste korral, seega uC2C tase on seotud pOA raskusastmega. uC2C väärtused on suurimad kOA lõppjärgus olevatel haigetel, kes jõuavad liigeseasenduseni suhteliselt noorelt (50–70 a vanuses). Pärast põlveliigese asendamist võib C2C eritumine uriiniga väheneda, suureneda või jääda muutumatuks. Seega ei peata liigeseasendus paljudel juhtudel Kol2 lammutamist organismis ja OA on süsteemsem haigus, kui on seni arvatud. uC2C näib olevat naistel võrreldes meestega parem pOA biomarker.Osteoarthritis (OA) is the most common joint disease, affecting about half a billion people worldwide. The knee is one of the main sites of impairment. According to the new approach to the disease, the alterations develop from the molecular level to structural changes in tissues (cartilage, bone, synovium, meniscus, ligaments). OA is a disease with an alternating course, with no signs of disease at an early stage. Therefore, molecular markers that reflect changes in tissue metabolism provide an early warning of tissue damage, an opportunity to assess the course of the disease, and a response to future treatment. Because type II collagen (Col2) is a major structural component of cartilage, several tests have been developed to measure Col2 degradation. In the current study, we evaluated the potential use of a new OA biomarker, C2C, in knee OA (kOA). uC2C is a Col2 cleavage neoepitope in urine. We compared uC2C values with X-ray findings, direct visual assessment of cartilage, and clinical status using different statistical models. uC2C is a good candidate for the development of an early diagnostic test for kOA. The level of uC2C is increased in the early stages of kOA and is related to several main processes of kOA: the cartilage lesions and the osteophytes in distinct knee compartments. uC2C is a good marker of progression in women–a higher baseline uC2C is an excellent predictor (> 90%) of the initiation or worsening of kOA over the next 3 years. uC2C is higher in higher X-ray grades, so uC2C levels are associated with the severity of kOA. uC2C values are highest in patients with end-stage kOA who reach joint replacement at a relatively young age (50-70 years). After knee replacement, urinary excretion of C2C may decrease, increase, or remain unchanged. Thus, in many cases, joint replacement does not stop the breakdown of Col2 in the body, and OA is a more systemic disease than previously thought. uC2C appears to be a better biomarker of pOA in women than in men.https://www.ester.ee/record=b550707

    Algorithms to estimate Shapley value feature attributions

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    Feature attributions based on the Shapley value are popular for explaining machine learning models; however, their estimation is complex from both a theoretical and computational standpoint. We disentangle this complexity into two factors: (1)~the approach to removing feature information, and (2)~the tractable estimation strategy. These two factors provide a natural lens through which we can better understand and compare 24 distinct algorithms. Based on the various feature removal approaches, we describe the multiple types of Shapley value feature attributions and methods to calculate each one. Then, based on the tractable estimation strategies, we characterize two distinct families of approaches: model-agnostic and model-specific approximations. For the model-agnostic approximations, we benchmark a wide class of estimation approaches and tie them to alternative yet equivalent characterizations of the Shapley value. For the model-specific approximations, we clarify the assumptions crucial to each method's tractability for linear, tree, and deep models. Finally, we identify gaps in the literature and promising future research directions

    The Neural Mechanisms of Value Construction

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    Research in decision neuroscience has characterized how the brain makes decisions by assessing the expected utility of each option in an abstract value space that affords the ability to compare dissimilar options. Experiments at multiple levels of analysis in multiple species have localized the ventromedial prefrontal cortex (vmPFC) and nearby orbitofrontal cortex (OFC) as the main nexus where this abstract value space is represented. However, much less is known about how this value code is constructed by the brain in the first place. By using a combination of behavioral modeling and cutting edge tools to analyze functional magnetic resonance imaging (fMRI) data, the work of this thesis proposes that the brain decomposes stimuli into their constituent attributes and integrates across them to construct value. These stimulus features embody appetitive or aversive properties that are either learned from experience or evaluated online by comparing them to previously experienced stimuli with similar features. Stimulus features are processed by cortical areas specialized for the perception of a particular stimulus type and then integrated into a value signal in vmPFC/OFC. The project presented in Chapter 2 examines how food items are evaluated by their constituent attributes, namely their nutrient makeup. A linear attribute integration model succinctly captures how subjective values can be computed from a weighted combination of the constituent nutritive attributes of the food. Multivariate analysis methods revealed that these nutrient attributes are represented in the lateral OFC, while food value is encoded both in medial and lateral OFC. Connectivity between lateral and medial OFC allows this nutrient attribute information to be integrated into a value representation in medial OFC. In Chapter 3, I show that this value construction process can operate over higher-level abstractions when the context requires bundles of items to be valued, rather than isolated items. When valuing bundles of items, the constituent items themselves become the features, and their values are integrated with a subadditive function to construct the value of the bundle. Multiple subregions of PFC including but not limited to vmPFC compute the value of a bundle with the same value code used to evaluate individual items, suggesting that these general value regions contextually adapt within this hierarchy. When valuing bundles and single items in interleaved trials, the value code rapidly switches between levels in this hierarchy by normalizing to the distribution of values in the current context rather than representing all options on an absolute scale. Although the attribute integration model of value construction characterizes human behavior on simple decision-making tasks, it is unclear how it can scale up to environments of real-world complexity. Taking inspiration from modern advances in artificial intelligence, and deep reinforcement learning in particular, in Chapter 4 I outline how connectionist models generalize the attribute integration model to naturalistic tasks by decomposing sensory input into a high dimensional set of nonlinear features that are encoded with hierarchical and distributed processing. Participants freely played Atari video games during fMRI scanning, and a deep reinforcement learning algorithm trained on the games was used as an end-to-end model for how humans evaluate actions in these high-dimensional tasks. The features represented in the intermediate layers of the artificial neural network were found to also be encoded in a distributed fashion throughout the cortex, specifically in the dorsal visual stream and posterior parietal cortex. These features emerge from nonlinear transformations of the sensory input that connect perception to action and reward. In contrast to the stimulus attributes used to evaluate the stimuli presented in the preceding chapters, these features become highly complex and inscrutable as they are driven by the statistical properties of high-dimensional data. However, they do not solely reflect a set of features that can be identified by applying common dimensionality reduction techniques to the input, as task-irrelevant sensory features are stripped away and task-relevant high-level features are magnified.</p

    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 afección potencialmente mortal causada por una respuesta anormal del huésped a una infección, produciendo respuestas fisiológicas alteradas que dañan los propios tejidos del paciente y pueden provocar disfunción orgánica e incluso la muerte. Asimismo, algunos pacientes sépticos progresan a shock séptico, caracterizado por alteraciones circulatorias, celulares y metabólicas sustanciales que aumentan el riesgo de mortalidad. A pesar de que la sepsis se caracteriza por un mal funcionamiento del sistema inmunológico, lo que a su vez conduce a una respuesta inmune alterada e inmunosupresión, la alta complejidad de la fisiopatología de la sepsis requiere una mayor investigación para comprender las respuestas inmunes que ocurren durante la sepsis. Asimismo, las histonas extracelulares circulantes han ganado relevancia como mediadores citotóxicos en la sepsis, ya que actúan como patrones moleculares asociados a daño, que inducen estrés oxidativo y activan el inflamasoma NLRP3. Estos mecanismos median la activación de la piroptosis, un mecanismo de muerte celular programada que produce inflamación mediante la expresión de IL-18, IL-1β and IL-1α. Sin embargo, a pesar de la evidencia de activación del inflamasoma en las células 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 activación del inflamasoma NLRP3 y la piroptosis en las células endoteliales, contribuyendo a la disfunción endotelial y la desregulación de la respuesta inmune mediada por el endotelio. Asimismo, también demostramos cómo la acetilación de histonas disminuye la activación de la piroptosis. Además, demostramos que la piroptosis se produce en pacientes con shock séptico y los niveles de histonas circulantes se correlacionan con la expresión de citoquinas proinflamatorias y citoquinas piroptóticas, la liberación de factores de adhesión endotelial y la gravedad de la enfermedad. Proponemos la piroptosis mediada por histonas como un nuevo objetivo para desarrollar intervenciones clínicas. 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 críticamente enfermos no sépticos, sépticos y de shock séptico. Nuestro enfoque ayudará a caracterizar rápidamente las respuestas inmunes alteradas en pacientes sépticos y de shock séptico ingresados en la Unidad de Cuidados Intensivos. Finalmente analizamos el papel de la metilación del ADN en el control del sistema inmune séptico. Nuestros resultados demostraron el papel central de la metilación del ADN modulando la respuesta molecular en los pacientes de shock séptico y contribuyendo a la inmunosupresión, a través de la alteración de los patrones de metilación 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-1β and IL-1α. 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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