67,847 research outputs found

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

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    La sepsis es una afecci贸n potencialmente mortal causada por una respuesta anormal del hu茅sped a una infecci贸n, produciendo respuestas fisiol贸gicas alteradas que da帽an los propios tejidos del paciente y pueden provocar disfunci贸n org谩nica e incluso la muerte. Asimismo, algunos pacientes s茅pticos progresan a shock s茅ptico, caracterizado por alteraciones circulatorias, celulares y metab贸licas sustanciales que aumentan el riesgo de mortalidad. A pesar de que la sepsis se caracteriza por un mal funcionamiento del sistema inmunol贸gico, lo que a su vez conduce a una respuesta inmune alterada e inmunosupresi贸n, la alta complejidad de la fisiopatolog铆a de la sepsis requiere una mayor investigaci贸n para comprender las respuestas inmunes que ocurren durante la sepsis. Asimismo, las histonas extracelulares circulantes han ganado relevancia como mediadores citot贸xicos en la sepsis, ya que act煤an como patrones moleculares asociados a da帽o, que inducen estr茅s oxidativo y activan el inflamasoma NLRP3. Estos mecanismos median la activaci贸n de la piroptosis, un mecanismo de muerte celular programada que produce inflamaci贸n mediante la expresi贸n de IL-18, IL-1尾 and IL-1伪. Sin embargo, a pesar de la evidencia de activaci贸n del inflamasoma en las c茅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贸n del inflamasoma NLRP3 y la piroptosis en las c茅lulas endoteliales, contribuyendo a la disfunci贸n endotelial y la desregulaci贸n de la respuesta inmune mediada por el endotelio. Asimismo, tambi茅n demostramos c贸mo la acetilaci贸n de histonas disminuye la activaci贸n de la piroptosis. Adem谩s, demostramos que la piroptosis se produce en pacientes con shock s茅ptico y los niveles de histonas circulantes se correlacionan con la expresi贸n de citoquinas proinflamatorias y citoquinas piropt贸ticas, la liberaci贸n de factores de adhesi贸n endotelial y la gravedad de la enfermedad. Proponemos la piroptosis mediada por histonas como un nuevo objetivo para desarrollar intervenciones cl铆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铆ticamente enfermos no s茅pticos, s茅pticos y de shock s茅ptico. Nuestro enfoque ayudar谩 a caracterizar r谩pidamente las respuestas inmunes alteradas en pacientes s茅pticos y de shock s茅ptico ingresados en la Unidad de Cuidados Intensivos. Finalmente analizamos el papel de la metilaci贸n del ADN en el control del sistema inmune s茅ptico. Nuestros resultados demostraron el papel central de la metilaci贸n del ADN modulando la respuesta molecular en los pacientes de shock s茅ptico y contribuyendo a la inmunosupresi贸n, a trav茅s de la alteraci贸n de los patrones de metilaci贸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-1尾 and IL-1伪. 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

    Rainfall Prediction: A Comparative Analysis of Modern Machine Learning Algorithms for Time-Series Forecasting

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    Rainfall forecasting has gained utmost research relevance in recent times due to its complexities and persistent applications such as flood forecasting and monitoring of pollutant concentration levels, among others. Existing models use complex statistical models that are often too costly, both computationally and budgetary, or are not applied to downstream applications. Therefore, approaches that use Machine Learning algorithms in conjunction with time-series data are being explored as an alternative to overcome these drawbacks. To this end, this study presents a comparative analysis using simplified rainfall estimation models based on conventional Machine Learning algorithms and Deep Learning architectures that are efficient for these downstream applications. Models based on LSTM, Stacked-LSTM, Bidirectional-LSTM Networks, XGBoost, and an ensemble of Gradient Boosting Regressor, Linear Support Vector Regression, and an Extra-trees Regressor were compared in the task of forecasting hourly rainfall volumes using time-series data. Climate data from 2000 to 2020 from five major cities in the United Kingdom were used. The evaluation metrics of Loss, Root Mean Squared Error, Mean Absolute Error, and Root Mean Squared Logarithmic Error were used to evaluate the models' performance. Results show that a Bidirectional-LSTM Network can be used as a rainfall forecast model with comparable performance to Stacked-LSTM Networks. Among all the models tested, the Stacked-LSTM Network with two hidden layers and the Bidirectional-LSTM Network performed best. This suggests that models based on LSTM-Networks with fewer hidden layers perform better for this approach; denoting its ability to be applied as an approach for budget-wise rainfall forecast applications

    The company she keeps : The social and interpersonal construction of girls same sex friendships

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    This thesis begins a critical analysis of girls' 'private' interpersonal and social relations as they are enacted within two school settings. It is the study of these marginal subordinated worlds productivity of forms of femininity which provides the main narrative of this project. I seek to understand these processes of (best) friendship construction through a feminist multi-disciplinary frame, drawing upon cultural studies, psychoanalysis and accounts of gender politics. I argue that the investments girls bring to their homosocial alliances and boundary drawing narry a psychological compulsion which is complexly connected to their own experiences within the mother/daughter bond as well as reflecting positively an immense social debt to the permissions girls have to be nurturant and ; negatively their own reproduction of oppressive exclusionary practices. Best friendship in particular gives girls therefore, the experience of 'monogamy' continuous of maternal/daughter identification, reminiscent of their positioning inside monopolistic forms of heterosexuality. But these subcultures also represent a subversive discontinuity to the public dominance of boys/teachers/adults in schools and to the ideologies and practices of heterosociality and heterosexuality. By taking seriously their transmission of the values of friendship in their chosen form of notes and diaries for example, I was able to access the means whereby they were able to resist their surveillance and control by those in power over them. I conclude by arguing that it is through a recognition of the valency of these indivisiblly positive and negative aspects to girls cultures that Equal Opportunities practitioners must begin if they are serious about their ambitions. Methods have to be made which enable girls to transfer their 'private' solidarities into the 'public' realm, which unquestionably demands contesting with them the causes and consequences of their implication in the divisions which also contaminate their lives and weaken them

    The Caribbean Syzygy: a study of the novels of Edgar Mittelholzer and Wilson Harris

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    The problem of racial inheritance - the "search for identity" - is a recurring theme in the criticism of Caribbean literature. It is a pre-occupation with Caribbean writers, affecting both subject matter and literary quality, as FM. Birbalsingh, for example, has shown with reference to the novels of John Hearne and E,R. Braithwaite (Caribbean quarterly Vols. 14, December 1968 and 16, March 1970). This study of the work of Edgar Mittelholzer and Wilson Harris will attempt to show that there are important areas still to be explored relating Caribbean literature to its complex racial and cultural background. Both Mittelholzer and Harris deserve close, critical study in their own right; but a parallel examination reveals similarities and differences which bring into sharper focus wider concerns of Caribbean literature. The two important directions of West Indian writing are more clearly seen: the one, pioneered by Mittelholzer, in which the writer looks outward towards a "parent" culture, and the other looking inward, seeking in its own, complex inheritance the raw material for new and original growth. Mittelholzer and Harris are both Guyanese of mixed racial stock, both deeply concerned with the psychological effects of this mixture, and both writers have a profound awareness of the Guyanese historical and cultural heritage. They also share a deep feeling for the Guyenese landscape which appears in their work as a brooding presence affecting radically -the lives of those who live within i-t. Mittelholzer's attitude to his mixed racial and cultural origins, however, produces in his work a schizophrenic Imbalance while Harris, by accepting racial and cultural complexity as a starting-point, initiates a uniquely creative and experimental art. Mittelholzer, in his approach to history, human character eM landscape, remains a vi "coastal" writer never really concerned (as Harris is) with. the deeper significance of the "Interior" and all that this implies, both in a geographical and psychological sense. The fact that Mittelbolzer's work reflects a psychological imbalance induced by a pre-occupation with racial identity has been demonstrated by Denis Williams in the 1968 Mittelholzer Lectures, and by Joyce Sparer in a series of articles in the Guyana Graphic. Mittelholzer's awareness of this imbalance, however, and his attempt to come to terms with it in his art remain to be examined and documented, as does Harris's attempt to create am "associative" art aimed at healing the breach in the individual consciousness of Caribbean Man. The aim of this study is to demonstrate that Mitteholzer and. Harris, although antithetical in impact and style (each representing an approach to fiction directly opposed to the other) are, in fact, the opposite elements of a dichotomy. Their work illustrates the negative and positive aspects of the racial and cultural schizophrenia of the Caribbean, for both writers in their different ways are preoccupied with (and therefore have embodied in their work) the juxtaposition and, contrasting of apparently irreconcilable emotional and intellectual qualities - the Caribbean Syzygy

    Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

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    Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases

    Investigating the potential role for RBMY in cancer

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    Introduction: Head and neck squamous cell carcinoma (HNSCC), is a major healthcare concern with a high male prevalence. We hypothesise that the testis specific mRNA splicing regulator, Y-linked RBMY gene, is aberrantly expressed in HNSCC in part promoting HNSCC through ZFY-short splicing. RBMY has been shown to enhance tumour development in male hepatocellular carcinoma (human tissue specimens and transgenic-mouse models) whilst ZFY-short is predicted to have anti-apoptotic properties and the deletion of RBMY locus on Y-chromosome resulted in lowered ZFY-short expression. Thus, we hypothesize that ZFY-short is generated by RBMY and exerts its anti-apoptotic effects to promote male HNSCC. Methods: Due to the coronavirus lockdown, bench work was restricted to 6 months, therefore, I conducted an extended analysis of RBMY expression in human cancer, including a computational analysis of RBMY gene expression with data from the cBioPortal database. In my bench-work, I attempted to establish GFP- RBMY expressing cell lines and conducted fluorescence microscopy, RT- PCR and qPCR to analyse RBMY expression in HNSCC cell lines and its impact on ZFY-short expression. Results: RBMY is expressed in several cancers, with no driver mutations. RBMY has nuclear localisation and is expressed in 93-UV-147T and UM-SCC-104 cell lines (both HPV16-positive HNSCC cell lines), with increased ZFY-short expression observed in UM- SCC-104. Discussion: Despite RBMY having been shown to be an oncogene in male liver cancer, our analysis of cBioPortal data suggests this activity may be restricted to the small minority of tumours of different cancer types that express RBMY. The paralleled expression of RBMY and ZFY-short in our cell lines indicate an association. UMSCC104 cell line originates from a highly an aggressive and recurrent tumour, RBMY is associated with tumour stemness, thus it is possible that via ZFY-short, RBMY could have promoted the aggressive phenotype in this, and in other HNSCCs

    In search of 'The people of La Manche': A comparative study of funerary practices in the Transmanche region during the late Neolithic and Early Bronze Age (250BC-1500BC)

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    This research project sets out to discover whether archaeological evidence dating between 2500 BC - 1500 BC from supposed funerary contexts in Kent, flanders and north-eastern Transmanche France is sufficient to make valid comparisons between social and cultural structures on either side of the short-sea Channel region. Evidence from the beginning of the period primarily comes in the form of the widespread Beaker phenomenon. Chapter 5 shows that this class of data is abundant in Kent but quite sparse in the Continental zones - most probably because it has not survived well. This problem also affects the human depositional evidence catalogued in Chapter 6, particularly in Fanders but also in north-eastern Transmanche France. This constricts comparative analysis, however, the abundant data from Kent means that general trends are still discernible. The quality and volume of data relating to the distribution, location, morphology and use of circular monuments in all three zones is far better - as demonstrated in Chapter 7 -mostly due to extensive aerial surveying over several decades. When the datasets are taken as a whole, it becomes possible to successfully apply various forms of comparative analyses. Most remarkably, this has revealed that some monuments apparently have encoded within them a sophisticated and potentially symbolically charged geometric shape. This, along with other less contentious evidence, demonstrates a level of conformity that strongly suggests a stratum of cultural homogeneity existed throughout the Transmanche region during the period 2500 BC - 1500 BC. The fact that such changes as are apparent seem to have developed simultaneously in each of the zones adds additional weight to the theory that contact throughout the Transmanche region was endemic. Even so, it may not have been continuous; there may actually have been times of relative isolation - the data is simply too course to eliminate such a possibility

    Anytime algorithms for ROBDD symmetry detection and approximation

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    Reduced Ordered Binary Decision Diagrams (ROBDDs) provide a dense and memory efficient representation of Boolean functions. When ROBDDs are applied in logic synthesis, the problem arises of detecting both classical and generalised symmetries. State-of-the-art in symmetry detection is represented by Mishchenko's algorithm. Mishchenko showed how to detect symmetries in ROBDDs without the need for checking equivalence of all co-factor pairs. This work resulted in a practical algorithm for detecting all classical symmetries in an ROBDD in O(|G|鲁) set operations where |G| is the number of nodes in the ROBDD. Mishchenko and his colleagues subsequently extended the algorithm to find generalised symmetries. The extended algorithm retains the same asymptotic complexity for each type of generalised symmetry. Both the classical and generalised symmetry detection algorithms are monolithic in the sense that they only return a meaningful answer when they are left to run to completion. In this thesis we present efficient anytime algorithms for detecting both classical and generalised symmetries, that output pairs of symmetric variables until a prescribed time bound is exceeded. These anytime algorithms are complete in that given sufficient time they are guaranteed to find all symmetric pairs. Theoretically these algorithms reside in O(n鲁+n|G|+|G|鲁) and O(n鲁+n虏|G|+|G|鲁) respectively, where n is the number of variables, so that in practice the advantage of anytime generality is not gained at the expense of efficiency. In fact, the anytime approach requires only very modest data structure support and offers unique opportunities for optimisation so the resulting algorithms are very efficient. The thesis continues by considering another class of anytime algorithms for ROBDDs that is motivated by the dearth of work on approximating ROBDDs. The need for approximation arises because many ROBDD operations result in an ROBDD whose size is quadratic in the size of the inputs. Furthermore, if ROBDDs are used in abstract interpretation, the running time of the analysis is related not only to the complexity of the individual ROBDD operations but also the number of operations applied. The number of operations is, in turn, constrained by the number of times a Boolean function can be weakened before stability is achieved. This thesis proposes a widening that can be used to both constrain the size of an ROBDD and also ensure that the number of times that it is weakened is bounded by some given constant. The widening can be used to either systematically approximate an ROBDD from above (i.e. derive a weaker function) or below (i.e. infer a stronger function). The thesis also considers how randomised techniques may be deployed to improve the speed of computing an approximation by avoiding potentially expensive ROBDD manipulation

    Disunity in society, fractures at home: family relating in the context of divisive socio-political issues

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    Section A A systematic literature review conducted to identify and explore research that has investigated adult intrafamilial relationships and divisive political issues since 2016. Ten papers are included in the review. The studies are critiqued using a mixed-methods risk of bias tool. Findings are collated using narrative synthesis. The synthesis focuses on relational responses鈥攖o divisive political issues鈥攖he potential reasons for these responses, and their consequences. Review findings are discussed in relation to previous theoretical and empirical literature. Finally, clinical and research implications are presented. Section B A grounded theory study to develop an understanding of adult intrafamilial invalidation in the context of social and political change. Brexit and COVID-19 serve as the contextual lens through which the phenomenon was observed. Data from 11 participants and 45 screening questionnaire respondents were analysed as part of the study. A model of family 鈥淩ejection of You鈥 experiences is presented outlining foundational and contextual factors that frame the experience, the experience itself, and relational, behavioural, cognitive, and emotional consequences. Findings are discussed in relation to previous theory and previous empirical research. Clinical implications are considered and possible directions for future research are set out
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