Developments of the cellular frustration approach to anomaly detection

Doutoramento em Engenharia FísicaNeste trabalho é desenvolvido um método de detecção de anomalias, baseado no mecanismo da frustração celular. Este método é capaz de detectar com grande precisão desvios de um comportamento característico de um sistema complexo. Estes desvios podem ser devidos a intrusões ou a anomalias no seu funcionamento. O método propõe ainda uma compreensão alternativa de diversos fenómenos observados em Imunologia.This work develops a method for anomaly detection, based on the cellular frustration mechanism. It is capable of detecting accurately deviations from a characteristic behavior of a complex system. These deviations may be due to intrusions or anomalies in the system’s normal functioning. The method also proposes an alternative conceptual approach to a diverse range of phenomena observed in immunology

Desenvolvimentos de uma nova abordagem em inteligência artificial para deteção de anomalias

Doutoramento em Engenharia InformáticaEste trabalho visou o desenvolvimento do modelo de frustração celular para aplicações à segurança informática. Neste âmbito foram desenvolvidos os processos necessários para materializar o modelo de frustração celular num algoritmo semi-supervisionado de deteção de anomalias. É por seguida efetuada uma comparação da capacidade de discriminação do algoritmo de frustração celular com algoritmos do estado de arte, nomeadamente máquinas de vetores de suporte e florestas aleatórias (com sigla em inglês de SVM e RF, respetivamente). Verifica-se que nos casos estudados o algoritmo de frustração celular obtém uma capacidade de discriminação de anomalias semelhante, senão melhor, que os algoritmos anteriormente descritos. São ainda descritas otimizações para reduzir o elevado custo computacional do algoritmo recorrendo a novos paradigmas de computação, i.e. pelo uso de placas gráficas, assim como otimizações que visam reduzir a complexidade do algoritmo. Em ambos os casos foi verificada uma redução do tempo computacional. Por fim, é ainda verificado que as melhorias introduzidas permitiram que a capacidade de discriminação do algoritmo se tornasse menos sensível à perturbação dos seus parâmetros.This work sought to develop the cellular frustration model for computer security applications. In this sense, the required processes to materialize the cellular frustration model in a semi-supervised anomaly detection algorithm were developed. The discrimination capability of the cellular frustration algorithm was then compared with the discrimination capability of state of the art algorithms, namely support vector machines and random forests (SVMs and RFs, respectively). In the studied cases it is observed that the cellular frustration algorithm exhibits comparable, if not better, anomaly detection capabilities. Optimizations to reduce the high computational cost that rely on new computational paradigms, i.e. by the use of graphic cards, as well as optimizations to reduce the algorithm complexity were also described. In both cases it was observed a reduction of the computational time required by the algorithm. Finally, it was verified that the introduced improvements allowed the anomaly detection capability of the algorithm to become less sensitive to the perturbation of its parameters

The Macrophage Scavenger Receptor Type A Is Expressed by Activated Macrophages and Protects the Host Against Lethal Endotoxic Shock

During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mφ) to release inflammatory mediators such as tumor necrosis factor (TNF)-α, which can cause hypotension, organ failure, and often death. Several different receptors on Mφ have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mφ express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mφ to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-α and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-α activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mφ, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mφ of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock

Agrupamentos de dados em modelos de frustração celular

Cellular frustrated systems are models of interacting agents displaying complex dynamics which can be used for anomaly detection applications. In their simplest versions, these models consist of two agent types, called presenters and detectors. Presenters display information from data samples. Detectors read this information and perceive it in a binary signal, depending on its frequency of appearance. The type of signal perceived will have an impact on the agents' decision dynamics. In particular, the presence of anomalies leads to less frustrated dynamics, i.e., more stable. In this thesis it is questioned if the mapping in binary signals could not bene t from the knowledge of the existence of clusters in the data set. To this end, a clustering technique was developed that gives particular attention to the fact that cellular frustrated systems discriminate samples depending on the number of features displaying rare values. The clusters obtained with this technique are also compared with those obtained using k-means or hierarchical agglomerative clustering. It is shown that using a clustering technique prior to application of cellular frustration system can improve anomaly detection rates. However, it is also shown that depending on the type of anomalies, this may not be generally the case, and therefore simpler cellular frustration algorithms may have the advantage of being simpler. It is believed that this study proposes new directions on how to improve the cellular frustration technique in a broader context.Sistemas de frustração celular são modelos de interação de agentes que demonstram uma dinâmica complexa que pode ser utilizada para aplicações de deteção de anomalias. Na sua versão mais simples, estes modelos são compostos por dois tipos de agentes, designados de apresentadores e detetores. Os apresentadores exibem a informação das amostras. Os detetores leem essa informação e percecionam-na em sinais binários, dependendo da frequência com que são apresentados. O tipo de sinal percecionado terá impacto na dinâmica de decisões dos agentes. Em particular, a presença de anomalias produz uma dinâmica menos frustrada, i.e., mais estável. Nesta tese é questionado se este mapeamento em sinais binários não poderá bene ciar do conhecimento da existência de grupos (clusters) nas amostras. Com esta nalidade, foi desenvolvida uma técnica de clustering, que dá particular atenção ao facto que os sistemas de frustração celular detetam as amostras dependendo do número de características que exibem valores extremos. Os clusters obtidos com esta técnica também são comparados com aqueles obtidos com técnicas conhecidas, como o k-means ou o clus- tering hierárquico aglomerativo. Nesta tese demonstra-se que a utilização de uma técnica de clustering antes da aplicação do sistema de frustração celular pode melhorar as taxas de deteção de anomalias. Contudo, também é demonstrado que dependendo do tipo de anomalias, esta alteração pode não ser bené ca, podendo ser mais vantajoso utilizar a técnica de frustração celular original, uma vez que é mais simples. Acredita-se que este estudo propõe direções claras sobre como se poderá vir a melhorar a técnica da frustração celular num contexto mais geral.Mestrado em Engenharia Físic

The cytoskeleton in cell-autonomous immunity: structural determinants of host defence

Host cells use antimicrobial proteins, pathogen-restrictive compartmentalization and cell death in their defence against intracellular pathogens. Recent work has revealed that four components of the cytoskeleton — actin, microtubules, intermediate filaments and septins, which are well known for their roles in cell division, shape and movement — have important functions in innate immunity and cellular self-defence. Investigations using cellular and animal models have shown that these cytoskeletal proteins are crucial for sensing bacteria and for mobilizing effector mechanisms to eliminate them. In this Review, we highlight the emerging roles of the cytoskeleton as a structural determinant of cell-autonomous host defence

Cellular immune responses of the insect Manduca sexta to bacteria and fungi

Available from British Library Document Supply Centre- DSC:DXN059681 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

Effects of Carboxylated Nanodiamonds on Macrophages During and After Differentiation

Nanodiamonds (ND) are a carbon-based nanomaterial that are increasingly being proposed for developing novel imaging techniques, as carriers of biomolecules and therapeutic drugs, as coatings for implants, and for other biomedical applications. The exceptional chemical, mechanical, and optical properties of ND make this material suitable in a wide range of fields. The application of ND in the biomedical field is attractive but requires more in-depth investigation into the safety of ND and its interactions with different cells and systems. The effects of ND on the immune system are not fully understood or investigated and there are several controverting reports regarding ND biocompatibility. Macrophages are found in almost all tissues of the body and are key players in the vertebrate immune system, maintaining homeostasis and initiating immune response to a wide range of pathogens and foreign or host mediators. I hypothesized that ND can affect macrophages and interfere with their functions, and aimed to study interactions of ND with these cells to better understand the potential impact of ND on the immune system. My studies included monitoring both cultured and bone-marrow-derived macrophages in vitro after different exposure conditions and assessment of their effects on cellular processes using molecular laboratory techniques. Results showed that these particles do not significantly increase cell death or changes in cell morphology. These macrophages internalized ND via phagocytic and clathrin-dependent endocytosis in a time- and dose-dependent manner. The internalized ND localized to the cytoplasm without eliciting an inflammatory response in macrophages. Investigations on the macrophage functions showed that treatment of macrophages with ND did not affect their ability to respond to lipopolysaccharides. On the other hand, their endocytic activity was reduced significantly, irrespective of ND dose. Exposure of bone marrow cells to ND early during their differentiation did not affect their morphology or reduce the percent of cells expressing macrophage surface markers. Nonetheless, ND exposure reduced the number of surface markers expressed on each cell. My findings suggest that ND are not cytotoxic to macrophages at the tested concentrations, but they can interfere with macrophage functions and differentiation. Further studies are needed to explore the mechanisms by which ND suppress macrophages endocytic activity and expression of surface markers and the downstream impact of these suppressed immune functions. In addition, the effects of ND on other cells’ immune functions and expression of other immune mediators yet to be studied before concluding the immunotoxicity or compatibility of ND

THE SOLE GATEWAY TO ENDOTOXIN RESPONSE: HOW LPS WAS IDENTIFIED AS TLR4, AND ITS ROLE IN INNATE IMMUNITY

ABSTRACT: Tlr4 has emerged as a specific conduit for the bacterial lipopolysaccharide (LPS) response. The fact that such a protein exists, and furthermore, the fact that it is one member of a family of proteins expressed by mononuclear cells, yields considerable insight into the mechanism by which phagocytes "see" the microbial universe. It cannot yet be assumed that all the Tlrs have specificity comparable to that of Tlr4, but it is probable that they do, given the molecular constraints to which all proteins are subject. Indeed, it is remarkable that Tlr4 is able to sense so diverse an array of LPS molecules as it does. The total number of Tlr proteins is not yet known. Although approximately 30 leucine-rich proteins bearing Toll-like cytoplasmic domains might be anticipated based on a survey of the genes in Drosophila, far fewer Toll-like genes have been found in mammals to date, although approximately 2 million expressed sequence tag sequences are now archived, and much of the genome has been covered. Some of the Toll-like proteins are, in fact, cytokine receptors. Ten leucine-rich Tlrs have been reported so far. Even a small number of receptors might be sufficient to confer recognition of most pathogens, be they fungi, bacteria, or protozoa. Some such receptors may also play developmental roles. The mutational deletion of Tlr genes alone and in combination with one another may help to establish the functions of each member of this newly emergent family of proteins. In 1908, Elie Metchnikoff and Paul Ehrlich shared the Nobel Prize in Medicine. Metchnikoff was honored for his discovery of phagocytes, which as he correctly surmised, were an essential component of host defense against infection. In effect, he identified the cellular basis of what we now call "innate immunity". Ehrlich was honored for his discovery of "antitoxins", known today as antibodies. In so doing, he laid the foundations of the science of humoral immunity. As the Nobel Committee clearly recognized at the time, phagocytes and antibodies operate in concert with one another, each providing an important measure of protection against microbial pathogens It is worth noting that Metchnikoff did not initially discover phagocytes in humans or in mice, nor in any other vertebrate, but in the larvae of starfish impaled by tangerine thorns, and in freshwater Daphnia, where he observed ingestion of fungal spores and anthrax bacilli. By contrast, antibodies have long been known to be produced by vertebrates only. As such, it is clear that innate immunity antedated humoral immunity. The latter system of defense was built to supplement the former. Humoral immunity is one of the crowning glories of evolution. It arose in a remarkably short period of time. To do so, it needed to satisfy two requirements of any immune system. First, it was necessary for specific immunity to deal with a diverse range of pathogens. Second, it was necessary for the system to discriminate between self and non-self, hence avoiding the scenario of horror autotoxicus, envisioned by Ehrlich himself. The first requirement was met through reliance upon an anticipatory strategy in which avid receptors (T-cell receptors and immunoglobulins) are fashioned for virtually any molecule that might ever be encountered. This process requires a mechanism of genomic rearrangement that is, as far as we know, unique in all of nature. The second requirement was met by the process of clonal selection; also something quite unique, and as yet, only partly understood. As might be assumed, the innate immune system overcame the dual problems of pathogen diversity and self-recognition long before vertebrates evolved. Yet only now have we begun to understand how this was accomplished. Lacking any known means by which to generate receptor diversity, cells of the innate immune system came to rely upon plasma membrane proteins that engage phylogenically conserved determinants on pathogens. These "pattern recognition receptors" Endotoxin and Gram-Negative Infection As recently recounte