Immunopathogenesis of canine chronic ulcerative stomatitis.

Canine Chronic Ulcerative Stomatitis is a spontaneously occurring inflammatory disease of the oral mucosa. An immune-mediated pathogenesis is suspected though not yet proven. We have recently reported on the clinical and histologic features, and identification of select leukocyte cell populations within the lesion. A clinical and histologic similarity to oral lichen planus of people was proposed. In the present study, these initial observations are extended by examining lesions from 24 dogs with clinical evidence of chronic ulcerative stomatitis. Because dogs with chronic ulcerative stomatitis often have concurrent periodontal disease, we wondered if dental plaque/biofilm may be a common instigator of inflammation in both lesions. We hypothesized that dogs with chronic ulcerative stomatitis would exhibit a spectrum of pathologic changes and phenotype of infiltrating leukocytes that would inform lesion pathogenesis and that these changes would differ from inflammatory phenotypes in periodontitis. Previously we identified chronic ulcerative stomatitis lesions to be rich in FoxP3+ and IL17+ cells. As such, we suspect that these leukocytes play an important role in lesion pathogenesis. The current study confirms the presence of moderate to large numbers of FoxP3+ T cells and IL17+ cells in all ulcerative stomatitis lesions using confocal immunofluorescence. Interestingly, the majority of IL17+ cells were determined to be non-T cells and IL17+ cell frequencies were negatively correlated with severity on the clinical scoring system. Three histologic subtypes of ulcerative stomatitis were determined; lichenoid, deep stomatitis and granulomatous. Periodontitis lesions, like stomatitis lesions, were B cell and plasma cell rich, but otherwise differed from the stomatitis lesions. Direct immunofluorescence results did not support an autoantibody-mediated autoimmune disease process. This investigation contributes to the body of literature regarding leukocyte involvement in canine idiopathic inflammatory disease pathogenesis

SoniBand: Understanding the Effects of Metaphorical Movement Sonifications on Body Perception and Physical Activity

Negative body perceptions are a major predictor of physical inactivity, a serious health concern. Sensory feedback can be used to alter such body perceptions; movement sonification, in particular, has been suggested to affect body perception and levels of physical activity (PA) in inactive people. We investigated how metaphorical sounds impact body perception and PA. We report two qualitative studies centered on performing different strengthening/flexibility exercises using SoniBand, a wearable that augments movement through different sounds. The first study involved physically active participants and served to obtain a nuanced understanding of the sonifications’ impact. The second, in the home of physically inactive participants, served to identify which effects could support PA adherence. Our findings show that movement sonification based on metaphors led to changes in body perception (e.g., feeling strong) and PA (e.g., repetitions) in both populations, but effects could differ according to the existing PA-level. We discuss principles for metaphor-based sonification design to foster PA

Finding the "Dark Matter'' in Human and Yeast Protein Network Prediction and Modelling

Accurate modelling of biological systems requires a deeper and more complete knowledge about the molecular components and their functional associations than we currently have. Traditionally, new knowledge on protein associations generated by experiments has played a central role in systems modelling, in contrast to generally less trusted bio-computational predictions. However, we will not achieve realistic modelling of complex molecular systems if the current experimental designs lead to biased screenings of real protein networks and leave large, functionally important areas poorly characterised. To assess the likelihood of this, we have built comprehensive network models of the yeast and human proteomes by using a meta-statistical integration of diverse computationally predicted protein association datasets. We have compared these predicted networks against combined experimental datasets from seven biological resources at different level of statistical significance. These eukaryotic predicted networks resemble all the topological and noise features of the experimentally inferred networks in both species, and we also show that this observation is not due to random behaviour. In addition, the topology of the predicted networks contains information on true protein associations, beyond the constitutive first order binary predictions. We also observe that most of the reliable predicted protein associations are experimentally uncharacterised in our models, constituting the hidden or "dark matter'' of networks by analogy to astronomical systems. Some of this dark matter shows enrichment of particular functions and contains key functional elements of protein networks, such as hubs associated with important functional areas like the regulation of Ras protein signal transduction in human cells. Thus, characterising this large and functionally important dark matter, elusive to established experimental designs, may be crucial for modelling biological systems. In any case, these predictions provide a valuable guide to these experimentally elusive regions

Towards an OpenSource Logger for the Analysis of RPA Projects

Process automation typically begins with the observation of humans conducting the tasks that will be eventually automated. Sim ilarly, successful RPA projects require a prior analysis of the undergo ing processes which are being executed by humans. The process of col lecting this type of information is known as user interface (UI) logging since it records the interaction against a UI. Main RPA platforms (e.g., Blueprism and UIPath) incorporate functionalities that allow the record ing of these UI interactions. However, the records that these platforms generate lack some functionalities that large-scale RPA projects require. Besides, they are only understandable by the proper RPA platforms. This paper presents an extensible and multi-platform OpenSource UI logger that generate UI logs in a standard format. This system collects information from all the computers it is running on and sends it to a central server for its processing. Treatment of the collected information will allow the creation of an enriched UI log which can be used, among others purposes, for smart process analysis, machine learning training, the creation of RPA robots, or, being more general, for task mining .Ministerio de Economía y Competitividad TIN2016-76956-C3-2-R (POLOLAS)Junta de Andalucía CEI-12-TIC021Centro para el Desarrollo Tecnol´ogico Industrial (CDTI) P011-19/E0

Análises fitoquímicas em extrato das folhas de Anthurium affine Schott (milho de urubu)

Apesar da ampla disposição de medicamentos no mercado, muitas dificuldades ainda existem quanto ao tratamento de determinados tipos de doenças, como é o caso das dermatites nos animais domésticos, mais especificamente nos cães. Apoiando-se na hipótese de que plantas da família das Araceae podem oferecer insumos importantes no tratamento deste tipo de doença, idealizou-se este trabalho tendo-se como principal objetivo estudar mais precisamente a composição fitoquímica do Anthurium affine Schott (A. affine), conhecido popularmente como “milho de urubu”. A partir de amostras da planta colhidas na Região Metropolitana do Grande Recife, foi confeccionado o extrato hidroalcóolico (etanol a 70%), das folhas da planta, sendo colocado para maceração por sete dias. A partir desta etapa o material foi submetido a procedimentos de filtragem e caracterização do extrato final obtido. Posteriormente, alíquotas deste material foram colhidas e trabalhadas para a realização dos ensaios de identificação fitoquímica, conforme protocolo padrão disponível na literatura. Como resultados, obteve-se um extrato hidroalcóolico da planta na concentração de 85 mg/mL; as análises fitoquímicas apresentaram resposta positiva para taninos, flavonóides, alcalóides e saponinas. Verificou-se que o A. affine apresentou um potencial fitoterápico mais rico do que normalmente se apresenta, embora estudos mais precisos sejam necessários para se avaliar os reais riscos de toxicidade no uso terapêutico da planta, como também para melhor definir os mecanismos de ação por traz dos efeitos farmacológicos atribuídos aos seus extratos

Non-human TRIM5 variants enhance recognition of HIV-1-infected cells by CD8+ T cells

Tripartite motif-containing protein 5 (TRIM5) restricts human immunodeficiency virus type-1 (HIV-1) in a species-specific manner by uncoating viral particles while activating early innate responses. Although the contribution of TRIM5 proteins to cellular immunity has not yet been studied, their interactions with the incoming viral capsid and the cellular proteasome led us to hypothesize a role for them. Here, we investigate whether the expression of two non-human TRIM5 orthologs, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), both of which are potent restrictors of HIV-1, could enhance immune recognition of infected cells by CD8+ T cells. We illustrate how TRIM5 restriction improves CD8+ T cell-mediated HIV-1 inhibition. Moreover, when TRIM5 activity was blocked by the non-immunosuppressive analog of cyclosporin A, SmBz-CsA, we found a significant reduction in CD107a/MIP1β expression in HIV-1-specific CD8+ T cells. This finding underscores the direct link between TRIM5 restriction and activation of CD8+ T-cell responses. Interestingly, cells expressing RhT5 induced stronger CD8+ T-cell responses through the specific recognition of the HIV-1 capsid by the immune system. The underlying mechanism of this process may involve TRIM5-specific capsid recruitment to cellular proteasomes and increase peptide availability for loading and presentation of HLA class I antigens. In summary, we identified a novel function for non-human TRIM5 variants in cellular immunity. We hypothesise that TRIM5 can couple innate viral sensing and CD8+ T-cell activation to increase species barriers against retrovirus infection. IMPORTANCE: New therapeutics to tackle HIV-1 infection should aim to combine rapid innate viral sensing and cellular immune recognition. Such strategies could prevent seeding of the viral reservoir and the immune damage that occurs during acute infection. The non-human TRIM5 variants, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), are attractive candidates owing to their potency in sensing HIV-1 and blocking its activity. Here, we show that expression of RhT5 and TCyp in HIV-1-infected cells improves CD8+ T cell-mediated inhibition through the direct activation of HIV-1-specific CD8+ T-cell responses. We found that the potency in CD8+ activation was stronger for RhT5 variants and capsid-specific CD8+ T-cells in a mechanism that relies on TRIM5-dependent particle recruitment to cellular proteasomes. This novel mechanism couples innate viral sensing with cellular immunity in a single protein and could be exploited to develop innovative therapeutics for control of HIV-1 infection

Towards a Taxonomy of Cognitive RPA Components

Robotic Process Automation (RPA) is a discipline that is increasingly growing hand in hand with Artificial Intelligence (AI) and Machine Learning enabling the so-called cognitive automation. In such context, the existing RPA platforms that include AI-based solutions clas sify their components, i.e. constituting part of a robot that performs a set of actions, in a way that seems to obey market or business deci sions instead of common-sense rules. To be more precise, components that present similar functionality are identified with different names and grouped in different ways depending on the platform that provides the components. Therefore, the analysis of different cognitive RPA platforms to check their suitability for facing a specific need is typically a time consuming and error-prone task. To overcome this problem and to pro vide users with support in the development of an RPA project, this paper proposes a method for the systematic construction of a taxonomy of cognitive RPA components. Moreover, such a method is applied over components that solve selected real-world use cases from the industry obtaining promising resultsMinisterio de Economía y Competitividad TIN2016-76956-C3-2-RJunta de Andalucía CEI-12-TIC021Centro para el Desarrollo Tecnológico Industrial P011-19/E0

Circulating microRNAs Reveal Time Course of Organ Injury in a Porcine Model of Acetaminophen-Induced Acute Liver Failure

Acute liver failure is a rare but catastrophic condition which can progress rapidly to multi-organ failure. Studies investigating the onset of individual organ injury such as the liver, kidneys and brain during the evolution of acute liver failure, are lacking. MicroRNAs are short, non-coding strands of RNA that are released into the circulation following tissue injury. In this study, we have characterised the release of both global microRNA and specific microRNA species into the plasma using a porcine model of acetaminophen-induced acute liver failure. Pigs were induced to acute liver failure with oral acetaminophen over 19h±2h and death occurred 13h±3h thereafter. Global microRNA concentrations increased 4h prior to acute liver failure in plasma (P<0.0001) but not in isolated exosomes, and were associated with increasing plasma levels of the damage-associated molecular pattern molecule, genomic DNA (P<0.0001). MiR122 increased around the time of onset of acute liver failure (P<0.0001) and was associated with increasing international normalised ratio (P<0.0001). MiR192 increased 8h after acute liver failure (P<0.0001) and was associated with increasing creatinine (P<0.0001). The increase in miR124-1 occurred concurrent with the pre-terminal increase in intracranial pressure (P<0.0001) and was associated with decreasing cerebral perfusion pressure (P<0.002)

Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans

Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans