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Tissue injury, including extracellular matrix (ECM) degradation, is a hallmark of group A Streptococcus (GAS) skin infection and is partially mediated by M proteins which possess lectin‐like properties. Hyaluronic acid is a glycosaminoglycan enriched in the cutaneous ECM, yet an interaction with M proteins has yet to be explored. This study revealed that hyaluronic acid binding was conserved across phylogenetically diverse M proteins, mediated by RR/SR motifs predominantly localized in the C repeat region. Keratinocyte wound healing was decreased through the recruitment of hyaluronic acid by M proteins in an M type‐specific manner. GAS strains 5448 (M1 serotype) and ALAB49 (M53 serotype) also bound hyaluronic acid via M proteins, but hyaluronic acid could increase bacterial adherence independently of M proteins. The identification of host–pathogen mechanisms that affect ECM composition and cell repair responses may facilitate the development of nonantibiotic therapeutics that arrest GAS disease progression in the skin. [ABSTRACT FROM AUTHOR]

Once grouted into place and compressed by ground and groundwater, modern segmental linings do not need additional connections except when the lining is required to withstand unusual conditions. Connection systems are provided for two reasons: to assist in the segment‐building process and/or to prevent undesirable actions. A particular focus is on creating and maintaining sufficient gasket compression to seal the lining in the short and long term. The evaluation and design of these connection systems usually involve a simple 1D calculation, ignoring the actual geometry and the presence of other segments and connectors. This study looks at an actual design situation highlighting the role of friction between adjacent segments and the utility of guide rods in the radial joints. [ABSTRACT FROM AUTHOR]

Underground engineering projects are often characterised by significant uncertainties, leading to complex decision‐making when selecting appropriate design methods. Traditional approaches, such as the observational method (OM), have been widely used but rarely explicitly account for the integration of risk, costs, construction timeframes and engineering judgement. Successfully reaching a consensus to implement the OM on tunnelling projects can be challenging and requires ensuring stakeholders understand how the method impacts structural safety. Fostering such understanding can be an arduous process. A risk‐based decision framework is introduced using expected utility theory to aid the decision to choose the OM, or not. The framework integrates risk, cost, construction timelines and engineering judgement within an economic decision model using a probabilistic approach. It is tested on a Sydney, Australia case study. A Monte Carlo model analysis examines contingency actions and structural failure probability when applying the OM. The case study highlights the significance of considering indirect costs in complex decisions and harnesses experienced professionals' insights for a comprehensive risk and cost assessment. We conclude that merging probabilistic‐based design with OM enhances the ability to demonstrate structural safety and economic factors within a unified model. [ABSTRACT FROM AUTHOR]

Tools for automatic grading programming assignments, also known as Online Judges, have been widely used to support computer science (CS) courses. Nevertheless, few studies have used these tools to acquire and analyse interaction data to better understand the students' performance and behaviours, often due to data availability or inadequate granularity. To address this problem, we propose an Online Judge called CodeBench, which allows for fine‐grained data collection of student interactions, at the level of, eg, keystrokes, number of submissions, and grades. We deployed CodeBench for 3 years (2016–18) and collected data from 2058 students from 16 introductory computer science (CS1) courses, on which we have carried out fine‐grained learning analytics, towards early detection of effective/ineffective behaviours regarding learning CS concepts. Results extract clear behavioural classes of CS1 students, significantly differentiated both semantically and statistically, enabling us to better explain how student behaviours during programming have influenced learning outcomes. Finally, we also identify behaviours that can guide novice students to improve their learning performance, which can be used for interventions. We believe this work is a step forward towards enhancing Online Judges and helping teachers and students improve their CS1 teaching/learning practices. [ABSTRACT FROM AUTHOR]

Colonization of the oropharynx is the initial step in Group A Streptococcus (GAS) pharyngeal infection. We have previously reported that the highly virulent M1T1 GAS clone attaches to oral epithelial cells via M1 protein interaction with blood group antigen carbohydrate structures. Here, we have identified that colonization of human oral epithelial cells by GAS serotypes M3 and M12 is mediated by human blood group antigens [ABO(H)] and Lewis (Le) antigen expression. Removal of linkage-specific fucose, galactose, N-acetylgalactosamine, and sialic acid modulated GAS colonization, dependent on host ABO(H) blood group and Le expression profile. Furthermore, N-linked glycans from human salivary glycoproteins, when released and purified, were potent inhibitors of M1, M3, and M12 GAS colonization ex vivo. These data highlight the important role played by human protein glycosylation patterns in GAS attachment to oral epithelial cell surfaces. [ABSTRACT FROM AUTHOR]

We have previously shown that oxidative stress is involved in the pathogenesis of a mercuric chloride (HgCl2)-induced, T helper type 2 (Th2)-driven autoimmune syndrome in Brown Norway (BN) rats. In the context of the syndrome, the oxidative stress-induced mast cell response seems to determine the development of the early phase of vasculitis, while oxidative stress-mediated interleukin (IL)-4 production may contribute to the subsequent Th2-driven autoimmune response. However, the molecular basis of IL-4 gene transcription induced by HgCl2 in mast cells remains unknown. In the present study, we dissect the critical regulatory mechanisms in the IL-4 gene promoter in the rat mast cell line RBL-2H3. Immunoprecipitation provided evidence that treatment with HgCl2 increased phosphorylation of signal transducer and activator of transcription 6 (STAT6). Transient transfection reporter analyses with a series of 5′ end deletions of the IL-4 promoter produced evidence that STAT6 and TATA box binding sites are important in HgCl2-induced IL-4 gene expression. Subsequent elimination of one or both sites by site-directed mutagenesis significantly inhibited IL-4 promoter activity. Our results provide evidence that STAT6 and TATA box regulatory elements play an important role in HgCl2-induced IL-4 transcription in rat mast cells. [ABSTRACT FROM AUTHOR]

Mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway rats is a spontaneously resolving autoimmune response driven by the activation of T helper type 2 lymphocytes (Th2 cells). Treatment with antibody to OX40-ligand (OX40-L) from the time of the first HgCl2 injection for 12 days had little effect. Delayed treatment commenced 8 days after the first HgCl2 injection significantly suppressed immunoglobulin E production, splenomegaly, weight loss and mortality. This makes OX40/OX40-L signalling an attractive therapeutic target for Th2-driven autoimmune diseases. Intravenous administration of the murine antibody to OX-40-L elicited a vigorous anti-mouse immunoglobulin antibody response that was significantly enhanced compared to the response to control immunoglobulin. It is likely that this response significantly reduced the plasma half-life of the anti-OX40-L antibody and this observation has clear implications for the interpretation of data from experiments where anti-OX40-L is used in vivo. [ABSTRACT FROM AUTHOR]

Administration of mercuric chloride (HgCl2) to Brown Norway rats causes Th2-dominated autoimmunity with raised immunoglobulin E concentrations and gut vasculitis, both of which are T-cell dependent, peak at 14 days after starting HgCl2 and then spontaneously resolve. If animals are re-challenged with HgCl2 6 weeks after initial exposure, they are resistant to autoimmunity, developing only attenuated disease. Recently, a separate phase of early caecal vasculitis was described beginning 24 h after initiating HgCl2 and prior to caecal entry of T cells. Previous work suggested this early vasculitis was αβ T-cell independent and implied a role for mast cells. We further tested this hypothesis by performing a histological study during the first 93 h following HgCl2 challenge defining the precise relationship between gut mast cell degranulation and appearing caecal vasculitis. We also studied whether early caecal vasculitis enters a resistant phase upon re-challenge with HgCl2. We show a direct correlation between mast cell degranulation and early caecal vasculitis following initial HgCl2 challenge. We demonstrate resistance to re-challenge in this phase of injury, with results at re-challenge also showing a correlation between mast cell degranulation and early caecal injury. [ABSTRACT FROM AUTHOR]

In the Brown Norway rat, mercuric chloride (HgCl2) induces an autoimmune syndrome characterized by necrotizing vasculitis, predominantly affecting the caecum, and a polyclonal B-cell response. The time course of vasculitis is biphasic, with an αβ T-cell independent phase occurring within 24 h, and a T-cell and neutrophil dependent phase, maximal at two weeks. The pathogenesis of the early phase of vasculitis is unclear, and this study aims to examine the role of neutrophils. Rat neutrophils were depleted using cyclophosphamide. RP3, an antirat neutrophil monoclonal antibody, inhibited neutrophil leucocytosis but did not deplete neutrophils. Vasculitis was induced by subcutaneous HgCl2 injection. Serial measurements of peripheral blood leucocyte count were made. Rats were killed after 24 or 72 h. The macroscopic appearance of the caecum was scored by an experienced observer, and samples taken for histological examination. Caecums were excised and myeloperoxidase, a marker enzyme for neutrophil infiltration, assayed. Cyclophosphamide induced marked neutropaenia whereas RP3 inhibited the neutrophilia observed after HgCl2 injection. Vasculitis was present in both treated and control animals, with no significant differences in macroscopic or microscopic scores between the groups. Tissue myeloperoxidase activity was low in all animals and did not differ significantly between groups. The data do not support a role for neutrophils in the initial pathogenesis of vasculitis in this model. [ABSTRACT FROM AUTHOR]