The Innate Immune Glycoprotein Lactoferrin Represses the Helicobacter pylori cag Type IV Secretion System

Chronic infection with Helicobacter pylori increases risk of gastric diseases including gastric cancer. Despite development of a robust immune response, H. pylori persists in the gastric niche. Progression of gastric inflammation to serious disease outcomes is associated with infection with H. pylori strains which encode the cag Type IV Secretion System (cag T4SS). The cag T4SS is responsible for translocating the oncogenic protein CagA into host cells and inducing pro-inflammatory and carcinogenic signaling cascades. Our previous work demonstrated that nutrient iron modulates the activity of the T4SS and biogenesis of T4SS pili. In response to H. pylori infection, the host produces a variety of antimicrobial molecules, including the iron-binding glycoprotein, lactoferrin. Our work shows that apo-lactoferrin exerts antimicrobial activity against H. pylori under iron-limited conditions, while holo-lactoferrin enhances bacterial growth. Culturing H. pylori in the presence of holo-lactoferrin prior to co-culture with gastric epithelial cells, results in repression of the cag T4SS activity. Concomitantly, a decrease in biogenesis of cag T4SS pili at the host-pathogen interface was observed under these culture conditions by high-resolution electron microscopy analyses. Taken together, these results indicate that acquisition of alternate sources of nutrient iron plays a role in regulating the pro-inflammatory activity of a bacterial secretion system and present novel therapeutic targets for the treatment of H. pylori-related disease.     

Direct writing of textured ceramics using anisotropic nozzles

Direct writing is a unique means to align anisotropic particles for the fabrication of textured ceramics by templated grain growth (TGG). We show that alignment of tabular barium titanate (BT) template particles (20–40 μm width and 0.5–2 μm thickness) in a PIN-PMN-PT matrix powder (d₅₀ = 280 nm) is significantly improved during direct writing using anisotropic nozzles at high printing rates. The particle orientation distribution in as-printed filaments, and the texture orientation distribution in sintered ceramic filaments are shown to directly correlate with COMSOL Multiphysics-predicted torque distributions for direct writing with aspect ratio 2, 3 and 5 oval nozzles. Electromechanical strain properties of the textured piezoelectric ceramics significantly improved relative to random ceramics when printed with anisotropic nozzles. Simulations of aspect ratio 20 nozzles and nozzles with interior baffles demonstrate significantly increased torque and near elimination of constant shear stress cores (i.e. plug flow).     

Challenges and new methods for designing reliability experiments

Abstract

Engineers use reliability experiments to determine the factors that drive product reliability, build robust products, and predict reliability under use conditions. This article uses recent testing of a howitzer to illustrate the challenges in designing reliability experiments for complex, repairable systems. We review research in complex system reliability models, failure-time experiments, and experimental design principles. We highlight the need for reliability experiments that account for various intended uses and environments. We leverage lessons learned from current research and propose methods for designing an experiment for a complex, repairable system.     

Pseudouridine synthase 7 impacts Candida albicans rRNA processing and morphological plasticity

RNA can be modified in over 100 distinct ways, and these modifications are critical for function. Pseudouridine synthases catalyse pseudouridylation, one of the most prevalent RNA modifications. Pseudouridine synthase 7 modifies a variety of substrates in Saccharomyces cerevisiae including tRNA, rRNA, snRNA, and mRNA, but the substrates for other budding yeast Pus7 homologues are not known. We used CRISPR-mediated genome editing to disrupt Candida albicans PUS7 and find absence leads to defects in rRNA processing and a decrease in cell surface hydrophobicity. Furthermore, C. albicans Pus7 absence causes temperature sensitivity, defects in filamentation, altered sensitivity to antifungal drugs, and decreased virulence in a wax moth model. In addition, we find C. albicans Pus7 modifies tRNA residues, but does not modify a number of other S. cerevisiae Pus7 substrates. Our data suggests C. albicans Pus7 is important for fungal vigour and may play distinct biological roles than those ascribed to S. cerevisiae Pus7.     

Distributed dynamic load balancing with applications in radio access networks

Managing and balancing load in distributed systems remains a challenging problem in resource management, especially in networked systems where scalability concerns favour distributed and dynamic approaches. Distributed methods can also integrate well with centralised control paradigms if they provide high‐level usage statistics and control interfaces for supporting and deploying centralised policy decisions. We present a general method to compute target values for an arbitrary metric on the local system state and show that autonomous rebalancing actions based on the target values can be used to reliably and robustly improve the balance for metrics based on probabilistic risk estimates. To balance the trade‐off between balancing efficiency and cost, we introduce 2 methods of deriving rebalancing actuations from the computed targets that depend on parameters that directly affects the trade‐off. This enables policy level control of the distributed mechanism based on collected metric statistics from network elements. Evaluation results based on cellular radio access network simulations indicate that load balancing based on probabilistic overload risk metrics provides more robust balancing solutions with fewer handovers compared to a baseline setting based on average load.     

Serum Amyloid A Receptor Blockade and Incorporation into High-Density Lipoprotein Modulates Its Pro-Inflammatory and Pro-Thrombotic Activities on Vascular Endothelial Cells

The acute phase protein serum amyloid A (SAA), a marker of inflammation, induces expression of pro-inflammatory and pro-thrombotic mediators including ICAM-1, VCAM-1, IL-6, IL-8, MCP-1 and tissue factor (TF) in both monocytes/macrophages and endothelial cells, and induces endothelial dysfunction—a precursor to atherosclerosis. In this study, we determined the effect of pharmacological inhibition of known SAA receptors on pro-inflammatory and pro-thrombotic activities of SAA in human carotid artery endothelial cells (HCtAEC). HCtAEC were pre-treated with inhibitors of formyl peptide receptor-like-1 (FPRL-1), WRW4; receptor for advanced glycation-endproducts (RAGE), (endogenous secretory RAGE; esRAGE) and toll-like receptors-2/4 (TLR2/4) (OxPapC), before stimulation by added SAA. Inhibitor activity was also compared to high-density lipoprotein (HDL), a known inhibitor of SAA-induced effects on endothelial cells. SAA significantly increased gene expression of TF, NFκB and TNF and protein levels of TF and VEGF in HCtAEC. These effects were inhibited to variable extents by WRW4, esRAGE and OxPapC either alone or in combination, suggesting involvement of endothelial cell SAA receptors in pro-atherogenic gene expression. In contrast, HDL consistently showed the greatest inhibitory action, and often abrogated SAA-mediated responses. Increasing HDL levels relative to circulating free SAA may prevent SAA-mediated endothelial dysfunction and ameliorate atherogenesis.     

Effects of skim milk concentrate dry matter and spray drying air temperature on formation of capsules with varying particle size and the survival microbial cultures in a microcapsule matrix

The impact of total solid (TS) content in combination with the feed rate and air inlet temperature on the survival of Lactobacillus paracasei ssp. paracasei F19 after spray drying in a skim milk matrix has been investigated and correlated with the capsule size. Depending on the experimental conditions, the survival rates ranged from 64 to 0.2%. The higher the air inlet temperature, the lower was the survival rate and an inversely correlation between the TS content and particle size has been determined. These results clearly indicate that process stress analyses and product-related characteristics must not be regarded separately.     

Hypervariate constitutive modeling illustrated via aleatory uncertainty in a foundation model

Even if a ceramic's homogenized properties (such as anisotropically evolving stiffness) truly can be predicted from complete knowledge of sub-continuum morphology (e.g., locations, sizes, shapes, orientations, and roughness of trillions of crystals, dislocations, impurities, pores, inclusions, and/or cracks), the necessary calculations are untenably hypervariate. Non-productive (almost derailing) debates over shortcomings of various first-principles ceramics theories are avoided in this work by discussing numerical coarsening in the context of a pedagogically appealing buckling foundation model that requires only sophomore-level understanding of springs, buckling hinges, dashpots, etc. Bypassing pre-requisites in constitutive modeling, this work aims to help students to understand the difference between damage and plasticity while also gaining experience in Monte-Carlo numerical optimization via scale-bridging that reduces memory and processor burden by orders of magnitude while accurately preserving aleatory (finite-sampling) perturbations that are crucial to accurately predict bifurcations, such as ceramic fragmentation.