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.     

Expanding the Spectrum of Antibiotics Capable of Killing Multidrug-Resistant Staphylococcus aureus and Pseudomonas aeruginosa

Infections from antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa are a serious threat because reduced antibiotic efficacy complicates treatment decisions and prolongs the disease state in many patients. To expand the arsenal of treatments against antimicrobial-resistant (AMR) pathogens, 600-Da branched polyethylenimine (BPEI) can overcome antibiotic resistance mechanisms and potentiate β-lactam antibiotics against Gram-positive bacteria. BPEI binds cell-wall teichoic acids and disables resistance factors from penicillin binding proteins PBP2a and PBP4. This study describes a new mechanism of action for BPEI potentiation of antibiotics generally regarded as agents effective against Gram-positive pathogens but not Gram-negative bacteria. 600-Da BPEI is able to reduce the barriers to drug influx and facilitate the uptake of a non-β-lactam co-drug, erythromycin, which targets the intracellular machinery. Also, BPEI can suppress production of the cytokine interleukin IL-8 by human epithelial keratinocytes. This enables BPEI to function as a broad-spectrum antibiotic potentiator, and expands the opportunities to improve drug design, antibiotic development, and therapeutic approaches against pathogenic bacteria, especially for wound care.     

Radon and moisture impacts from interventions integrated with housing energy retrofits

Energy retrofits can reduce air exchange, raising the concern of whether indoor radon and moisture levels could increase. This pre/post-intervention study explored whether simple radon interventions implemented in conjunction with energy retrofits can prevent increases in radon and moisture levels. Treatment homes (n = 98) were matched with control (no energy retrofits or radon intervention) homes (n = 12). Control homes were matched by geographic location and foundation type. t-tests were used to determine whether post-energy retrofit radon and moisture level changes in treatment homes significantly differed from those in control homes. The radon interventions succeeded in preventing statistically significant increases in first floor radon using arithmetic (p = 0.749) and geometric means (p = 0.120). In basements, arithmetic (p = 0.060) and geometric (p = 0.092) mean radon levels statistically significantly increased, consistent with previous studies which found that basement radon levels may increase even if first floor levels remain unchanged. Changes in infiltration were related to changes in radon (p = 0.057 in basements; p = 0.066 on first floors). Only 58% of the change in infiltration was due to air sealing, with the rest due to weather changes. There was no statistically significant association between air sealing itself and radon levels on the first floor (p = 0.664). Moisture levels also did not significantly increase.     

Some physiological characteristics to estimate species potential as a mine reclamation ground cover

In finding what physiological characteristics can be used to predict ground cover success on mine reclamation sites, 14 herb and grass species were tested. Establishment and early growth was tested on three different soils, ie vermiculate and quartz sand mixture, quarry overburden and coal mine overburden in a greenhouse. The results indicate that plant height and cover, transpiration rate and foliar pigments may be used to select plant adaptability to mined soil. White clover (Trifolium repens L.) showed the greatest potential as ground cover for mined soils. Species most widely used in reclamation tended to be perennials of moderate rate.     

Microbial Production of Natural and Unnatural Monolignols with Escherichia coli

Phenylpropanoids and phenylpropanoid-derived plant polyphenols find numerous applications in the food and pharmaceutical industries. In recent years, several microbial platform organisms have been engineered towards producing such compounds. However, for the most part, microbial (poly)phenol production is inspired by nature, so naturally occurring compounds have predominantly been produced to date. Here we have taken advantage of the promiscuity of the enzymes involved in phenylpropanoid synthesis and exploited the versatility of an engineered Escherichia coli strain harboring a synthetic monolignol pathway to convert supplemented natural and unnatural phenylpropenoic acids into their corresponding monolignols. The performed biotransformations showed that this strain is able to catalyze the stepwise reduction of chemically interesting unnatural phenylpropenoic acids such as 3,4,5-trimethoxycinnamic acid, 5-bromoferulic acid, 2-nitroferulic acid, and a “bicyclic” p-coumaric acid derivative, in addition to six naturally occurring phenylpropenoic acids.     

Peaks Over Thresholds Modeling With Multivariate Generalized Pareto Distributions

When assessing the impact of extreme events, it is often not just a single component, but the combined behavior of several components which is important. Statistical modeling using multivariate generalized Pareto (GP) distributions constitutes the multivariate analogue of univariate peaks over thresholds modeling, which is widely used in finance and engineering. We develop general methods for construction of multivariate GP distributions and use them to create a variety of new statistical models. A censored likelihood procedure is proposed to make inference on these models, together with a threshold selection procedure, goodness-of-fit diagnostics, and a computationally tractable strategy for model selection. The models are fitted to returns of stock prices of four UK-based banks and to rainfall data in the context of landslide risk estimation. Supplementary materials and codes are available online.     

Failure Analysis and Robust Optimization of an Exhaust Manifold Diffuser Plate

Diffuser plates in exhaust system manifolds are designed to provide uniform flow pattern within the manifold for maximum utilization of the catalytic converter substrate during high-temperature applications. In this paper, failure analysis of a diffuser which survived only 20% duration of a manifold crack test and various design optimization studies of the diffuser plate using computer-aided engineering (CAE) analyses are presented. During the manifold crack test, the failure occurred at the inner and outer periphery of the diffuser. Metallurgical failure analysis coupled with CAE thermal fatigue analysis of the component concluded that thermal fatigue was the root cause of the failure. The new recommended robust design showed considerable improvement in the thermal durability of the diffuser plate assembly.