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1.
Jacky Lu Kathryn P. Haley Jamisha D. Francis Miriam A. Guevara Ryan S. Doster Kelly M. Craft Rebecca E. Moore Schuyler A. Chambers Alberto G. Delgado Maria Blanca Piazuelo Steven M. Damo Dr. Steven D. Townsend Dr. Jennifer A. Gaddy 《Chembiochem : a European journal of chemical biology》2021,22(18):2783-2790
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. 相似文献
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Anh K. Lam Hannah Panlilio Jennifer Pusavat Cassandra L. Wouters Erika L. Moen Prof. Robert E. Brennan Prof. Charles V. Rice 《ChemMedChem》2020,15(15):1421-1428
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. 相似文献
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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. 相似文献
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Jennifer Aschenbrenner Patrick Marx Jörg Pietruszka Dr. Jan Marienhagen 《Chembiochem : a European journal of chemical biology》2019,20(7):949-954
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. 相似文献
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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. 相似文献
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Dr. Blijke S. Kroezen Gabriele Conti Benedetta Girardi Dr. Jonathan Cramer Dr. Xiaohua Jiang Dr. Said Rabbani Jennifer Müller Maja Kokot Enrico Luisoni Prof. Daniel Ricklin Dr. Oliver Schwardt Prof. Beat Ernst 《ChemMedChem》2020,15(18):1706-1719
Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewisx has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewisx and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved. 相似文献
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Anne M. Riederer Jennifer E. Krenz Maria I. Tchong-French Elizabeth Torres Adriana Perez Lisa R. Younglove Karen L. Jansen David C. Hardie Stephanie A. Farquhar Paul D. Sampson Catherine J. Karr 《Indoor air》2021,31(2):454-466
We conducted a randomized trial of portable HEPA air cleaners with pre-filters designed to also reduce NH3 in non-smoking homes of children age 6-12 with asthma in Yakima Valley (Washington, USA). Participants were recruited through the Yakima Valley Farm Workers Clinic asthma education program. All participants received education on home triggers while intervention families additionally received two HEPA cleaners (child's sleeping area, main living area). Fourteen-day integrated samples of PM2.5 and NH3 were measured at baseline and one-year follow-up. We fit ANCOVA models to compare follow-up concentrations in HEPA vs control homes, adjusting for baseline concentrations. Seventy-one households (36 HEPA, 35 control) completed the study. Most were single-family homes, with electric heat and stove, A/C, dogs/cats, and mean (SD) 5.3 (1.8) occupants. In the sleeping area, baseline geometric mean (GSD) PM2.5 was 10.7 (2.3) μg/m3 (HEPA) vs 11.2 (1.9) μg/m3 (control); in the living area, it was 12.5 (2.3) μg/m3 (HEPA) vs 13.6 (1.9) μg/m3 (control). Baseline sleeping area NH3 was 62.4 (1.6) μg/m3 (HEPA) vs 65.2 (1.8) μg/m3 (control). At follow-up, HEPA families had 60% (95% CI, 41%-72%; p < .0001) and 42% (19%-58%; p = .002) lower sleeping and living area PM2.5, respectively, consistent with prior studies. NH3 reductions were not observed. 相似文献