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.     

Enriched multi-agent middleware for building rule-based distributed security solutions for IoT environments

The Journal of Supercomputing - The increasing number of connected devices and the complexity of Internet of Things (IoT) ecosystems are demanding new architectures for managing and securing these...     

α-Methylene-β-Lactone Scaffold for Developing Chemical Probes at the Two Ends of the Selectivity Spectrum

The utilities of an α-methylene-β-lactone (MeLac) moiety as a warhead composed of multiple electrophilic sites are reported. We demonstrate that a MeLac-alkyne not only reacts with diverse proteins as a broadly reactive measurement probe, but also recruits reduced endogenous glutathione (GSH) to assemble a selective chemical probe of GSH-β-lactone (GSH-Lac)-alkyne in live cells. Tandem mass spectrometry reveals that MeLac reacts with nucleophilic cysteine, serine, lysine, threonine, and tyrosine residues, through either Michael or acyl addition. A peptide-centric proteomics platform demonstrates that the proteomic selectivity profiles of orlistat and parthenolide, which have distinct reactivities, are measurable by MeLac-alkyne as a high-coverage probe. The GSH-Lac-alkyne selectively probes the glutathione S-transferase P responsible for multidrug resistance. The assembly of the GSH-Lac probe exemplifies a modular and scalable route to develop selective probes with different recognizing moieties.     

A pragmatic approach to hierarchical categorization of research expertise in the presence of scarce information

International Journal on Digital Libraries - Throughout the history of science, different knowledge areas have collaborated to overcome major research challenges. The task of associating a...     

The posthuman: AI,dronology, and “becoming alien”

AI & SOCIETY - This paper is addressed to recent theoretical discussions of the Anthropocene, in particular Bernard Stiegler’s Neganthropocene (Open Universities Press, 2018), which...     

Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents

Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC₅₀ value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC₅₀ value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.     

Comparative Genomics Reveals 13 Different Isoforms of Mytimycins (A-M) in Mytilus galloprovincialis

Mytimycins are cysteine-rich antimicrobial peptides that show antifungal properties. These peptides are part of the immune network that constitutes the defense system of the Mediterranean mussel (Mytilus galloprovincialis). The immune system of mussels has been increasingly studied in the last decade due to its great efficiency, since these molluscs, particularly resistant to adverse conditions and pathogens, are present all over the world, being considered as an invasive species. The recent sequencing of the mussel genome has greatly simplified the genetic study of some of its immune genes. In the present work, we describe a total of 106 different mytimycin variants in 16 individual mussel genomes. The 13 highly supported mytimycin clusters (A–M) identified with phylogenetic inference were found to be subject to the presence/absence variation, a widespread phenomenon in mussels. We also identified a block of conserved residues evolving under purifying selection, which may indicate the “functional core” of the mature peptide, and a conserved set of 10 invariable plus 6 accessory cysteines which constitute a plastic disulfide array. Finally, we extended the taxonomic range of distribution of mytimycins among Mytilida, identifying novel sequences in M. coruscus, M. californianus, P. viridis, L. fortunei, M. philippinarum, M. modiolus, and P. purpuratus.     

Rock brittleness indices and their applications to different fields of rock engineering:A review

Brittleness is an important parameter controlling the mechanical behavior and failure characteristics of rocks under loading and unloading conditions,such as fracability,cutability,drillability and rockburst proneness.As such,it is of high practical value to correctly evaluate rock brittleness.However,the definition and measurement method of rock brittleness have been very diverse and not yet been standardized.In this paper,the definitions of rock brittleness are firstly reviewed,and several representative definitions of rock brittleness are identified and briefly discussed.The development and role of rock brittleness in different fields of rock engineering are also studied.Eighty brittleness indices publicly available in rock mechanics literature are compiled,and the measurement method,applicability and limitations of some indices are discussed.The results show that(1)the large number of brittleness indices and brittleness definitions is attributed to the different foci on the rock behavior when it breaks;(2)indices developed in one field usually are not directly applicable to other fields;and(3)the term“brittleness”is sometimes misused,and many empirically-obtained brittleness indices,which lack theoretical basis,fail to truly reflect rock brittleness.On the basis of this review,three measurement methods are identified,i.e.(1)elastic deformation before fracture,(2)shape of post-peak stressestrain curves,and(3)methods based on fracture mechanics theory,which have the potential to be further refined and unified to become the standard measurement methods of rock brittleness.It is highly beneficial for the rock mechanics community to develop a robust definition of rock brittleness.This study will undoubtedly provide a comprehensive timely reference for selecting an appropriate brittleness index for their applications,and will also pave the way for the development of a standard definition and measurement method of rock brittleness in the long term.