Ab Initio Uncertainty Quantification of Neutrinoless Double-Beta Decay in

The observation of neutrinoless double-beta (0νßß) decay would offer proof of lepton number violation, demonstrating that neutrinos are Majorana particles, while also helping us understand why there is more matter than antimatter in the Universe. If the decay is driven by the exchange of the three known light neutrinos, a discovery would, in addition, link the observed decay rate to the neutrino mass scale through a theoretical quantity known as the nuclear matrix element (NME). Accurate values of the NMEs for all nuclei considered for use in 0νßß experiments are therefore crucial for designing and interpreting those experiments. Here, we report the first comprehensive ab initio uncertainty quantification of the 0νßß-decay NME, in the key nucleus ^{76}Ge. Our method employs nuclear strong and weak interactions derived within chiral effective field theory and recently developed many-body emulators. Our result, with a conservative treatment of uncertainty, is an NME of 2.60_{-1.36}^{+1.28}, which, together with the best-existing half-life sensitivity and phase-space factor, sets an upper limit for effective neutrino mass of 187_{-62}^{+205} meV. The result is important for designing next-generation germanium detectors aiming to cover the entire inverted hierarchy region of neutrino masses.

Ab Initio Neutrinoless Double-Beta Decay Matrix Elements for

We calculate basis-space converged neutrinoless ßß-decay nuclear matrix elements for the lightest candidates: ^{48}Ca, ^{76}Ge, and ^{82}Se. Starting from initial two- and three-nucleon forces, we apply the ab initio in-medium similarity renormalization group to construct valence-space Hamiltonians and consistently transformed ßß-decay operators. We find that the tensor component is non-negligible in ^{76}Ge and ^{82}Se, and the resulting nuclear matrix elements are overall 25%-45% smaller than those obtained from the phenomenological shell model. While a final matrix element with uncertainties still requires substantial developments, this work nevertheless opens a path toward a true first-principles calculation of neutrinoless ßß decay in all nuclei relevant for ongoing large-scale searches.

Intestinal mucins in colonization and host defense against pathogens.

Intestinal mucins are key components of the first line of host defense against intestinal pathogens. These large glycoconjugates secreted by specialized exocrine goblet cells form viscous gels that trap microorganisms and irritants and limit their diffusion to the intestinal epithelium. Moreover, they allow for colonization by indigenous bacterial flora that prevents attachment of pathogenic microbes. The interaction between microbes and mucins involves mucin carbohydrate side chains and microbial adhesin molecules. Certain microorganisms and disease states may alter mucin biochemistry or expression. Although these alterations most likely contribute to disease processes, the full impact of these phenomena are still unclear. The development of mucin-secreting cell lines has facilitated the study of mucin biology and aided our understanding of mucin-microbial interactions.

Eicosanoid production by parasites: from pathogenesis to immunomodulation?

In this review, Adam Belley and Kris Chadee discuss eicosanoid production by various parasites and propose roles they may play in pathogenesis and immunomodulation. The commonality between parasites is prostaglandin production and, therefore, special attention is given to the cyclooxygenase pathway, highlighting the enzymes and functions of prostaglandins.

Prostaglandin E(2) stimulates rat and human colonic mucin exocytosis via the EP(4) receptor.

BACKGROUND & AIMS: Mucins form an integral part of innate host defenses against intestinal pathogens and irritants. However, the mechanisms whereby mucin secretion is regulated during inflammation are poorly understood. Because prostaglandin E(2) (PGE(2)) is prominent during intestinal inflammation, we investigated its receptor-signaling pathway coupled to mucin exocytosis in the colonic epithelial cell line LS174T and rat colon. METHODS: Reverse-transcription polymerase chain reaction (RT-PCR) and [(3)H]PGE(2) binding assays were used to identify the PGE(2) receptors (EP). Intracellular cyclic adenosine monophosphate ([cAMP](i)) was quantified by enzyme immunoassay. Mucins were metabolically labeled with [(3)H]glucosamine, and mucin secretion was quantified by Sepharose 4B column chromatography, immunoblot analysis, and cesium chloride density gradient centrifugation. RESULTS: RT-PCR and DNA sequence analysis identified EP(2), EP(3), and EP(4) receptors. Mucin secretion and [cAMP](i) production by LS174T cells were stimulated dose-dependently by PGE(2), the EP(4)-receptor agonist 1-OH-PGE(1), and the EP(3)/EP(4) agonist M&B28767 and were inhibited with the adenylate cyclase inhibitor SQ22536. The EP(1), EP(2), and EP(3)/EP(1)-receptor agonists iloprost, butaprost, and sulprostone, respectively, had no effect. Similar results were obtained in rat colonic loop studies confirming that the EP(4) receptor is linked to mucin exocytosis in vivo. [(3)H]PGE(2) binding to cell membranes identified a high-affinity binding site that was competitively inhibited by M&B28767 (EP(3)/EP(4)) > 1-OH-PGE(1) (EP(4)) > sulprostone (EP(3)/EP(1)) > butaprost (EP(2)). CONCLUSIONS: PGE(2) coupling to the EP(4) receptor stimulates [cAMP](i)-dependent mucin exocytosis.

Nonsteroidal antiinflammatory drugs inhibit cyclooxygenase-2 enzyme activity but not mRNA expression in human macrophages.

At present it is unclear whether nonsteroidal antiinflammatory drugs (NSAIDs) can inhibit cyclooxygenase (COX) gene expression. In some cells that express COX-2, NSAIDs can inhibit enzymatic activity and gene expression. In this study we evaluated the effect of several NSAIDs on COX-1 and COX-2 mRNA, protein expression and PGE2 production in PMA-differentiated THP-1 and U937 human macrophages stimulated with LPS. Macrophages pre-treated with acetylsalicylic acid, indomethacin, naproxen or NS-398 and stimulated with LPS showed a marked inhibition on PGE2 production but not on COX-1 or COX-2 mRNA and protein expression. Furthermore, COX-2 mRNA levels induced by LPS were transient (peak 3-4 h), suggesting that PGE2 was unable to regulate COX-2 expression in an autocrine manner. These results demonstrate that NSAID's action in human macrophages is not directed towards the transcription or translation of the COX genes but only to the enzymatic activity of the proteins.

Interaction of LS174T human colon cancer cell mucins with Entamoeba histolytica: an in vitro model for colonic disease.

BACKGROUND & AIMS: Colonic mucins secreted by goblet cells protect the colon by preventing the attachment of enteric pathogens to the epithelium. Entamoeba histolytica overcomes this protective barrier and causes ulcerations, allowing the parasite to disseminate to the liver and form abscesses. An in vitro model is used to study the interaction between E. histolytica and colonic mucins. METHODS: Secretory mucins from the colonic adenocarcinoma cell line LS174T were collected and their functions assessed by their ability to inhibit amebic adherence to target cells and killing. The cytoprotective effect of mucus against E. histolytica cytolysis of LS174T monolayers was studied at 37 degrees C. RESULTS: Sepharose 4B column chromatography, metabolic labeling with [3H]glucosamine, cesium chloride density gradient centrifugation, and amino acid and carbohydrate compositional analysis revealed that LS174T cell mucins were typical of native colonic mucins. Mucin O-linked oligosaccharides bound to and inhibited the adherence of amebae to Chinese hamster ovary cells. E. histolytica killing of Chinese hamster ovary cell monolayers occurred rapidly, whereas killing of LS174T monolayers with an intact mucus layer was significantly retarded. CONCLUSIONS: Our results show that colonic mucins serve as the first line of host defense against amebic invasion and provide a useful model to study pathogen-mucin interactions.

Functional heterogeneity of colonic adenocarcinoma mucins for inhibition of Entamoeba histolytica adherence to target cells.

Mucins secreted from the gastrointestinal epithelium from the basis of the adherent mucus layer which is the host's first line of defense against invasion by Entamoeba histolytica. Galactose and N-acetyl-D-galactosamine residues of mucins specifically inhibit binding of the amebic 170 kDa heavy subunit Gal-lectin to target cells, an absolute prerequisite for pathogenesis. Herein we characterized the secretory mucins isolated from the human colon and from three human colonic adenocarcinoma cell lines: two with goblet cell-like (LS174T and T84) and one with absorptive cell-like morphology (Caco-2). By Northern blot analysis the intestinal mucin genes MUC2 and MUC3 were constitutively expressed by confluent LS174T and Caco-2 cells, whereas T84 cells only transcribed MUC2 and not MUC3 mRNA. 3H-glucosamine and 3H-threonine metabolically labeled proteins separated as high M, mucins in the void (Vo > 10(6) Da) of Sepharose-4B column chromatography and remained in the stacking gel of SDS-PAGE as depicted by fluorography. All mucin preparations contained high amounts of N-acetyl-glucosamine, galactose, N-acetyl-galactosamine, fucose and sialic acid, saccharides typical of the O-linked carbohydrate side chains. Mucin samples from the human colon and from LS174T and Caco-2 cells inhibited E. histolytica adherence to chinese hamster ovary cells, whereas mucins from T84 cells did not. These results suggest that genetic heterogeneity and/or posttranslational modification in glycosylation of colonic mucins can affect specific epithelial barrier function against intestinal pathogens.