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ObjectiveUsing faecal shotgun metagenomic sequencing, we identified the depletion ofLactobacillus gallinarumin patients with colorectal cancer (CRC). We aimed to determine the potential antitumourigenic role ofL. gallinarumin colorectal tumourigenesis.DesignThe tumor-suppressive effect ofL. gallinarumwas assessed in murine models of CRC. CRC cell lines and organoids derived from patients with CRC were cultured withL. gallinarumorEscherichia coliMG1655 culture-supernatant to evaluate cell proliferation, apoptosis and cell cycle distribution. Gut microbiota was assessed by 16S ribosomal DNA sequencing. Antitumour molecule produced fromL. gallinarumwas identified by liquid chromatography mass spectrometry (LC-MS/MS) and targeted mass spectrometry.ResultsL. gallinarumsignificantly reduced intestinal tumour number and size compared withE. coliMG1655 and phosphate-buffered saline in both male and female murine intestinal tumourigenesis models. Faecal microbial profiling revealed enrichment of probiotics and depletion of pathogenic bacteria inL. gallinarum-treated mice. Culturing CRC cells withL. gallinarumculture-supernatant (5%, 10% and 20%) concentration-dependently suppressed cell proliferation and colony formation.L. gallinarumculture-supernatant significantly promoted apoptosis in CRC cells and patient-derived CRC organoids, but not in normal colon epithelial cells. OnlyL. gallinarumculture-supernatant with fraction size L. gallinarumculture-supernatant and the gut ofL. gallinarum-treated mice. ILA displayed anti-CRC growthin vitroand inhibited intestinal tumourigenesisin vivo.ConclusionL. gallinarumprotects against intestinal tumourigenesis by producing protective metabolites that can promote apoptosis of CRC cells.

Non-steroidal anti-inflammatory drugs (NSAIDs) cause damage in the small intestine in a bacteria-dependent manner. As high-fat diet (HFD) is a potent inducer of gut dysbiosis, we investigated the effects of HFD on bacterial flora in the small intestine and NSAID-induced enteropathy. 16S rRNA gene analysis revealed that the population of Bifidobacterium spp. significantly decreased by fold change of individual operational taxonomic units in the small intestine of mice fed HFD for 8 weeks. HFD increased intestinal permeability, as indicated by fluorescein isothiocyanate-dextran absorption and serum lipopolysaccharide levels, accompanied by a decrease in the protein expressions of ZO-1 and occludin and elevated mRNA expression of interleukin (IL)-17A in the small intestine. HFD-fed mice exhibited increased susceptibility to indomethacin-induced damage in the small intestine; this phenotype was observed in normal diet-fed mice that received small intestinal microbiota from HFD-fed mice. Administration of neutralizing antibodies against IL-17A to HFD-fed mice reduced intestinal permeability and prevented exacerbation of indomethacin-induced damage. Thus, HFD-induced microbial dysbiosis in small intestine caused microinflammation through the induction of IL-17A and increase in intestinal permeability, resulting in the aggravation of NSAID-induced small intestinal damage.

Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1β in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.

An efficient calculation scheme for the method of characteristics, which allows coarser ray separation width, is newly proposed. Effective lengths of characteristics lines are evaluated from the viewpoint of preservation of transmission probability in the present method. The effective lengths to preserve transmission probabilities can be rigorously estimated through detailed numerical integrations. However, calculation and storage of all effective lengths is inefficient since the transmission probabilities depend on many parameters such as azimuthal angle, polar angle, position of characteristics line, and total cross section. To resolve this issue, in this paper, the analytical equations for the effective lengths are derived from an assumption that distribution function of actual characteristics lengths can be expressed by a linear function. The new approach introduced in this paper is named as transmission probability preservation through linear approximation (TPPL). Verification results indicate that a...

When the transport correction is applied to the total cross-section, the self-scattering cross-section could have a negative value in order to preserve the balance of partial cross-sections. The negative self-scattering cross-section may lead to a negative impact on the convergence behavior for the method of characteristics (MOC), especially in a problem with large moderator regions containing hydrogen. In order to address this issue, the spectral radius of the inner iteration of MOC is theoretically estimated for various self-scattering cross-sections. It is found that the spectral radius of the inner iteration of MOC could exceed unity for a large negative self-scattering cross-section, which results in numerical divergence. A countermeasure for the divergence using the successive over relaxation method is also discussed in this paper.

The inflammasomes induce maturation of pro-interleukin-1β (IL-1β) and pro-IL-18. We investigated roles of the NLRP3 inflammasome in the pathogenesis of ulcerative colitis (UC). After induction of oxazolone-induced colitis, a mouse UC model, colonic tissues were assayed for inflammatory mediators. Histological studies were performed on inflamed colonic tissue from mice and UC patients. Histological severity of murine colitis peaked on day 1, accompanied by an increase in the expression of Th2 cytokines including IL-4 and IL-13. Oxazolone treatment stimulated maturation of pro-caspase-1 and pro-IL-1β, while it reduced IL-18 expression. Either exogenous IL-1β or IL-18 ameliorated the colitis with or without reduction in Th2 cytokine expression, respectively. Induction of colitis decreased MUC2 expression, which was reversed by administration of IL-18, but not IL-1β. Compared to wild-type mice, NLRP3−/− mice exhibited higher sensitivity to oxazolone treatment with enhancement of Th2 cytokine expression and reduction of mature IL-1β and IL-18 production; this phenotype was rescued by exogenous IL-1β or IL-18. Immunofluorescent studies revealed positive correlation of NLRP3 expression with disease severity in UC patients, and localization of the inflammasome-associated molecules in macrophages. The NLRP3 inflammasome-derived IL-1β and IL-18 may play a protective role against UC through different mechanisms.

AEGIS is a lattice physics code incorporating the latest advances in lattice physics computation, innovative calculation models and efficient numerical algorithms and is mainly used for light water reactor analyses. Though the primary objective of the AEGIS code is the preparation of a cross section set for SCOPE2 that is a three-dimensional pin-by-pin core analysis code, the AEGIS code can handle not only a fuel assembly but also multi-assemblies and a whole core geometry in twodimensional geometry. The present paper summarizes the major calculation models and part of the verification/validation efforts related to the AEGIS code.

Background & Aims Patients with colorectal cancer (CRC) have a different gut microbiome signature than individuals without CRC. Little is known about the viral component of CRC-associated microbiome. We aimed to identify and validate viral taxonomic markers of CRC that might be used in detection of the disease or predicting outcome. Methods We performed shotgun metagenomic analyses of viromes of fecal samples from 74 patients with CRC (cases) and 92 individuals without CRC (controls) in Hong Kong (discovery cohort). Viral sequences were classified by taxonomic alignment against an integrated microbial reference genome database. Viral markers associated with CRC were validated using fecal samples from 3 separate cohorts: 111 patients with CRC and 112 controls in Hong Kong, 46 patients with CRC and 63 controls in Austria, and 91 patients with CRC and 66 controls in France and Germany. Using abundance profiles of CRC-associated virome genera, we constructed random survival forest models to identify those associated with patient survival times. Results The diversity of the gut bacteriophage community was significantly increased in patients with CRC compared with controls. Twenty-two viral taxa discriminated cases from controls with an area under the receiver operating characteristic curve of 0.802 in the discovery cohort. The viral markers were validated in 3 cohorts, with area under the receiver operating characteristic curves of 0.763, 0.736, and 0.715, respectively. Clinical subgroup analysis showed that dysbiosis of the gut virome was associated with early- and late-stage CRC. A combination of 4 taxonomic markers associated with reduced survival of patients with CRC (log-rank test, P = 8.1 × 10–6) independently of tumor stage, lymph node metastases, or clinical parameters. We found altered interactions between bacteriophages and oral bacterial commensals in fecal samples from patients with CRC compared with controls. Conclusions In a metagenomic analysis of fecal samples from patients and controls, we identified virome signatures associated with CRC. These data might be used to develop tools to identify individuals with CRC or predict outcomes.

The Krylov subspace method is applied to solve nuclide burnup equations used for lattice physics calculations. The Krylov method is an efficient approach for solving ordinary differential equations with stiff nature such as the nuclide bunrup with short lived nuclides. Some mathematical fundamentals of the Krylov subspace method and its application to burnup equations are discussed. Verification calculations are carried out in a PWR pin-cell geometry with UO2 fuel. A detailed burnup chain that includes 193 fission products and 28 heavy nuclides is used in the verification calculations. Shortest half life found in the present burnup chain is approximately 30 s (106Rh). Therefore, conventional methods (e.g., the Taylor series expansion with scaling and squaring) tend to require longer computation time due to numerical stiffness. Comparison with other numerical methods (e.g., the 4-th order Runge-Kutta-Gill) reveals that the Krylov subspace method can provide accurate solution for a detailed burnup chain use...

A simple and efficient method to estimate the Dancoff factor in a complicated geometry, named “the Neutron current method,” is presented in this paper. In this method, Dancoff factors are evaluated from the flux values obtained by the method of characteristics (MOC). By setting appropriate neutron sources in the non-fuel regions of target geometry and then executing fixed source calculation by MOC, the neutron current method can evaluate Dancoff factors for complicated geometry. It was demonstrated that the neutron current method can easily be adopted for complicated geometries, such as a PWR fuel assembly or large-scale geometry that is difficult to handle by the traditional collision probability method. By utilizing the neutron current method instead of a traditional collision probability method, the calculation time of Dancoff factors in complicated large geometry is drastically reduced.

This paper presents a description of the Hybrid Core Calculation System which is based on a very rigorous but practical method utilizing best estimate core design calculations and taking advantage of the recent remarkable progress of computers. The basic idea of this system is to generate the correction factors for assembly-homogenized cross sections, discontinuity factors, etc. by comparing the CASMO-4 and SIMULATE-3 2-D full-core calculation results under the consistent calculation condition and applying them to the SIMULATE-3 3-D calculation. The CASMO-4 2-D heterogeneous core calculation is performed for each depletion step using the core conditions previously determined by ordinary SIMULATE-3 core calculations. This avoids time-consuming iterative calculations of the critical boron concentration search and the thermal hydraulic feedback. These calculations are instead performed in the final SIMULATE-3 3-D calculation using the previously determined correction factors. The Hybrid Core Calculation Syst...

The coarse mesh rebalance (CMR) is a simple acceleration method that is commonly used for transport calculations though it is conditionally stable, i.e. acceleration failed under certain calculation conditions. In this paper, a new acceleration scheme, i.e. the generalized coarse mesh rebalance (GCMR) method, is proposed and applied to improve convergence property of the CMR method. Definitions of partial neutron currents used in CMR are modified in the present method and convergence property of CMR is improved by the modifications. The proposed method was applied to transport calculations in slab and light water reactor assembly geometries. The calculation results were compared with those by the CMR and the coarse mesh finite-difference (CMFD) acceleration methods, and it was revealed that the present method significantly improves the convergence property of the traditional CMR method. Since the present method can be easily applied to existing transport codes using the CMR method, it is considered as a p...