Trehalose is a disaccharide that might be used in the treatment of cardiometabolic diseases. However, trehalose consumption promotes the expansion of Clostridioides difficile ribotypes that ...metabolize trehalose via trehalose-6-phosphate hydrolase. Furthermore, brush border and renal trehalases can reduce the efficacy of trehalose by cleaving it into monosaccharides. We investigated whether a trehalase-resistant analogue of trehalose (lactotrehalose) has the same metabolic effects of trehalose without expanding C difficile.
We performed studies with HEK293 and Caco2 cells, primary hepatocytes from mice, and human intestinal organoids. Glucose transporters were overexpressed in HEK293 cells, and glucose tra2nsport was quantified. Primary hepatocytes were cultured with or without trehalose or lactotrehalose, and gene expression patterns were analyzed. C57B6/J mice were given oral antibiotics and trehalose or lactotrehalose in drinking water, or only water (control), followed by gavage with the virulent C difficile ribotype 027 (CD027); fecal samples were analyzed for toxins A (ToxA) or B (ToxB) by enzyme-linked immunosorbent assay. Other mice were given trehalose or lactotrehalose in drinking water for 2 days before placement on a chow or 60% fructose diet for 10 days. Liver tissues were collected and analyzed by histologic, serum biochemical, RNA sequencing, autophagic flux, and thermogenesis analyses. We quantified portal trehalose and lactotrehalose bioavailability by gas chromatography mass spectrometry. Fecal microbiomes were analyzed by 16S ribosomal RNA sequencing and principal component analyses.
Lactotrehalose and trehalose each blocked glucose transport in HEK293 cells and induced a gene expression pattern associated with fasting in primary hepatocytes. Compared with mice on the chow diet, mice on the high-fructose diet had increased circulating cholesterol, higher ratios of liver weight–to–body weight, hepatic lipid accumulation (steatosis), and liver gene expression patterns of carbohydrate-responsive de novo lipogenesis. Mice given lactotrehalose while on the high-fructose diet did not develop any of these features and had increased whole-body caloric expenditure compared with mice given trehalose or water and fed a high-fructose diet. Livers from mice given lactotrehalose had increased transcription of genes that regulate mitochondrial energy metabolism compared with liver from mice given trehalose or controls. Lactotrehalose was bioavailable in venous and portal circulation and fecal samples. Lactotrehalose reduced fecal markers of microbial branched-chain amino acid biosynthesis and increased expression of microbial genes that regulate insulin signaling. In mice given antibiotics followed by CD027, neither lactotrehalose nor trehalose increased levels of the bacteria or its toxin in stool—in fact, trehalose reduced the abundance of CD027 in stool. Lactotrehalose and trehalose reduced markers of inflammation in rectal tissue after CD027 infection.
Lactotrehalose is a trehalase-resistant analogue that increases metabolic parameters, compared with trehalose, without increasing the abundance or virulence of C difficile strain CD027. Trehalase-resistant trehalose analogues might be developed as next-generation fasting-mimetics for the treatment of diabetes and nonalcoholic fatty liver disease.
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Late-onset sepsis (LOS) is a highly consequential complication of preterm birth and is defined by a positive blood culture obtained after 72 h of age. The causative bacteria can be found in patients' ...intestinal tracts days before dissemination, and cohort studies suggest reduced LOS risk in breastfed preterm infants through unknown mechanisms. Reduced concentrations of epidermal growth factor (EGF) of maternal origin within the intestinal tract of mice correlated to the translocation of a gut-resident human pathogen
, which spreads systemically and caused a rapid, fatal disease in pups. Translocation of
was associated with the formation of colonic goblet cell-associated antigen passages (GAPs), which translocate enteric bacteria across the intestinal epithelium. Thus, maternally derived EGF, and potentially other EGFR ligands, prevents dissemination of a gut-resident pathogen by inhibiting goblet cell-mediated bacterial translocation. Through manipulation of maternally derived EGF and alteration of the earliest gut defenses, we have developed an animal model of pathogen dissemination which recapitulates gut-origin neonatal LOS.
A highly accessible alternative approach to basic statisticsPraise for the First Edition:"Certainly one of the most impressive little paperback 200-page introductory statistics books that I will ever ...see . . . it would make a good nightstand book for every statistician."TechnometricsWritten in a highly accessible style, Introduction to Statistics through Resampling Methods and R, Second Editionguides students in the understanding of descriptive statistics, estimation, hypothesis testing, and model building. The book emphasizes the discovery method, enabling readers to ascertain solutions on their own rather than simply copy answers or apply a formula by rote.The Second Editionutilizes the R programming language to simplify tedious computations, illustrate new concepts, and assist readers in completing exercises. The text facilitates quick learning through the use of:More than 250 exerciseswith selected "hints"scattered throughout to stimulate readers' thinking and to actively engage them in applying their newfound skillsAn increased focus on whya method is introducedMultiple explanations of basic conceptsReal-life applications in a variety of disciplinesA companion site that provides access to all data sets and R programs discussed in the textDozens of thought-provoking, problem-solving questions in the final chapter to assist readers in applying statistics to real-life applicationsIntroduction to Statistics through Resampling Methods and R, Second Editionis an excellent resource for students and practitioners in the fields of agriculture, astrophysics, bacteriology, biology, botany, business, climatology, clinical trials, economics, education, epidemiology, genetics, geology, growth processes, hospital administration, law, manufacturing, marketing, medicine, mycology, physics, political science, psychology, social welfare, sports, and toxicology who want to master and learn to apply statistical methods.
".the author has packaged an excellent and modern set of topics around the development and use of quantitative models... If you need to learn about resampling, this book would be a good place to ...start."
-Technometrics (Review of the Second Edition)
This thoroughly revised and expanded third edition is a practical guide to data analysis using the bootstrap, cross-validation, and permutation tests. Only requiring minimal mathematics beyond algebra, the book provides a table-free introduction to data analysis utilizing numerous exercises, practical data sets, and freely available statistical shareware.
Topics and Features
* Practical presentation covers both the bootstrap and permutations along with the program code necessary to put them to work.
* Includes a systematic guide to selecting the correct procedure for a particular application.
* Detailed coverage of classification, estimation, experimental design, hypothesis testing, and modeling.
* Suitable for both classroom use and individual self-study.
New to the Third Edition
* Procedures are grouped by application; a prefatory chapter guides readers to the appropriate reading matter.
* Program listings and screen shots now accompany each resampling procedure: Whether one programs in C++, CART, Blossom, Box Sampler (an Excel add-in), EViews, MATLAB, R, Resampling Stats, SAS macros, S-PLUS, Stata, or StatXact, readers will find the program listings and screen shots needed to put each resampling procedure into practice.
* To simplify programming, code for readers to download and apply is posted at http://www.springeronline.com/0-8176-4386-9.
* Notation has been simplified and, where possible, eliminated.
* A glossary and answers to selected exercises are included.
With its accessible style and intuitive topic development, the book is an excellent basic resource for the power, simplicity, and versatility of resampling methods. It is an essential resource for statisticians, biostatisticians, statistical consultants, students, and research professionals in the biological, physical, and social sciences, engineering, and technology.
Allergic disorders, characterized by Th2 immune responses to environmental substances, are increasingly common in children in Western societies. Multiple studies indicate that breastfeeding, early ...complementary introduction of food allergens, and antibiotic avoidance in the first year of life reduces allergic outcomes in at-risk children. Why the benefit of these practices is restricted to early life is largely unknown. We identified a preweaning interval during which dietary antigens are assimilated by the colonic immune system. This interval is under maternal control via temporal changes in breast milk, coincides with an influx of naive T cells into the colon, and is followed by the development of a long-lived population of colonic peripherally derived Tregs (pTregs) that can be specific for dietary antigens encountered during this interval. Desynchronization of mothers and offspring produced durable deficits in these pTregs, impaired tolerance to dietary antigens introduced during and after this preweaning interval, and resulted in spontaneous Th2 responses. These effects could be rescued by pTregs from the periweaning colon or by Tregs generated in vitro using periweaning colonic antigen-presenting cells. These findings demonstrate that mothers and their offspring are synchronized for the development of a balanced immune system.
A highly accessible alternative approach to basic statistics Praise for the First Edition: "Certainly one of the most impressive little paperback 200-page introductory statistics books that I will ...ever see . . . it would make a good nightstand book for every statistician."—TechnometricsWritten in a highly accessible style, Introduction to Statistics through Resampling Methods and R, Second Edition guides students in the understanding of descriptive statistics, estimation, hypothesis testing, and model building. The book emphasizes the discovery method, enabling readers to ascertain solutions on their own rather than simply copy answers or apply a formula by rote. The Second Edition utilizes the R programming language to simplify tedious computations, illustrate new concepts, and assist readers in completing exercises. The text facilitates quick learning through the use of:More than 250 exercises—with selected "hints"—scattered throughout to stimulate readers' thinking and to actively engage them in applying their newfound skillsAn increased focus on why a method is introducedMultiple explanations of basic conceptsReal-life applications in a variety of disciplinesDozens of thought-provoking, problem-solving questions in the final chapter to assist readers in applying statistics to real-life applicationsIntroduction to Statistics through Resampling Methods and R, Second Edition is an excellent resource for students and practitioners in the fields of agriculture, astrophysics, bacteriology, biology, botany, business, climatology, clinical trials, economics, education, epidemiology, genetics, geology, growth processes, hospital administration, law, manufacturing, marketing, medicine, mycology, physics, political science, psychology, social welfare, sports, and toxicology who want to master and learn to apply statistical methods.
Our theory of the origins of the universe based on old inflationary theory makes the minimum of assumptions, yet is consistent with observations. The properties of the scalar field, the discrete ...nonsymmetric phase, and their interactions are examined. Immediate consequences are that regions of the new phase never merge but persist as islands in the scalar field, and that the persistent scalar field is responsible for the effects attributed to cold dark matter. c 2010 Physics Essays Publication. DOI: 10.4006/1.3425751
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