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Swayampakula M.,University of Alberta | Baral P.K.,University of Alberta | Aguzzi A.,University of Zurich | Kav N.N.V.,Food and Nutritional Science | James M.N.G.,University of Alberta
Protein Science | Year: 2013

Prion diseases are progressive, infectious neurodegenerative disorders caused primarily by the misfolding of the cellular prion protein (PrPc) into an insoluble, protease-resistant, aggregated isoform termed PrPsc. In native conditions, PrPc has a structured C-terminal domain and a highly flexible N-terminal domain. A part of this N-terminal domain consists of 4-5 repeats of an unusual glycine-rich, eight amino acids long peptide known as the octapeptide repeat (OR) domain. In this article, we successfully report the first crystal structure of an OR of PrPc bound to the Fab fragment of the POM2 antibody. The structure was solved at a resolution of 2.3 A ° by molecular replacement. Although several studies have previously predicted a b-turn-like structure of the unbound ORs, our structure shows an extended conformation of the OR when bound to a molecule of the POM2 Fab indicating that the bound Fab disrupts any putative native b turn conformation of the ORs. Encouraging results from several recent studies have shown that administering small molecule ligands or antibodies targeting the OR domain of PrP result in arresting the progress of peripheral prion infections both in ex vivo and in in vivo models. This makes the structural study of the interactions of POM2 Fab with the OR domain very important as it would help us to design smaller and tighter binding OR ligands. © 2013 The Protein Society.

Azad M.B.,University of Alberta | Coneys G.J.,University of Manitoba | Kozyrskyj Prof. A.L.,University of Alberta | Field Prof. C.J.,Food and Nutritional Science | And 6 more authors.
BMJ (Online) | Year: 2013

during pregnancy or infancy with childhood asthma and wheeze. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, and Central (Cochrane Library) databases from inception to August 2013, plus the World Health Organization's international clinical trials registry platform and relevant conference proceedings for the preceding five years. Included trials and relevant reviews were forward searched in Web of Science. Review methods Two reviewers independently identified randomised controlled trials evaluating probiotics administered to mothers during pregnancy or to infants during the first year of life. The primary outcome was doctor diagnosed asthma; secondary outcomes included wheeze and lower respiratory tract infection. Results We identified 20 eligible trials including 4866 children. Trials were heterogeneous in the type and duration of probiotic supplementation, and duration of follow-up. Only five trials conducted follow-up beyond participants' age of 6 years (median 24 months), and none were powered to detect asthma as the primary outcome. The overall rate of doctor diagnosed asthma was 10.7%; overall rates of incident wheeze and lower respiratory tract infection were 33.3% and 13.9%, respectively. Among 3257 infants enrolled in nine trials contributing asthma data, the risk ratio of doctor diagnosed asthma in participants randomised to receive probiotics was 0.99 (95% confidence interval 0.81 to 1.21, I2=0%). The risk ratio of incident wheeze was 0.97 (0.87 to 1.09, I2=0%, 9 trials, 1949 infants). Among 1364 infants enrolled in six trials, the risk ratio of lower respiratory tract infection after probiotic supplementation was 1.26 (0.99 to 1.61, I2=0%). We adjudicated most trials to be of high (ten trials) or unclear (nine trials) risk of bias, mainly due to attrition. Conclusions We found no evidence to support a protective association between perinatal use of probiotics and doctor diagnosed asthma or childhood wheeze. Randomised controlled trials to date have not yielded sufficient evidence to recommend probiotics for the primary prevention of these disorders. Extended follow-up of existing trials, along with further clinical and basic research, are needed to accurately define the role of probiotics in the prevention of childhood asthma.

Bindels L.B.,University of Nebraska - Lincoln | Walter J.,Food and Nutritional Science | Walter J.,University of Alberta | Ramer-Tait A.E.,University of Nebraska - Lincoln
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2015

Purpose of review Recent clinical trials and animal studies indicate that resistant starches may be beneficial therapeutic tools for the management of metabolic diseases. The purpose of this review is to summarize these findings and discuss the established and proposed mechanisms by which resistant starches exert their benefits. We also examine open questions regarding how resistant starches improve metabolism and propose future research directions for the field. Recent findings Data from both humans and animal models clearly support a role for resistant starches in improving a variety of metabolic features; however, discrepancies do exist regarding specific effects. Concomitant improvements in both insulin levels and body fat depots are often reported in rodents fed resistant starches, whereas resistant starch feeding in humans improves insulin sensitivity without having a major impact on fat mass. These differences could be explained by the coexistence of several mechanisms (both gut microbiotadependent and gut microbiota-independent) underpinning the metabolic benefits of resistant starches. Summary Together, the studies presented in this review offer new insights into the potential pathways by which resistant starches enhance metabolic health, including modulation of the gut microbiota, gut peptides, circulating inflammatory mediators, innate immune cells, and the bile acid cycle. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Konya T.,Lana | Maughan H.,University of Toronto | Guttman D.S.,University of Toronto | Field C.J.,Food and Nutritional Science | And 6 more authors.
CMAJ | Year: 2013

Background: The gut microbiota is essential to human health throughout life, yet the acquisition and development of this microbial community during infancy remains poorly understood. Meanwhile, there is increasing concern over rising rates of cesarean delivery and insufficient exclusive breastfeeding of infants in developed countries. In this article, we characterize the gut microbiota of healthy Canadian infants and describe the influence of cesarean delivery and formula feeding. Methods: We included a subset of 24 term infants from the Canadian Healthy Infant Long itudinal Development (CHILD) birth cohort. Mode of delivery was obtained from medical records, and mothers were asked to report on infant diet and medication use. Fecal samples were collected at 4 months of age, and we characterized the microbiota composition using high-throughput DNA sequencing. Results: We observed high variability in the profiles of fecal microbiota among the in - fants. The profiles were generally dominated by Actinobacteria (mainly the genus Bifidobacterium) and Firmicutes (with diverse representation from numerous genera). Compared with breastfed infants, formula-fed infants had increased richness of species, with overrepresentation of Clostridium difficile. Escherichia- Shigella and Bacteroides species were underrepresented in infants born by cesarean delivery. Infants born by elective cesarean delivery had particularly low bacterial richness and diversity. Interpretation: These findings advance our understanding of the gut microbiota in healthy infants. They also provide new evidence for the effects of delivery mode and infant diet as determinants of this essential microbial community in early life. © 2013 Canadian Medical Association or its licensors.

Ametaj B.N.,Food and Nutritional Science | Zebeli Q.,Food and Nutritional Science | Iqbal S.,Food and Nutritional Science
Revista Brasileira de Zootecnia | Year: 2010

In this review article we present an overall summary of the role that high-grain/low forage diets have on rumen composition of microbiota and how changes in the diet affect the release of bacterial cell wall components that are toxic to the host. One of these toxic compounds is lipopolysaccharide or endotoxin, a component of the outer membrane of all Gram-negative bacteria. Moreover, data are provided that support the concept that endotoxin translocates into the blood circulation and show that rumen endotoxin is associated with multiple perturbations of blood variables related to carbohydrate, lipid, and mineral metabolism. In addition, endotoxin induces a general, nonspecific immune response known as acute phase response. We also pinpoint the fact that high-grain diets are associated with distinct clusters of plasma metabolites and immune variables suggesting that changing cereal grain to forage ratio in the diet is very important for the health of dairy cattle. Furthermore, we provide information that support the concept that endotoxin is involved in multiple metabolic diseases such as fatty liver, milk fever, laminitis, retained placenta, displaced abomasum, and downer cow syndrome. More research is warranted to clarify the mechanisms by which nutrition, microbiota, and endotoxin contribute to development of metabolic diseases in dairy cattle. It is concluded that besides the aforementioned causal agents other compounds generated in the gastrointestinal tract such as lipoteichoic acid or methylated amines might be involved in the etiology of several metabolic diseases. © 2010 Sociedade Brasileira de Zootecnia.

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