Differential pathways to adult metabolic dysfunction following poor nutrition at two critical developmental periods in sheep

Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1–31 days gestation) or 50% nutritional requirements (104–127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk

Dietary nitrate increases arginine availability and protects mitochondrial complex I and energetics in the hypoxic rat heart

This is the final version. It was first published by Wiley in The Journal of Physiology at http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2014.275263/abstract.Hypoxic exposure is associated with impaired cardiac energetics in humans and altered mitochondrial function, with suppressed complex I-supported respiration, in rat heart. This response might limit reactive oxygen species (ROS) generation, but at the cost of impaired electron transport chain (ETC) activity. Dietary nitrate supplementation improves mitochondrial efficiency and can promote tissue oxygenation by enhancing blood flow. We therefore hypothesised that ETC dysfunction, impaired energetics and oxidative damage in the hearts of rats exposed to chronic hypoxia could be alleviated by sustained administration of a moderate dose of dietary nitrate. Male Wistar rats (n=40) were given water supplemented with 0.7 mmol/L NaCl (as control) or 0.7 mmol/L NaNO3, elevating plasma nitrate levels by 80%, and were exposed to 13% O2 (hypoxia) or normoxia (n=10 per group) for 14 days. Respiration rates, ETC protein levels, mitochondrial density, ATP content and protein carbonylation were measured in cardiac muscle. Complex I respiration rates and protein levels were 33% lower in hypoxic/NaCl rats compared with normoxic/NaCl controls. Protein carbonylation was 65% higher in hearts of hypoxic rats compared with controls, indicating increased oxidative stress, whilst ATP levels were 62% lower. Respiration rates, complex I protein and activity, protein carbonylation and ATP levels were all fully protected in the hearts of nitrate-supplemented hypoxic rats. Both in normoxia and hypoxia, dietary nitrate suppressed cardiac arginase expression and activity and markedly elevated cardiac L-arginine concentrations, unmasking a novel mechanism of action by which nitrate enhances tissue NO bioavailability. Dietary nitrate therefore alleviates metabolic abnormalities in the hypoxic heart, improving myocardial energetics

Disrupting AMPK-glycogen binding in mice increases carbohydrate utilization and reduces exercise capacity

The AMP-activated protein kinase (AMPK) is a central regulator of cellular energy balance and metabolism and binds glycogen, the primary storage form of glucose in liver and skeletal muscle. The effects of disrupting whole-body AMPK-glycogen interactions on exercise capacity and substrate utilization during exercise in vivo remain unknown. We used male whole-body AMPK double knock-in (DKI) mice with chronic disruption of AMPK-glycogen binding to determine the effects of DKI mutation on exercise capacity, patterns of whole-body substrate utilization, and tissue metabolism during exercise. Maximal treadmill running speed and whole-body energy utilization during submaximal running were determined in wild type (WT) and DKI mice. Liver and skeletal muscle glycogen and skeletal muscle AMPK α and β2 subunit content and signaling were assessed in rested and maximally exercised WT and DKI mice. Despite a reduced maximal running speed and exercise time, DKI mice utilized similar absolute amounts of liver and skeletal muscle glycogen compared to WT. DKI skeletal muscle displayed reduced AMPK α and β2 content versus WT, but intact relative AMPK phosphorylation and downstream signaling at rest and following exercise. During submaximal running, DKI mice displayed an increased respiratory exchange ratio, indicative of greater reliance on carbohydrate-based fuels. In summary, whole-body disruption of AMPK-glycogen interactions reduces maximal running capacity and skeletal muscle AMPK α and β2 content and is associated with increased skeletal muscle glycogen utilization. These findings highlight potential unappreciated roles for AMPK in regulating tissue glycogen dynamics and expand AMPK’s known roles in exercise and metabolism

Educating for Practical Wisdom: An Ideal and a Journey

This working paper details the work of the Habits of Inquiry and Reflection Practical Wisdom Fellows. It offers an understanding of the term, discusses opportunities for growing in practical wisdom, and connects it to learning across campus

The effect of medications which cause inflammation of the gastro-oesophageal tract on cancer risk : a nested case–control study of routine Scottish data

Peer reviewedPostprin

Approximating A Dsm‐5 Diagnosis Of Ptsd Using Dsm‐Iv Criteria

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111929/1/da22364.pd

Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets.

The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity makes them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies have prompted exploration of a variety of synthetic materials capable of specific molecular recognition. Unfortunately, it remains a fundamental challenge to create a chemically diverse population of protein-like, folded synthetic nanostructures with defined molecular conformations in water. Here we report the synthesis and screening of combinatorial libraries of sequence-defined peptoid polymers engineered to fold into ordered, supramolecular nanosheets displaying a high spatial density of diverse, conformationally constrained peptoid loops on their surface. These polyvalent, loop-functionalized nanosheets were screened using a homogeneous Förster resonance energy transfer (FRET) assay for binding to a variety of protein targets. Peptoid sequences were identified that bound to the heptameric protein, anthrax protective antigen, with high avidity and selectivity. These nanosheets were shown to be resistant to proteolytic degradation, and the binding was shown to be dependent on the loop display density. This work demonstrates that key aspects of antibody structure and function-the creation of multivalent, combinatorial chemical diversity within a well-defined folded structure-can be realized with completely synthetic materials. This approach enables the rapid discovery of biomimetic affinity reagents that combine the durability of synthetic materials with the specificity of biomolecular materials

Structure and oxidative stability of oil in water emulsions as affected by rutin and homogenization procedure

[EN] The structural properties of oil-in-water (O/W) emulsions, as well as their oxidative stability upon storage at 50 °C, were studied. Eight different formulations were prepared, with the aim of studying the effect of three variables: the composition of the oil phase, the presence of the flavonoid rutin and the homogenization procedure on the structure and the oxidative stability. It was found that high pressure homogenization, through droplet size reduction, stabilized the emulsions both against creaming and oil oxidation. The interfacial protein was also partially replaced by rutin, further improving the stability of the emulsions, whereas purification of the oil phase had hardly any effect. Thus, the structural and oxidative stability of emulsions was controlled by the size of the droplets and improved by the addition of rutin. © 2012 Elsevier Ltd. All rights reserved.Lorena Atares would like to thank the financial support given by the Programa de Apoyo a la Investigacion y Desarrollo (PAID-00-11) from the Universitat Politecnica de Valencia.Atarés Huerta, LM.; Marshall, LJ.; Akhtar, M.; Murray, BS. (2012). Structure and oxidative stability of oil in water emulsions as affected by rutin and homogenization procedure. Food Chemistry. 134(3):1418-1424. https://doi.org/10.1016/j.foodchem.2012.02.221S14181424134

Global Mangrove Extent Change 1996–2020:Global Mangrove Watch Version 3.0

Mangroves are a globally important ecosystem that provides a wide range of ecosystem system services, such as carbon capture and storage, coastal protection and fisheries enhancement. Mangroves have significantly reduced in global extent over the last 50 years, primarily as a result of deforestation caused by the expansion of agriculture and aquaculture in coastal environments. However, a limited number of studies have attempted to estimate changes in global mangrove extent, particularly into the 1990s, despite much of the loss in mangrove extent occurring pre-2000. This study has used L-band Synthetic Aperture Radar (SAR) global mosaic datasets from the Japan Aerospace Exploration Agency (JAXA) for 11 epochs from 1996 to 2020 to develop a long-term time-series of global mangrove extent and change. The study used a map-to-image approach to change detection where the baseline map (GMW v2.5) was updated using thresholding and a contextual mangrove change mask. This approach was applied between all image-date pairs producing 10 maps for each epoch, which were summarised to produce the global mangrove time-series. The resulting mangrove extent maps had an estimated accuracy of 87.4% (95th conf. int.: 86.2–88.6%), although the accuracies of the individual gain and loss change classes were lower at 58.1% (52.4–63.9%) and 60.6% (56.1–64.8%), respectively. Sources of error included misregistration in the SAR mosaic datasets, which could only be partially corrected for, but also confusion in fragmented areas of mangroves, such as around aquaculture ponds. Overall, 152,604 km2 (133,996–176,910) of mangroves were identified for 1996, with this decreasing by -5245 km2 (-13,587–1444) resulting in a total extent of 147,359 km2 (127,925–168,895) in 2020, and representing an estimated loss of 3.4% over the 24-year time period. The Global Mangrove Watch Version 3.0 represents the most comprehensive record of global mangrove change achieved to date and is expected to support a wide range of activities, including the ongoing monitoring of the global coastal environment, defining and assessments of progress toward conservation targets, protected area planning and risk assessments of mangrove ecosystems worldwide