Investigating the molecular mechanisms of the metabolic syndrome

This thesis aims to highlight molecular mechanisms that have been altered by prenatal undernutrition and may be involved in the metabolic syndrome. Two sepa- rate studies were conducted both using a rat model developed through manipulation of the maternal diet to provoke the key features of the metabolic syndrome in adult o spring. Microarray technology was used to detect changes in gene expression in tar- get tissues between o spring of control (normally fed, AD) and undernourished (UN) mothers to obtain a broader picture of the cellular functions and genetic pathways that may be implicated in the metabolic syndrome. The rst study compared gene expression di erences in liver, skeletal muscle, and white adipose tissue between 55 day old male o spring of AD and UN mothers. No signi cant changes were found in muscle or adipose tissue; however, the di erences in the liver suggested the UN animals had been metabolically programmed to favour fat as an energy source. To investigate whether DNA methylation might be responsible for the observed transcriptional changes, pooled liver samples from the rst study were used with the McrBC restriction enzyme assay to determine full, partial, incomplete, or no methylation between AD and UN. Two di erentially expressed genes (Zfand2a and Mapk4) showed methylation changes. The same liver samples were hybridised to a miRNA array. Two miRNAs showed a nearly 2-fold upregulation in the UN livers. Both were found to be either directly or indirectly associated with the metabolic syndrome. MiR-335 has been shown to be upregulated in the livers of obese/diabetic mice. By association with miR-27a, miR-451 might be involved in aspects of lipid metabolism in adipose tissue. A second study used microarray to analyse the liver tissues of day 170 female o - spring of the same rat model with additional insults (neonatal leptin treatment and post-weaning high-fat (HF) diet). Leptin has been shown to reverse the programming e ects of the restricted maternal diet and this study aimed to highlight mechanisms that could be involved in this reversal. The results revealed the importance of the in- teraction between treatments. Signi cant gene expression changes were only present when two or more treatments were combined. This study revealed signi cantly, dif- ferentially expressed genes involved in immune function, regulation of the circadian rhythm, and metabolism. These ndings provide a number of interesting genes and pathways for further studies and also highlight the need to conduct a thorough study in multiple tissues at di erent time-points to pinpoint the window of developmental plasticity.University of Auckland Liggins Institut

Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal leptin treatment, but masked in the presence of both: implications for models of developmental programming.

BACKGROUND: Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring. RESULTS: We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that "leptin reversal" is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring. CONCLUSIONS: We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This "calibration model" for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities

Non-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells.

Non-CG methylation is an unexplored epigenetic hallmark of pluripotent stem cells. Here we report that a reduction in non-CG methylation is associated with impaired differentiation capacity into endodermal lineages. Genome-wide analysis of 2,670 non-CG sites in a discovery cohort of 25 phenotyped human induced pluripotent stem cell (hiPSC) lines revealed unidirectional loss (Δβ=13%, P<7.4 × 10(-4)) of non-CG methylation that correctly identifies endodermal differentiation capacity in 23 out of 25 (92%) hiPSC lines. Translation into a simplified assay of only nine non-CG sites maintains predictive power in the discovery cohort (Δβ=23%, P<9.1 × 10(-6)) and correctly identifies endodermal differentiation capacity in nine out of ten pluripotent stem cell lines in an independent replication cohort consisting of hiPSCs reprogrammed from different cell types and different delivery systems, as well as human embryonic stem cell (hESC) lines. This finding infers non-CG methylation at these sites as a biomarker when assessing endodermal differentiation capacity as a readout.We thank Kerra Pearce (UCL Genomics) for array processing, and Tim Fell and Jonathan Best (CellCentric), Jason Wray (UCL) and Rosemary Drake (TAP Biosystems) for discussions. We also thank Minal Patel, Chris Kirton, Anja Kolb-Kokocinski, Willem H. Ouwehand, Richard Durbin and Fiona M. Watt on behalf of the Human Induced Pluripotent Stem Cell Initiative (HipSci) funded by grant WT098503 from the Wellcome Trust and the Medical Research Council, for sharing data and materials. This work was supported in part by a TSB/EPSRC grant (TS/H000933/1). The Vallier lab is supported by the Cambridge Hospitals National Institute for Health Research Biomedical Research Center and an ERC Starting Grant (Relieve IMDS). F.A.C.S. is funded by a PhD studentship from Fundação para a Ciência e a Tecnologia (SFRH/BD/69033/2010). The Ferguson-Smith lab is supported by grants from the MRC and Wellcome Trust, and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510). The Beck lab is supported by the Wellcome Trust (084071), a Royal Society Wolfson Research Merit Award (WM100023), and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1045

Contributions of organic and inorganic matter to sediment volume and accretion in tidal wetlands at steady state

A mixing model derived from first principles describes the bulk density (BD) of intertidal wetland sediments as a function of loss on ignition (LOI). The model assumes that the bulk volume of sediment equates to the sum of self-packing volumes of organic and mineral components or BD = 1/[LOI/k1 + (1-LOI)/k2], where k1 and k2 are the self-packing densities of the pure organic and inorganic components, respectively. The model explained 78% of the variability in total BD when fitted to 5075 measurements drawn from 33 wetlands distributed around the conterminous United States. The values of k1 and k2 were estimated to be 0.085 ± 0.0007 g cm−3 and 1.99 ± 0.028 g cm−3, respectively. Based on the fitted organic density (k1) and constrained by primary production, the model suggests that the maximum steady state accretion arising from the sequestration of refractory organic matter is ≤ 0.3 cm yr−1. Thus, tidal peatlands are unlikely to indefinitely survive a higher rate of sea-level rise in the absence of a significant source of mineral sediment. Application of k2 to a mineral sediment load typical of East and eastern Gulf Coast estuaries gives a vertical accretion rate from inorganic sediment of 0.2 cm yr−1. Total steady state accretion is the sum of the parts and therefore should not be greater than 0.5 cm yr−1 under the assumptions of the model. Accretion rates could deviate from this value depending on variation in plant productivity, root:shoot ratio, suspended sediment concentration, sediment-capture efficiency, and episodic events

Uncertainty in United States coastal wetland greenhouse gas inventorying

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Environmental Research Letters 13 (2018): 115005, doi:10.1088/1748-9326/aae157.Coastal wetlands store carbon dioxide (CO2) and emit CO2 and methane (CH4) making them an important part of greenhouse gas (GHG) inventorying. In the contiguous United States (CONUS), a coastal wetland inventory was recently calculated by combining maps of wetland type and change with soil, biomass, and CH4 flux data from a literature review. We assess uncertainty in this developing carbon monitoring system to quantify confidence in the inventory process itself and to prioritize future research. We provide a value-added analysis by defining types and scales of uncertainty for assumptions, burial and emissions datasets, and wetland maps, simulating 10 000 iterations of a simplified version of the inventory, and performing a sensitivity analysis. Coastal wetlands were likely a source of net-CO2-equivalent (CO2e) emissions from 2006–2011. Although stable estuarine wetlands were likely a CO2e sink, this effect was counteracted by catastrophic soil losses in the Gulf Coast, and CH4 emissions from tidal freshwater wetlands. The direction and magnitude of total CONUS CO2e flux were most sensitive to uncertainty in emissions and burial data, and assumptions about how to calculate the inventory. Critical data uncertainties included CH4 emissions for stable freshwater wetlands and carbon burial rates for all coastal wetlands. Critical assumptions included the average depth of soil affected by erosion events, the method used to convert CH4 fluxes to CO2e, and the fraction of carbon lost to the atmosphere following an erosion event. The inventory was relatively insensitive to mapping uncertainties. Future versions could be improved by collecting additional data, especially the depth affected by loss events, and by better mapping salinity and inundation gradients relevant to key GHG fluxes. Social Media Abstract: US coastal wetlands were a recent and uncertain source of greenhouse gasses because of CH4 and erosion.Financial support was provided primarily by NASA Carbon Monitoring Systems (NNH14AY67I) and the USGS Land Carbon Program, with additional support from The Smithsonian Institution, The Coastal Carbon Research Coordination Network (DEB-1655622), and NOAA Grant: NA16NMF4630103

Emotional Labor in Mathematics: Reflections on Mathematical Communities, Mentoring Structures, and EDGE

Terms such as "affective labor" and "emotional labor" pepper feminist critiques of the workplace. Though there are theoretical nuances between the two phrases, both kinds of labor involve the management of emotions; some acts associated with these constructs involve caring, listening, comforting, reassuring, and smiling. In this article I explore the different ways academic mathematicians are called to provide emotional labor in the discipline, thereby illuminating a rarely visible component of a mathematical life in the academy. Underlying this work is my contention that a conceptualization of labor involved in managing emotions is of value to the project of understanding the character, values, and boundaries of such a life. In order to investigate the various dimensions of emotional labor in the context of academic mathematics, I extend the basic framework of Morris and Feldman [33] and then apply this extended framework to the mathematical sciences. Other researchers have mainly focused on the negative effects of emotional labor on a laborer's physical, emotional, and mental health, and several examples in this article align with this framing. However, at the end of the article, I argue that mathematical communities and mentoring structures such as EDGE help diminish some of the negative aspects of emotional labor while also accentuating the positives.Comment: Revised version to appear in the upcoming volume A Celebration of EDGE, edited by Sarah Bryant, Amy Buchmann, Susan D'Agostino, Michelle Craddock Guinn, and Leona Harri

ActEarly: a City Collaboratory approach to early promotion of good health and wellbeing.

Economic, physical, built, cultural, learning, social and service environments have a profound effect on lifelong health. However, policy thinking about health research is dominated by the 'biomedical model' which promotes medicalisation and an emphasis on diagnosis and treatment at the expense of prevention. Prevention research has tended to focus on 'downstream' interventions that rely on individual behaviour change, frequently increasing inequalities. Preventive strategies often focus on isolated leverage points and are scattered across different settings. This paper describes a major new prevention research programme that aims to create City Collaboratory testbeds to support the identification, implementation and evaluation of upstream interventions within a whole system city setting. Prevention of physical and mental ill-health will come from the cumulative effect of multiple system-wide interventions. Rather than scatter these interventions across many settings and evaluate single outcomes, we will test their collective impact across multiple outcomes with the goal of achieving a tipping point for better health. Our focus is on early life (ActEarly) in recognition of childhood and adolescence being such critical periods for influencing lifelong health and wellbeing