Top-down systems biology modeling of host metabotype-microbiome associations in obese rodents

Covariation in the structural composition of the gut microbiome and the spectroscopically derived metabolic phenotype (metabotype) of a rodent model for obesity were investigated using a range of multivariate statistical tools. Urine and plasma samples from three strains of 10-week-old male Zucker rats (obese (fa/fa, n = 8), lean (fal-, n = 8) and lean (-/-, n = 8)) were characterized via high-resolution H-1 NMR spectroscopy, and in parallel, the fecal microbial composition was investigated using fluorescence in situ hydridization (FISH) and denaturing gradient gel electrophoresis (DGGE) methods. All three Zucker strains had different relative abundances of the dominant members of their intestinal microbiota (FISH), with the novel observation of a Halomonas and a Sphingomonas species being present in the (fa/fa) obese strain on the basis of DGGE data. The two functionally and phenotypically normal Zucker strains (fal- and -/-) were readily distinguished from the (fa/fa) obese rats on the basis of their metabotypes with relatively lower urinary hippurate and creatinine, relatively higher levels of urinary isoleucine, leucine and acetate and higher plasma LDL and VLDL levels typifying the (fa/fa) obese strain. Collectively, these data suggest a conditional host genetic involvement in selection of the microbial species in each host strain, and that both lean and obese animals could have specific metabolic phenotypes that are linked to their individual microbiomes.

The gut microbiota in obesity and metabolic disease - a novel therapeutic target

Obesity is sweeping the westernized world at a rate which far outstrips human genomic evolution, highlighting the importance of the obesogenic environment. Diet is an important component of this obesogenic environment, with certain diets (high fat, high refined carbohydrates and sugar) predisposing to overweight. On the other hand, there are also foods shown to protect against obesity and the diseases of obesity, including whole plant foods, dairy products, dietary fibre and functional foods like probiotics, prebiotics and phytochemicals. Interestingly, many of these foods mediate their health-promoting activities through the gut microbiota. The human gut microbiota itself has recently been identified as a contributory factor in this obesogenic environment, with differences observed between lean and obese. Evidence from human studies indicates that important groups of fermentative bacteria differ in abundance between lean and obese. Recently it has been suggested that anomalous microbiota composition in infancy can predispose to overweight in later life, highlighting the important role of optimal microbiota successional development, and that – as observed in laboratory animals – the gut microbiota may contribute to the aetiology of obesity. In this review we will introduce the gut microbiota, describe its interactions with major dietary components and the host, and then go on to discuss evidence indicating that the gut microbiota may contribute to the obesogenic environment. Finally, we will explore possible strategies for modulating the composition and activity of the human gut microbiota which may impact on obesity or the metabolic diseases associated with obesity. (Nutritional Therapy & Metabolism 2009; 27: 113-33)

Sugars and related compounds as flavour precursors in meat

Sugars and related substances, namely sugar phosphates and ribonucleotides, are important meat flavour precursors. In particular, ribose and ribose 5-phosphate have been shown to be important in aroma development in heated model systems. There are few quantitative data on the concentrations and the variations of sugars and related substances in meat. This paper will report on the analysis of glucose, fructose, ribose, ribose 5-phosphate, fructose 6-phosphate, glucose 6-phosphate and inosine 5'-monophosphate (IMP) in aged beef. Sugars and related compounds were extracted from lean meat and derivatised to the corresponding TMS ethers. Analysis and quantitation of the sugars and sugar phosphates were performed using GC and GC/MS, while IMP analysis was performed using capillary electrophoresis (CE).

Associations between dairy consumption and body weight: a review of the evidence and underlying mechanisms

As the incidence of obesity is reaching 'epidemic' proportions, there is currently widespread interest in the impact of dietary components on body-weight and food intake regulation. The majority of data available from both epidemiological and intervention studies provide evidence of a negative but modest association between milk and dairy product consumption and BMI and other measures of adiposity, with indications that higher intakes result in increased weight loss and lean tissue maintenance during energy restriction. The purported physiological and molecular mechanisms underlying the impact of dairy constituents on adiposity are incompletely understood but may include effects on lipolysis, lipogeneis and fatty acid absorption. Furthermore, accumulating evidence indicates an impact of dairy constituents, in particular whey protein derivatives, on appetite regulation and food intake. The present review summarises available data and provides an insight into the likely contribution of dairy foods to strategies aimed at appetite regulation, weight loss or the prevention of weight gain.

Changes in fat, fat-free mass and body water in human normal pregnancy

Measurements of body weight, total body water and total body potassium (40K) were made serially on three occasions during pregnancy and once post partum in 27 normal pregnant women. Skinfold thickness and fat cell diameter were also measured. A model of body composition was formulated to permit the estimation of changes in fat, lean tissue and water content of the maternal body. Total maternal body fat increased during pregnancy, reaching a peak towards the end of the second trimester before diminishing. Serial measurements of fat cell diameter showed poor correlation, whilst total body fat calculated from skinfold thickness correlated well with our estimated values for total body fat in pregnancy.

The technocratic totalitarianism of construction process improvement: a critical perspective

The current research agenda for construction process improvement is heavily influenced by the rhetoric of business process re-engineering (BPR). In contrast to the wider literature on BPR, there is little evidence of critical thought within the construction management research community. A postmodernist interpretation is advocated whereby the reality of management practice is defined by the dominant management discourse. The persuasiveness of BPR rhetoric is analysed with particular reference to the way in which it plays on the insecurity of modern managers. Despite the lip service given to ‘empowerment’ and ‘teamwork’, the dominant theme of the re-engineering movement is that of technocratic totalitarianism. From a critical perspective, it is suggested that BPR is imposed on construction organizations to ensure continued control by the industry's dominant power groups. Whilst industry leaders are fond of calling for ‘attitudinal and cultural improvement’, the language of the accepted research agenda continually reinforces the industry's dominant culture of ‘control and command’. Therefore, current research directions in process improvement perpetuate existing attitudes rather than facilitating cultural change. The concept of lean construction is seen to be the latest manifestation of this phenomenon.

Immune factors and fatty acid composition in human milk from river/lake, coastal and inland regions of China

Breast milk fatty acid composition may be affected by maternal diet during gestation and lactation. The influence of dietary and breast milk fatty acids on breast milk immune factors is poorly defined. We determined the fatty acid composition and immune factor concentrations of breast milk from women residing in river & lake, coastal, and inland regions of China, which differ in their consumption of lean fish and oily fish. Breast milk samples were collected on days 3 to 5 (colostrum), 14 and 28 post-partum and analysed for soluble CD14 (sCD14), transforming growth factor (TGF)-β1, TGF-β2, secretory immunoglobulin A (sIgA) and fatty acids. The fatty acid composition of breast milk differed between regions and with time post-partum. The concentrations of all four immune factors in breast milk decreased over time, with sCD14, sIgA and TGF-β1 being highest in colostrum in the river & lake region. Breast milk DHA and arachidonic acid (AA) were positively associated, and γ-linolenic acid and EPA negatively associated, with the concentrations of each of the four immune factors. In conclusion, breast milk fatty acids and immune factors differ between regions in China characterised by different patterns of fish consumption and change during the course of lactation. A higher breast milk DHA and AA concentration is associated with higher concentrations of immune factors in breast milk, suggesting a role for these fatty acids in promoting gastrointestinal and immune maturation of the infant.

Real-time multi-model decadal climate predictions

We present the first climate prediction of the coming decade made with multiple models, initialized with prior observations. This prediction accrues from an international activity to exchange decadal predictions in near real-time, in order to assess differences and similarities, provide a consensus view to prevent over-confidence in forecasts from any single model, and establish current collective capability. We stress that the forecast is experimental, since the skill of the multi-model system is as yet unknown. Nevertheless, the forecast systems used here are based on models that have undergone rigorous evaluation and individually have been evaluated for forecast skill. Moreover, it is important to publish forecasts to enable open evaluation, and to provide a focus on climate change in the coming decade. Initialized forecasts of the year 2011 agree well with observations, with a pattern correlation of 0.62 compared to 0.31 for uninitialized projections. In particular, the forecast correctly predicted La Niña in the Pacific, and warm conditions in the north Atlantic and USA. A similar pattern is predicted for 2012 but with a weaker La Niña. Indices of Atlantic multi-decadal variability and Pacific decadal variability show no signal beyond climatology after 2015, while temperature in the Niño3 region is predicted to warm slightly by about 0.5 °C over the coming decade. However, uncertainties are large for individual years and initialization has little impact beyond the first 4 years in most regions. Relative to uninitialized forecasts, initialized forecasts are significantly warmer in the north Atlantic sub-polar gyre and cooler in the north Pacific throughout the decade. They are also significantly cooler in the global average and over most land and ocean regions out to several years ahead. However, in the absence of volcanic eruptions, global temperature is predicted to continue to rise, with each year from 2013 onwards having a 50 % chance of exceeding the current observed record. Verification of these forecasts will provide an important opportunity to test the performance of models and our understanding and knowledge of the drivers of climate change.

A ‘Boscastle-type’ quasi-stationary convective system over the UK Southwest Peninsula

An investigation is presented of a quasi-stationary convective system (QSCS) which occurred over the UK Southwest Peninsula on 21 July 2010. This system was remarkably similar in its location and structure to one which caused devastating flash flooding in the coastal village of Boscastle, Cornwall on 16 August 2004. However, in the 2010 case rainfall accumulations were around four times smaller and no flooding was recorded. The more extreme nature of the Boscastle case is shown to be related to three factors: (1) higher rain rates, associated with a warmer and moister tropospheric column and deeper convective clouds; (2) a more stationary system, due to slower evolution of the large-scale flow; and (3) distribution of the heaviest precipitation over fewer river catchments. Overall, however, the synoptic setting of the two events was broadly similar, suggesting that such conditions favour the development of QSCSs over the Southwest Peninsula. A numerical simulation of the July 2010 event was performed using a 1.5-km grid length configuration of the Met Office Unified Model. This reveals that convection was repeatedly initiated through lifting of low-level air parcels along a quasi-stationary coastal convergence line. Sensitivity tests are used to show that this convergence line was a sea breeze front which temporarily stalled along the coastline due to the retarding influence of an offshore-directed background wind component. Several deficiencies are noted in the 1.5-km model’s representation of the storm system, including delayed convective initiation; however, significant improvements are observed when the grid length is reduced to 500 m. These result in part from an improved representation of the convergence line, which enhances the associated low-level ascent allowing air parcels to more readily reach their level of free convection. The implications of this finding for forecasting convective precipitation are discussed.

The surprising role of orography in the initiation of an isolated thunderstorm in southern England

Many factors, both mesoscale and larger scale, often come together in order for a particular convective initiation to take place. The authors describe a modeling study of a case from the Convective Storms Initiation Project (CSIP) in which a single thunderstorm formed behind a front in the southern United Kingdom. The key features of the case were a tongue of low-level high θw air associated with a forward-sloping split front (overrunning lower θw air above), a convergence line, and a “lid” of high static stability air, which the shower was initially constrained below but later broke through. In this paper, the authors analyze the initiation of the storm, which can be traced back to a region of high ground (Dartmoor) at around 0700 UTC, in more detail using model sensitivity studies with the Met Office Unified Model (MetUM). It is established that the convergence line was initially caused by roughness effects but had a significant thermal component later. Dartmoor had a key role in the development of the thunderstorm. A period of asymmetric flow over the high ground, with stronger low-level descent in the lee, led to a hole in a layer of low-level clouds downstream. The surface solar heating through this hole, in combination with the tongue of low-level high θw air associated with the front, caused the shower to initiate with sufficient lifting to enable it later to break through the lid.

Characteristics of high-resolution versions of the Met Office unified model for forecasting convection over the United Kingdom

With many operational centers moving toward order 1-km-gridlength models for routine weather forecasting, this paper presents a systematic investigation of the properties of high-resolution versions of the Met Office Unified Model for short-range forecasting of convective rainfall events. The authors describe a suite of configurations of the Met Office Unified Model running with grid lengths of 12, 4, and 1 km and analyze results from these models for a number of convective cases from the summers of 2003, 2004, and 2005. The analysis includes subjective evaluation of the rainfall fields and comparisons of rainfall amounts, initiation, cell statistics, and a scale-selective verification technique. It is shown that the 4- and 1-km-gridlength models often give more realistic-looking precipitation fields because convection is represented explicitly rather than parameterized. However, the 4-km model representation suffers from large convective cells and delayed initiation because the grid length is too long to correctly reproduce the convection explicitly. These problems are not as evident in the 1-km model, although it does suffer from too numerous small cells in some situations. Both the 4- and 1-km models suffer from poor representation at the start of the forecast in the period when the high-resolution detail is spinning up from the lower-resolution (12 km) starting data used. A scale-selective precipitation verification technique implies that for later times in the forecasts (after the spinup period) the 1-km model performs better than the 12- and 4-km models for lower rainfall thresholds. For higher thresholds the 4-km model scores almost as well as the 1-km model, and both do better than the 12-km model.

Scale-selective verification of rainfall accumulations from high-resolution forecasts of convective events

The development of NWP models with grid spacing down to 1 km should produce more realistic forecasts of convective storms. However, greater realism does not necessarily mean more accurate precipitation forecasts. The rapid growth of errors on small scales in conjunction with preexisting errors on larger scales may limit the usefulness of such models. The purpose of this paper is to examine whether improved model resolution alone is able to produce more skillful precipitation forecasts on useful scales, and how the skill varies with spatial scale. A verification method will be described in which skill is determined from a comparison of rainfall forecasts with radar using fractional coverage over different sized areas. The Met Office Unified Model was run with grid spacings of 12, 4, and 1 km for 10 days in which convection occurred during the summers of 2003 and 2004. All forecasts were run from 12-km initial states for a clean comparison. The results show that the 1-km model was the most skillful over all but the smallest scales (approximately <10–15 km). A measure of acceptable skill was defined; this was attained by the 1-km model at scales around 40–70 km, some 10–20 km less than that of the 12-km model. The biggest improvement occurred for heavier, more localized rain, despite it being more difficult to predict. The 4-km model did not improve much on the 12-km model because of the difficulties of representing convection at that resolution, which was accentuated by the spinup from 12-km fields.

Premature impairment of methylation pathway and cardiac metabolic dysfunction in fa/fa obese Zucker rats

Increasing evidence suggests that obesity is a chronic inflammatory disease, in which adipose tissue is involved in a network of endocrine signals to modulate energy homeostasis. These oxidative-inflammatory pathways, which are associated with cardiovascular complications, are also observed during the aging process. In this study, we investigated the interaction between aging and the development of obesity in a hyperphagic rat model. Metabolic profiles of the liver, white adipose tissue (WAT) and heart from young and adult Zucker lean (fa/+) and obese (fa/fa) rats were characterized using a (1)H NMR-based metabonomics approach. We observed premature metabolic modifications in all studied organs in obese animals, some of which were comparable to those observed in adult lean animals. In the cardiac tissue, young obese rats displayed lower lactate and scyllo-inositol levels associated with higher creatine, choline and phosphocholine levels, indicating an early modulation of energy and membrane metabolism. An early alteration of the hepatic methylation and transsulfuration pathways in both groups of obese rats indicated that these pathways were affected before diabetic onset. These findings therefore support the hypothesis that obesity parallels some metabolic perturbations observed in the aging process and provides new insights into the metabolic modifications occurring in pre-diabetic state.