Macronutrients and obesity: Revisiting the calories in,calories out framework

Recent clinical research has studied weight responses to varying diet composition, but the contribution of changes in macronutrient intake and physical activity to rising population weight remains controversial. Research on the economics of obesity typically assumes a “calories in, calories out” framework, but a weight production model separating caloric intake into carbohydrates, fat, and protein, has not been explored in an economic framework. To estimate the contributions of changes in macronutrient intake and physical activity to changes in population weight, we conducted dynamic time series and structural VAR analyses of U.S. data between 1974 and 2006 and a panel analysis of 164 countries between 2001 and 2010. Findings from all analyses suggest that increases in carbohydrates are most strongly and positively associated with increases in obesity prevalence even when controlling for changes in total caloric intake and occupation-related physical activity. Our structural VAR results suggest that, on the margin, a 1% increase in carbohydrates intake yields a 1.01 point increase in obesity prevalence over 5 years while an equal percent increase in fat intake decreases obesity prevalence by 0.24 points.     

New synchrotron radiation circular dichroism end-station on DISCO beamline at SOLEIL synchrotron for biomolecular analysis

The novel Synchrotron Radiation Circular Dichroism (SRCD) technique is becoming a new tool of investigation for the molecular structures of biomolecules, like proteins, carbohydrates or others bio-materials. Here, we describe the characteristics of a new experimental end-station for circular dichroism studies, in construction on DISCO beamline at SOLEIL synchrotron (Saint-Aubin, France). This experimental end-station will be an open facility for the community of researchers in structural biology. In order to show the kind of information accessible with this type of technique, we give an example: the conformational study of the galactose mutarotase from Escherichia coli, an enzyme involved in the galactose metabolism. This study was made using an operational SRCD station available at SRS (Daresbury Laboratory, UK).     

Prediction of the pilot-scale recovery of a recombinant yeast enzyme using integrated models

This article describes the rapid prediction of recovery process performance for a new recombinant enzyme product on the basis of a broad portfolio of computer models and highly targeted experimentation. A process model for the recombinant system was generated by linking unit operation models in an integrated fashion, with required parameter estimation and physical property determination accomplished using data from scale-down studies. This enabled the generic modeling framework established for processing of a natural enzyme from bakers' yeast to be applied. An experimental study of the same operations at the pilot scale showed that the process model gave a conservative prediction of recombinant enzyme recovery. The model successfully captured interactions leading to a low overall product yield and indicated the need for further study of precipitate breakage in the feed zone of a disc stack centrifuge in order to improve performance. The utility of scale-down units as an aid to fast model generation and the advantage of integrating computer modeling and scale-down studies to accelerate bioprocess development are highlighted.     

Equilibrium Modeling of the Mechanics and Structure of the Cancer Glycocalyx

The glycocalyx is a thick coat of proteins and carbohydrates on the outer surface of all eukaryotic cells. Overproduction of large, flexible or rod-like biopolymers, including hyaluronic acid and mucins, in the glycocalyx strongly correlates with the aggression of many cancer types. However, theoretical frameworks to predict the effects of these changes on cancer cell adhesion and other biophysical processes remain limited. Here, we propose a detailed modeling framework for the glycocalyx incorporating important physical effects of biopolymer flexibility, excluded volume, counterion mobility, and coupled membrane deformations. Because mucin and hyaluronic biopolymers are proposed to extend and rigidify depending on the extent of their decoration with side chains, we propose and consider two limiting cases for the structural elements of the glycocalyx: stiff beams and flexible chains. Simulations predict the mechanical response of the glycocalyx to compressive loads, which are imposed on cells residing in the highly confined spaces of the solid tumor or invaded tissues. Notably, the shape of the mechanical response transitions from hyperbolic to sigmoidal for more rod-like glycocalyx elements. These mechanical responses, along with the corresponding equilibrium protein organizations and membrane topographies, are summarized to aid in hypothesis generation and the evaluation of future experimental measurements. Overall, the modeling framework developed provides a theoretical basis for understanding the physical biology of the glycocalyx in human health.     

Modeling catalytic reaction mechanisms in glycoside hydrolases

Modeling catalysis in carbohydrate-active enzymes is a daunting challenge because of the high flexibility and diversity of both enzymes and carbohydrates. Glycoside hydrolases (GHs) are an illustrative example, where conformational changes and subtle interactions have been shown to be critical for catalysis. GHs have pivotal roles in industry (e.g. biofuel or detergent production) and biomedicine (e.g. targets for cancer and diabetes), and thus, a huge effort is devoted to unveil their molecular mechanisms. Besides experimental techniques, computational methods have served to provide an in-depth understanding of GH mechanisms, capturing complex reaction coordinates and the conformational itineraries that substrates follow during the whole catalytic pathway, providing a framework that ultimately may assist the engineering of these enzymes and the design of new inhibitors.     

Physical Properties of Bacterial Outer Membrane Models: Neutron Reflectometry & Molecular Simulation

The outer membrane (OM) of Gram-negative bacteria is an asymmetric bilayer having phospholipids in the inner leaflet and lipopolysaccharides in the outer leaflet. This unique asymmetry and the complex carbohydrates in lipopolysaccharides make it a daunting task to study the asymmetrical OM structure and dynamics, its interactions with OM proteins, and its roles in translocation of substrates, including antibiotics. In this study, we combine neutron reflectometry and molecular simulation to explore the physical properties of OM mimetics. There is excellent agreement between experiment and simulation, allowing experimental testing of the conclusions from simulations studies and also atomistic interpretation of the behavior of experimental model systems, such as the degree of lipid asymmetry, the lipid component (tail, head, and sugar) profiles along the bilayer normal, and lateral packing (i.e., average surface area per lipid). Therefore, the combination of both approaches provides a powerful new means to explore the biological and biophysical behavior of the bacterial OM.     

Revisiting macronutrient regulation in the polyphagous herbivore Helicoverpa zea (Lepidoptera: Noctuidae): New insights via nutritional geometry

Insect herbivores that ingest protein and carbohydrates in physiologically-optimal proportions and concentrations show superior performance and fitness. The first-ever study of protein–carbohydrate regulation in an insect herbivore was performed using the polyphagous agricultural pest Helicoverpa zea. In that study, experimental final instar caterpillars were presented two diets – one containing protein but no carbohydrates, the other containing carbohydrates but no protein – and allowed to self-select their protein–carbohydrate intake. The results showed that H. zea selected a diet with a protein-to-carbohydrate (p:c) ratio of 4:1. At about this same time, the geometric framework (GF) for the study of nutrition was introduced. The GF is now established as the most rigorous means to study nutrient regulation (in any animal). It has been used to study protein–carbohydrate regulation in several lepidopteran species, which exhibit a range of self-selected p:c ratios between 0.8 and 1.5. Given the economic importance of H. zea, and it is extremely protein-biased p:c ratio of 4:1 relative to those reported for other lepidopterans, we decided to revisit its protein–carbohydrate regulation. Our results, using the experimental approach of the GF, show that H. zea larvae self-select a p:c ratio of 1.6:1. This p:c ratio strongly matches that of its close relative, Heliothis virescens, and is more consistent with self-selected p:c ratios reported for other lepidopterans. Having accurate protein and carbohydrate regulation information for an insect herbivore pest such as H. zea is valuable for two reasons. First, it can be used to better understand feeding patterns in the field, which might lead to enhanced management. Second, it will allow researchers to develop rearing diets that more accurately reflect larval nutritional needs, which has important implications for resistance bioassays and other measures of physiological stress.     

Histochemistry of carbohydrates as performed by physical development procedures

Summary The histochemistry of carbohydrates demonstrated by means of physical development procedures has been reviewed in terms of the use and reliability of the procedures, physical developers, practice of the procedures, a fundamental series of light and electron microscopic methods and certain other promising aspects of this area of histochemistry. A line of fundamental light- and electron-microscopic histochemical methods for carbohydrates using physical development procedures such as periodic acid thiocarbohydrazide-silver protein-physical development (PA-TCH-SP-PD), high- or low-iron diamine (HID or LID)-TCH-SP-PD and lectin-gold (LT-G)-PD and related methods has been found to be more efficient, compared with those without physical development procedures. Since a series of other promising histochemical methods for carbohydrates using physical development procedures have been derived or are now being introduced, these procedures could be regarded as an unusually potent vehicle for effectively advancing carbohydrate histochemistry in both light and electron microscopy.     

Hierarchical kernel mixture models for the prediction of AIDS disease progression using HIV structural gp120 profiles

Changes to the glycosylation profile on HIV gp120 can influence viral pathogenesis and alter AIDS disease progression. The characterization of glycosylation differences at the sequence level is inadequate as the placement of carbohydrates is structurally complex. However, no structural framework is available to date for the study of HIV disease progression. In this study, we propose a novel machine-learning based framework for the prediction of AIDS disease progression in three stages (RP, SP, and LTNP) using the HIV structural gp120 profile. This new intelligent framework proves to be accurate and provides an important benchmark for predicting AIDS disease progression computationally. The model is trained using a novel HIV gp120 glycosylation structural profile to detect possible stages of AIDS disease progression for the target sequences of HIV+ individuals. The performance of the proposed model was compared to seven existing different machine-learning models on newly proposed gp120-Benchmark_1 dataset in terms of error-rate (MSE), accuracy (CCI), stability (STD), and complexity (TBM). The novel framework showed better predictive performance with 67.82% CCI, 30.21 MSE, 0.8 STD, and 2.62 TBM on the three stages of AIDS disease progression of 50 HIV+ individuals. This framework is an invaluable bioinformatics tool that will be useful to the clinical assessment of viral pathogenesis.     

A sensitive method for the histochemical demonstration of vicinal diols of carbohydrates

Summary A new sensitive method has been established for the histochemical demonstration of vicinal diols of carbohydrates in light microscopy. It consists of a periodic acid-thiocarbohydrazide-silver proteinate (PA-TCH-SP) sequence followed by physical development. The new method is more sensitive than the PA-TCH-SP and periodic acid-Schiff (PAS) methods employed hitherto. Its specificity is sufficient.     

The mathematical modelling of cell kinetics in corneal epithelial wound healing

This paper considers the comparison of experimental spatial and temporal data of mitotic rates measured during corneal epithelial wound healing (CEWH) of a rat model with the predictions of a computer modelling framework. We begin by briefly showing that previous models, used in the study of corneal epithelial wound healing speeds, are inadequate for the study of cell kinetics. We proceed to formulate a new modelling framework more suited to such a study. This framework is simulated in its simplest form, and the results from this motivate a new realisation of the modelling framework, including a caricature of age structuring. Finally, a model with a simple representation of juxtacrine signalling is considered. The final model captures many, though not all, of the trends of the experimental data. This paper thus lays a foundation for the modelling of the cell kinetics of corneal epithelial wound healing, and yields valuable insight regarding the important mechanisms a model should consider in order to reproduce the observed experimental trends.     

Contrasting effects of warming on pioneer and fibrous roots growth in <Emphasis Type="Italic">Abies faxoniana</Emphasis> seedlings at low and high planting density

Key message

Distinct differences in pioneer and fibrous roots acclimation to climate warming.

Abstract

This study was conducted to determine whether belowground parts of plants at different planting density differ in their responses to elevated temperature (ET). We investigated plant growth, pioneer and fibrous roots growth, root nonstructural carbohydrates, and root colonization of Abies faxoniana seedlings grown in environment-controlled chambers with two different planting densities. Warming has more pronounced positive effects at low density. Although ET did not affect total root biomass, fibrous roots biomass increased under ET at low planting density while pioneer roots biomass was unaffected by ET, indicating that this species may maintain the main framework of the root system with a high capability for water and N absorption under ET. ET increased root nonstructural carbohydrates concentration and ectomycorrhiza colonization in fibrous roots. Increased root nonstructural carbohydrates in response to ET might be associated with the increased roots ectomycorrhizal infection under ET. The present study provided experimental evidence of distinct differences in pioneer and fibrous roots acclimation to climate change.

     

On clinical efficacy: why biofeedback does--and does not--work

Questions of clinical efficacy are becoming more prominent in this era of diminishing funds for research and clinical care, and new treatment procedures, in particular, are being rigorously scrutinized. This presents a challenge for the relatively recent field of biofeedback and applied psychophysiology. This field has a strong scientific orientation and a rapidly expanding research base, which includes many well-controlled clinical outcome studies. The point is raised, and illustrated with data from current clinical outcome studies, that it is time for a shift in emphasis away from simply piling study upon study and toward more thoughtful interpretation of experimental and clinical findings and the development of a clearer conceptual framework for biofeedback therapy and research.     

DRUM: A New Framework for Metabolic Modeling under Non-Balanced Growth. Application to the Carbon Metabolism of Unicellular Microalgae

Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.     

Interpreting meta-analyses of genome-wide association studies

Meta-analysis is an increasingly popular tool for combining multiple genome-wide association studies in a single analysis to identify associations with small effect sizes. The effect sizes between studies in a meta-analysis may differ and these differences, or heterogeneity, can be caused by many factors. If heterogeneity is observed in the results of a meta-analysis, interpreting the cause of heterogeneity is important because the correct interpretation can lead to a better understanding of the disease and a more effective design of a replication study. However, interpreting heterogeneous results is difficult. The standard approach of examining the association p-values of the studies does not effectively predict if the effect exists in each study. In this paper, we propose a framework facilitating the interpretation of the results of a meta-analysis. Our framework is based on a new statistic representing the posterior probability that the effect exists in each study, which is estimated utilizing cross-study information. Simulations and application to the real data show that our framework can effectively segregate the studies predicted to have an effect, the studies predicted to not have an effect, and the ambiguous studies that are underpowered. In addition to helping interpretation, the new framework also allows us to develop a new association testing procedure taking into account the existence of effect.     

Will a 385 million year‐struggle for light become a struggle for water and for carbon? – How trees may cope with more frequent climate change‐type drought events

Trees are exceptional organisms that have evolved over some 385 million years and have overtaken other plants in order to harvest light first. However, this advantage comes with a cost: trees must transport water all the way up to their crowns and inherent physical limitations make them vulnerable to water deficits. Because climate change scenarios predict more frequent extreme drought events, trees will increasingly need to cope with water stress. Recent occurrences of climate change‐type droughts have had severe impacts on several forest ecosystems. Initial experimental studies have been undertaken and show that stomatal control of water loss hinders carbon assimilation and could lead to starvation during droughts. Other mechanisms of drought‐induced mortality are catastrophic xylem dysfunction, impeded long‐distance transport of carbohydrates (translocation) and also symplastic failure (cellular breakdown). However, direct empirical support is absent for either hypothesis. More experimental studies are necessary to increase our understanding of these processes and to resolve the mystery of drought‐related tree mortality. Instead of testing the validity of particular hypothesis as mechanisms of drought‐induced tree mortality, future research should aim at revealing the temporal dynamics of these mechanisms in different species and over a gradient of environmental conditions. Only such studies will reveal whether the struggle for light will become a struggle for water and/or for carbon in drought‐affected areas.     

Occurrence patterns of aspen‐feeding wood‐borers (Coleoptera: Cerambycidae) along the wood decay gradient: active selection for specific host types or neutral mechanisms?

Abstract.  1. Determinants of host-use patterns in plant-feeding insects have been extensively studied, usually within the framework of optimality theory. Comparatively, factors driving host selection in saprophagous insects have received little attention.
2. In this study, mechanisms creating occurrence peaks of saprophagous wood-borers (Cerambycidae: Coleoptera) in standing dead aspen in the middle and late stages of decay were investigated by correlating insect occurrence with variations in substrate-related nutritional and physical parameters. Twenty-four snags at four decay stages were dissected from a mature stand in western Quebec, Canada. Wood samples were taken to measure levels of nitrogen, non-structural carbohydrates, phenols, wood density, water content and snag age.
3. Several nutritional and physical parameters varied significantly along the decay gradient and were correlated with insect occurrence, but all significant parameters were also strongly correlated with snag age and wood density. Model selection using Akaike's second order information criteria was used to rank the different models; the model including snag age only performed best, with a w_i of 0.873.
4. This importance of snag age gives support to a proposed hypothesis of host selection in which temporal autocorrelation in probability of insect occurrence explains peaks observed in the middle and late stages of decay. However, further studies will be needed to confirm the prevalence of such neutral mechanisms over active selection in the determination of host-use patterns in decaying aspen.     

Molecular simulations of complex carbohydrates and glycoconjugates

Complex carbohydrates (glycans) are the most abundant and versatile biopolymers in nature. The broad diversity of biochemical functions that carbohydrates cover is a direct consequence of the variety of 3D architectures they can adopt, displaying branched or linear arrangements, widely ranging in sizes, and with the highest diversity of building blocks of any other natural biopolymer. Despite this unparalleled complexity, a common denominator can be found in the glycans’ inherent flexibility, which hinders experimental characterization, but that can be addressed by high-performance computing (HPC)-based molecular simulations. In this short review, I present and discuss the state-of-the-art of molecular simulations of complex carbohydrates and glycoconjugates, highlighting methodological strengths and weaknesses, important insights through emblematic case studies, and suggesting perspectives for future developments.     

Mechanosensitive Channels: Insights from Continuum-Based Simulations

Mechanotransduction plays an important role in regulating cell functions and it is an active topic of research in biophysics. Despite recent advances in experimental and numerical techniques, the intrinsic multiscale nature imposes tremendous challenges for revealing the working mechanisms of mechanosensitive channels. Recently, a continuum-mechanics-based hierarchical modeling and simulation framework has been established and applied to study the mechanical responses and gating behaviors of a prototypical mechanosensitive channel, the mechanosensitive channel of large conductance (MscL) in bacteria Escherichia coli (E. coli), from which several putative gating mechanisms have been tested and new insights are deduced. This article reviews these latest findings using the continuum mechanics framework and suggests possible improvements for future simulation studies. This computationally efficient and versatile continuum-mechanics-based protocol is poised to make contributions to the study of a variety of mechanobiology problems.