The silicon trypanosome

African trypanosomes have emerged as promising unicellular model organisms for the next generation of systems biology. They offer unique advantages, due to their relative simplicity, the availability of all standard genomics techniques and a long history of quantitative research. Reproducible cultivation methods exist for morphologically and physiologically distinct life-cycle stages. The genome has been sequenced, and microarrays, RNA-interference and high-accuracy metabolomics are available. Furthermore, the availability of extensive kinetic data on all glycolytic enzymes has led to the early development of a complete, experiment-based dynamic model of an important biochemical pathway. Here we describe the achievements of trypanosome systems biology so far and outline the necessary steps towards the ambitious aim of creating a , a comprehensive, experiment-based, multi-scale mathematical model of trypanosome physiology. We expect that, in the long run, the quantitative modelling enabled by the Silicon Trypanosome will play a key role in selecting the most suitable targets for developing new anti-parasite drugs

Impact of the Volkswagen emissions control defeat device on US public health

The US Environmental Protection Agency (EPA) has alleged that Volkswagen Group of America (VW) violated the Clean Air Act (CAA) by developing and installing emissions control system 'defeat devices' (software) in model year 2009–2015 vehicles with 2.0 litre diesel engines. VW has admitted the inclusion of defeat devices. On-road emissions testing suggests that in-use NO[subscript x] emissions for these vehicles are a factor of 10 to 40 above the EPA standard. In this paper we quantify the human health impacts and associated costs of the excess emissions. We propagate uncertainties throughout the analysis. A distribution function for excess emissions is estimated based on available in-use NO[subscript x] emissions measurements. We then use vehicle sales data and the STEP vehicle fleet model to estimate vehicle distance traveled per year for the fleet. The excess NO[subscript x] emissions are allocated on a 50 km grid using an EPA estimate of the light duty diesel vehicle NO[subscript x] emissions distribution. We apply a GEOS-Chem adjoint-based rapid air pollution exposure model to produce estimates of particulate matter and ozone exposure due to the spatially resolved excess NO[subscript x] emissions. A set of concentration-response functions is applied to estimate mortality and morbidity outcomes. Integrated over the sales period (2008–2015) we estimate that the excess emissions will cause 59 (95% CI: 10 to 150) early deaths in the US. When monetizing premature mortality using EPA-recommended data, we find a social cost of ~$450m over the sales period. For the current fleet, we estimate that a return to compliance for all affected vehicles by the end of 2016 will avert ~130 early deaths and avoid ~$840m in social costs compared to a counterfactual case without recall

Exercise intensity and postprandial health outcomes in adolescents

© 2014, Springer-Verlag Berlin Heidelberg. Method: Twenty adolescents (10 male, 14.3 ± 0.3 years) completed three 1-day trials: (1) rest (CON); (2) 8 × 1 min cycling at 90 % peak power with 75 s recovery (HIIE); (3) cycling at 90 % of the gas exchange threshold (MIE), 1 h before consuming a high-fat milkshake (1.50 g fat and 80 kJ kg−1). Postprandial TAG, SBP and fat oxidation were assessed over 4 h Results : Compared to CON, the incremental area under the curve for TAG (IAUC-TAG) was not significantly lowered in HIIE [P = 0.22, effect size (ES) = 0.24] or MIE (P = 0.65, ES = 0.04) for boys. For girls, HIIE and MIE lowered IAUC-TAG by 34 % (P = 0.02, ES = 0.58) and 38 % (P = 0.09, ES = 0.73), respectively, with no difference between HIIE and MIE (P = 0.74, ES = 0.14). Changes in TAG were not related to energy expenditure during exercise or postprandial fat oxidation. Postprandial SBP (total-AUC pooled for both sexes) was lower in HIIE compared to CON (P = 0.01, ES = 0.68) and MIE (P = 0.02, ES = 0.60), with no difference between MIE and CON (P = 0.45, ES = 0.14). Purpose: The effect of exercise intensity and sex on postprandial risk factors for cardiovascular disease in adolescents is unknown. We examined the effect of a single bout of work-matched high-intensity interval exercise (HIIE) and moderate-intensity exercise (MIE) on postprandial triacylglycerol (TAG) and systolic blood pressure (SBP) in adolescents. Conclusion: A single bout of HIIE and MIE, performed 1 h before an HFM, can meaningfully attenuate IAUC-TAG in girls but not boys. Additionally, HIIE, but not MIE, may lower postprandial SBP in normotensive adolescents

Dynamic nuclear polarization at the edge of a two-dimensional electron gas

We have used gated GaAs/AlGaAs heterostructures to explore nonlinear transport between spin-resolved Landau level (LL) edge states over a submicron region of two-dimensional electron gas (2DEG). The current I flowing from one edge state to the other as a function of the voltage V between them shows diode-like behavior---a rapid increase in I above a well-defined threshold V_t under forward bias, and a slower increase in I under reverse bias. In these measurements, a pronounced influence of a current-induced nuclear spin polarization on the spin splitting is observed, and supported by a series of NMR experiments. We conclude that the hyperfine interaction plays an important role in determining the electronic properties at the edge of a 2DEG.Comment: 8 pages RevTeX, 7 figures (GIF); submitted to Phys. Rev.

Metabolomics guides rational development of a simplified cell culture medium for drug screening against <i>Trypanosoma brucei</i>

n vitro culture methods underpin many experimental approaches to biology and drug discovery. The modification of established cell culture methods to make them more biologically relevant or to optimize growth is traditionally a laborious task. Emerging metabolomic technology enables the rapid evaluation of intra- and extracellular metabolites and can be applied to the rational development of cell culture media. In this study, untargeted semiquantitative and targeted quantitative metabolomic analyses of fresh and spent media revealed the major nutritional requirements for the growth of bloodstream form &lt;i&gt;Trypanosoma brucei&lt;/i&gt;. The standard culture medium (HMI11) contained unnecessarily high concentrations of 32 nutrients that were subsequently removed to make the concentrations more closely resemble those normally found in blood. Our new medium, Creek's minimal medium (CMM), supports in vitro growth equivalent to that in HMI11 and causes no significant perturbation of metabolite levels for 94% of the detected metabolome (&#60;3-fold change; α = 0.05). Importantly, improved sensitivity was observed for drug activity studies in whole-cell phenotypic screenings and in the metabolomic mode of action assays. Four-hundred-fold 50% inhibitory concentration decreases were observed for pentamidine and methotrexate, suggesting inhibition of activity by nutrients present in HMI11. CMM is suitable for routine cell culture and offers important advantages for metabolomic studies and drug activity screening

An evaluation of the error and uncertainty in epibenthos cover estimates from AUV images collected with an efficient, spatially-balanced design

<div><p>Efficient monitoring of organisms is at the foundation of protected area and biodiversity management. Such monitoring programs are based on a systematically selected set of survey locations that, while able to track trends at those locations through time, lack inference for the overall region being “monitored”. Advances in spatially-balanced sampling approaches offer alternatives but remain largely untested in marine ecosystems. This study evaluated the merit of using a two-stage, spatially-balanced survey framework, in conjunction with generalized additive models, to estimate epifauna cover at a reef-wide scale for mesophotic reefs within a large, cross-shelf marine park. Imagery acquired by an autonomous underwater vehicle was classified using a hierarchical scheme developed under the Collaborative and Automated Tools for Analysis of Marine Imagery (CATAMI). At a realistic image subsampling intensity, the two-stage, spatially-balanced framework provided accurate and precise estimates of reef-wide cover for a select number of epifaunal classes at the coarsest CATAMI levels, in particular bryozoan and porifera classes. However, at finer hierarchical levels, accuracy and/or precision of cover estimates declined, primarily because of the natural rarity of even the most common of these classes/morphospecies. Ranked predictor importance suggested that bathymetry, backscatter and derivative terrain variables calculated at their smallest analysis window scales (i.e. 81 m²) were generally the most important variables in the modeling of reef-wide cover. This study makes an important step in identifying the constraints and limitations that can be identified through a robust statistical approach to design and analysis. The two-stage, spatially-balanced framework has great potential for effective quantification of epifaunal cover in cross-shelf mesophotic reefs. However, greater image subsampling intensity than traditionally applied is required to ensure adequate observations for finer-level CATAMI classes and associated morphospecies.</p></div

Beyond element-wise interactions: identifying complex interactions in biological processes

Background: Biological processes typically involve the interactions of a number of elements (genes, cells) acting on each others. Such processes are often modelled as networks whose nodes are the elements in question and edges pairwise relations between them (transcription, inhibition). But more often than not, elements actually work cooperatively or competitively to achieve a task. Or an element can act on the interaction between two others, as in the case of an enzyme controlling a reaction rate. We call “complex” these types of interaction and propose ways to identify them from time-series observations. Methodology: We use Granger Causality, a measure of the interaction between two signals, to characterize the influence of an enzyme on a reaction rate. We extend its traditional formulation to the case of multi-dimensional signals in order to capture group interactions, and not only element interactions. Our method is extensively tested on simulated data and applied to three biological datasets: microarray data of the Saccharomyces cerevisiae yeast, local field potential recordings of two brain areas and a metabolic reaction. Conclusions: Our results demonstrate that complex Granger causality can reveal new types of relation between signals and is particularly suited to biological data. Our approach raises some fundamental issues of the systems biology approach since finding all complex causalities (interactions) is an NP hard problem

Results from the centers for disease control and prevention's predict the 2013-2014 Influenza Season Challenge

Background: Early insights into the timing of the start, peak, and intensity of the influenza season could be useful in planning influenza prevention and control activities. To encourage development and innovation in influenza forecasting, the Centers for Disease Control and Prevention (CDC) organized a challenge to predict the 2013-14 Unites States influenza season. Methods: Challenge contestants were asked to forecast the start, peak, and intensity of the 2013-2014 influenza season at the national level and at any or all Health and Human Services (HHS) region level(s). The challenge ran from December 1, 2013-March 27, 2014; contestants were required to submit 9 biweekly forecasts at the national level to be eligible. The selection of the winner was based on expert evaluation of the methodology used to make the prediction and the accuracy of the prediction as judged against the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet). Results: Nine teams submitted 13 forecasts for all required milestones. The first forecast was due on December 2, 2013; 3/13 forecasts received correctly predicted the start of the influenza season within one week, 1/13 predicted the peak within 1 week, 3/13 predicted the peak ILINet percentage within 1 %, and 4/13 predicted the season duration within 1 week. For the prediction due on December 19, 2013, the number of forecasts that correctly forecasted the peak week increased to 2/13, the peak percentage to 6/13, and the duration of the season to 6/13. As the season progressed, the forecasts became more stable and were closer to the season milestones. Conclusion: Forecasting has become technically feasible, but further efforts are needed to improve forecast accuracy so that policy makers can reliably use these predictions. CDC and challenge contestants plan to build upon the methods developed during this contest to improve the accuracy of influenza forecasts. © 2016 The Author(s)

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness

Radio Astronomy

Contains table of contents and reports on seven research projects.National Science Foundation (Grant AST 86-17172)National Aeronautics and Space AdministrationJet Propulsion LaboratoryNASA/Goddard Space Flight Center (Grant NAG5-10)SM Systems and Research, Inc.U.S. Navy Office of Naval Research (Contract N00014-86-C-2114)Center for Advanced Television StudiesNASA/Goddard Space Flight Center (Grant NAG5-537