Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Home and Online Management and Evaluation of Blood Pressure (HOME BP) using a digital intervention in poorly controlled hypertension: randomised controlled trial

Objective: The HOME BP (Home and Online Management and Evaluation of Blood Pressure) trial aimed to test a digital intervention for hypertension management in primary care by combining self-monitoring of blood pressure with guided self-management. Design: Unmasked randomised controlled trial with automated ascertainment of primary endpoint. Setting: 76 general practices in the United Kingdom. Participants: 622 people with treated but poorly controlled hypertension (>140/90 mm Hg) and access to the internet. Interventions: Participants were randomised by using a minimisation algorithm to self-monitoring of blood pressure with a digital intervention (305 participants) or usual care (routine hypertension care, with appointments and drug changes made at the discretion of the general practitioner; 317 participants). The digital intervention provided feedback of blood pressure results to patients and professionals with optional lifestyle advice and motivational support. Target blood pressure for hypertension, diabetes, and people aged 80 or older followed UK national guidelines. Main outcome measures: The primary outcome was the difference in systolic blood pressure (mean of second and third readings) after one year, adjusted for baseline blood pressure, blood pressure target, age, and practice, with multiple imputation for missing values. Results: After one year, data were available from 552 participants (88.6%) with imputation for the remaining 70 participants (11.4%). Mean blood pressure dropped from 151.7/86.4 to 138.4/80.2 mm Hg in the intervention group and from 151.6/85.3 to 141.8/79.8 mm Hg in the usual care group, giving a mean difference in systolic blood pressure of −3.4 mm Hg (95% confidence interval −6.1 to −0.8 mm Hg) and a mean difference in diastolic blood pressure of −0.5 mm Hg (−1.9 to 0.9 mm Hg). Results were comparable in the complete case analysis and adverse effects were similar between groups. Within trial costs showed an incremental cost effectiveness ratio of £11 ($15, €12; 95% confidence interval £6 to £29) per mm Hg reduction. Conclusions: The HOME BP digital intervention for the management of hypertension by using self-monitored blood pressure led to better control of systolic blood pressure after one year than usual care, with low incremental costs. Implementation in primary care will require integration into clinical workflows and consideration of people who are digitally excluded. Trial registration: ISRCTN13790648

Multi-period multi-time optimisation of CO2 based district energy systems

Energy system design should take into account the hourly, daily and seasonal variations of both the energy demand and the considered utilities, and therefore requires a multi-time-resolution problem formulation. Multi-period / multi-time optimization is needed when a multi-time (e.g. hourly) optimization is performed inside another multi-period (e.g. typical day) optimization. However, optimizations over large temporal or spatial horizons tend to become computationally expensive, due to the large number of variables and constraints indexed over the times and over the periods. Employing typical operating periods (e.g. a number of typical operating days during the year) offers an interesting solution for problem size reduction. A variety of data clustering algorithms have been proposed in literature in order to select the best typical periods for different applications. This work uses a MILP formulation of a k-medoids based algorithm (PAM) in order to obtain typical operating periods which pass energy from one period to another, in view of performing long term energy storage. The algorithm is used coupled with an optimization of a CO2 based district energy network in a typical urban center. The intra-daily resolution allows the exploration of short term energy storage in the form of batteries located in the medium and low voltage grid. Coupled with the seasonal resolution, it offers a better understanding of the impact of daily storage on the long term storage and on the total energy requirement. The results show that implementing short-term energy storage leads to reductions of 2% in the size of the long term storage tank and 7.5 - 7.8% in the size of the main energy providers (PV panels). © 2018 Elsevier B.V

Lunar Topographic Mapping Using a New High Resolution Mode for the GSSR Radar

Mapping the Moon's topography using Earth based radar interferometric measurements by the Goldstone Solar System Radar (GSSR) has been done several times since the mid 1990s. In 2008 we reported at this conference the generation of lunar topographic maps having approximately 4 m height accuracy at a horizontal posting of 40 m. Since then GSSR radar has been improved to allow 40 MHz bandwidth imaging and consequently obtained images and interferograms with a resolution of about 4 m in range by 5 m in azimuth. The long synthetic aperture times of approximately 90 minutes in duration necessitated a migration from range/Doppler image formation techniques to spotlight mode processing and autofocusing methods. The improved resolution imagery should permit the generation of topographic maps with a factor of two better spatial resolution with about same height accuracy. Coupled the with the recent availability of new lidar topography maps of the lunar surface made by orbiting satellites of Japan and the United States the geodetic control of the radar generated maps products can be improved dramatically. This paper will discuss the hardware and software improvements made to the GSSR and present some of the new high resolution products

The NORMAN interlaboratory study on biotesting of spiked water extracts

The NORMAN network is a permanent self-sustaining network for the monitoring and biomonitoring of emerging environmental contaminants. The NORMAN working group on Bioassays (Bio WG) focuses on the application of bioanalytical tools for environmental quality monitoring. A main objective is to provide recommendations for the implementation of effect-based tools into regulatory frameworks. In this context, a blind interlaboratory study (ILS) was performed. The aim was to verify if a bioassay battery conducted in different laboratories following own protocols would produce comparable results when testing spiked surface water extracts. The lead in planning and organizing was taken by the Department of Ecosystem Analysis (ESA), RWTH Aachen University (DE). The ILS bioassay battery included acute-toxicity assays with organisms from different trophic levels (Algae, Daphnia, Zebrafish embryos); and mechanism-specific bioassays for estrogenicity (YES, ER-Luc cell lines) and mutagenicity (Ames fluctuation) assessment. Three to four participants performed each bioassay, including: BfG (DE), Waternet (NL), Waterproef (NL), INERIS (FR), IFREMER (FR), RECETOX (CZ), ISSeP (BE), ITM (SE), IVM-VU (NL), Entox/University of Queensland (AU), Ecotox Centre (CH), ESA-RWTH (DE). Clean water from a reference site was concentrated 10.000 times with large volume solid-phase extraction. Four emerging pollutants were used for spiking: triclosan, acridine, 3-nitrobezanthrone and 17-alpha-ethinylestradiol. Extracts were spiked with either single chemicals or a mixture, in concentrations aimed to produce full dose-response curves in bioassays. The spiked extracts were prepared, separated in aliquots, identified with codes, and sent to the participating laboratories. Standardized bioassay methods (OECD, ISO) were recommended but not mandatory, and biotesters could use their own protocols. Results were sent to RWTH, and a summary of the full ILS was provided to the ILS participants. In October 2014, a workshop was held at RWTH Aachen to present and discuss the ILS results. Bioassays produced mostly highly comparable results, even when protocols differed significantly. Suggestions for future improvements include harmonization of methods for data analysis and results evaluation. An important expected outcome of the ILS is the promotion of biotesting for water quality monitoring at the level of European policy-makers

Bioassay battery interlaboratory investigation of emerging contaminants in spiked water extracts - Towards the implementation of bioanalytical monitoring tools in water quality assessment and monitoring

Bioassays are particularly useful tools to link the chemical and ecological assessments in water quality monitoring. Different methods cover a broad range of toxicity mechanisms in diverse organisms, and account for risks posed by non-target compounds and mixtures. Many tests are already applied in chemical and waste assessments, and stakeholders from the science-police interface have recommended their integration in regulatory water quality monitoring. Still, there is a need to address bioassay suitability to evaluate water samples containing emerging pollutants, which are a current priority in water quality monitoring. The presented interlaboratory study (ILS) verified whether a battery of miniaturized bioassays, conducted in 11 different laboratories following their own protocols, would produce comparable results when applied to evaluate blinded samples consisting of a pristine water extract spiked with four emerging pollutants as single chemicals or mixtures, i.e. triclosan, acridine, 17 alpha-ethinylestradiol (EE2) and 3-nitrobenzanthrone (3-NBA). Assays evaluated effects on aquatic organisms from three different trophic levels (algae, daphnids, zebrafish embryos) and mechanism-specific effects using in vitro estrogenicity (ER-Luc, YES) and mutagenicity (Ames fluctuation) assays. The test battery presented complementary sensitivity and specificity to evaluate the different blinded water extract spikes. Aquatic organisms differed in terms of sensitivity to triclosan (algae > daphnids > fish) and acridine (fish > daphnids > algae) spikes, confirming the complementary role of the three taxa for water quality assessment. Estrogenicity and mutagenicity assays identified with high precision the respective mechanism-specific effects of spikes even when non-specific toxicity occurred in mixture. For estrogenicity, although differences were observed between assays and models, EE2 spike relative induction EC50 values were comparable to the literature, and E2/EE2 equivalency factors reliably reflected the sample content. In the Ames, strong revertant induction occurred following 3-NBA spike incubation with the TA98 strain, which was of lower magnitude after metabolic transformation and when compared to TA100. Differences in experimental protocols, model organisms, and data analysis can be sources of variation, indicating that respective harmonized standard procedures should be followed when implementing bioassays in water monitoring. Together with other ongoing activities for the validation of a basic bioassay battery, the present study is an important step towards the implementation of bioanalytical monitoring tools in water quality assessment and monitoring. (C) 2016 Elsevier Ltd. All rights reserved

Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism

International audienceBackground: Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. Results; We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10 −3 ), and combined dataset (p = 1.1 × 10 −4 ). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10 −35 , loss-of-function p = 2.26 × 10 −13 ) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10 −6 , OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia. Conclusions: In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs