Publications by authors named "Christian Ludwig"

100 Publications

Systemic and adipocyte transcriptional and metabolic dysregulation in Idiopathic Intracranial Hypertension.

JCI Insight 2021 Apr 13. Epub 2021 Apr 13.

Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.

Background: Idiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess and an increased risk of cardiovascular morbidity. Here we evaluate systemic and adipose specific metabolic determinants of the IIH phenotype.

Methods: In fasted, matched IIH (N=97) and control (N=43) patients, we assessed: glucose and insulin homeostasis and leptin levels. Body composition was assessed along with an interrogation of adipose tissue function via nuclear magnetic resonance metabolomics and RNA sequencing in paired omental and subcutaneous biopsies in a case control study.

Results: We demonstrate an insulin and leptin resistant phenotype in IIH in excess to that driven by obesity. Adiposity in IIH is preferentially centripetal and is associated with increased disease activity and insulin resistance. IIH adipocytes appear transcriptionally and metabolically primed towards depot-specific lipogenesis.

Conclusions: These data show that IIH is a metabolic disorder in which adipose tissue dysfunction is a feature of the disease. Managing IIH as a metabolic disease could reduce disease morbidity and improving cardiovascular outcomes.

Funding: This study was supported by the National Institute of Health Research UK (NIHR-CS-011-028), the Medical Research Council UK (MR/K015184/1) and the Midlands Neuroscience Teaching and Research Fund.
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http://dx.doi.org/10.1172/jci.insight.145346DOI Listing
April 2021

Thermodynamics and Dynamics of Supercritical Water Pseudo-Boiling.

Adv Sci (Weinh) 2021 Feb 16;8(3):2002312. Epub 2020 Dec 16.

Laboratory for Bioenergy and Catalysis (LBK) ENE Division Paul Scherrer Institute Villigen PSI 5232 Switzerland.

Supercritical fluid pseudo-boiling (PB), recently brought to the attention of the scientific community, is the phenomenon occurring when fluid changes its structure from liquid-like (LL) to gas-like (GL) states across the Widom line. This work provides the first quantitative analysis on the thermodynamics and the dynamics of water's PB, since the understanding of this phase transition is mandatory for the successful implementation of technologies using supercritical water (scHO) for environmental, energy, and nanomaterial applications. The study combines computational techniques with in situ neutron imaging measurements. The results demonstrate that, during isobaric heating close to the critical point, while water density drops by a factor of three in the PB transitional region, the system needs >16 times less energy to increase its temperature by 1 K than to change its structure from LL to GL phase. Above the PB-Widom line, the structure of LL water consists mainly of tetramers and trimers, while below the line mostly dimers and monomers form in the GL phase. At atomic level, the PB dynamics are similar to those of the subcritical water vaporization. This fundamental knowledge has great impact on water science, as it helps to establish the structure-properties relationship of scHO.
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http://dx.doi.org/10.1002/advs.202002312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856905PMC
February 2021

A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis.

iScience 2021 Jan 11;24(1):101931. Epub 2020 Dec 11.

University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh BioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.

Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent form of liver disease worldwide. This term encompasses a spectrum of pathologies, from benign hepatic steatosis to non-alcoholic steatohepatitis, which have, to date, been challenging to model in the laboratory setting. Here, we present a human pluripotent stem cell (hPSC)-derived model of hepatic steatosis, which overcomes inherent challenges of current models and provides insights into the metabolic rewiring associated with steatosis. Following induction of macrovesicular steatosis in hepatocyte-like cells using lactate, pyruvate, and octanoate (LPO), respirometry and transcriptomic analyses revealed compromised electron transport chain activity. C isotopic tracing studies revealed enhanced TCA cycle anaplerosis, with concomitant development of a compensatory purine nucleotide cycle shunt leading to excess generation of fumarate. This model of hepatic steatosis is reproducible, scalable, and overcomes the challenges of studying mitochondrial metabolism in currently available models.
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http://dx.doi.org/10.1016/j.isci.2020.101931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773967PMC
January 2021

Global 30-day outcomes after bariatric surgery during the COVID-19 pandemic (GENEVA): an international cohort study.

Lancet Diabetes Endocrinol 2021 01 27;9(1):7-9. Epub 2020 Nov 27.

Bariatric Unit, South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK.

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http://dx.doi.org/10.1016/S2213-8587(20)30375-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832244PMC
January 2021

Optimised collection of non-uniformly sampled 2D-HSQC NMR spectra for use in metabolic flux analysis.

Magn Reson Chem 2021 03 27;59(3):287-299. Epub 2020 Aug 27.

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Nuclear magnetic resonance (NMR) spectroscopy is integral to metabolic studies; yet, it can suffer from the long acquisition times required to collect data of sufficient signal strength and resolution. The use of non-uniform sampling (NUS) allows faster collection of NMR spectra without loss of spectral integrity. When planning experimental methodologies to perform metabolic flux analysis (MFA) of cell metabolism, a variety of options are available for the acquisition of NUS NMR data. Before beginning data collection, decisions have to be made regarding selection of pulse sequence, number of transients and NUS specific parameters such as the sampling level and sampling schedule. Poor choices will impact data quality, which may have a negative effect on the subsequent analysis and biological interpretation. Herein, we describe factors that should be considered when setting up non-uniformly sampled 2D- H, C HSQC NMR experiments for MFA and provide a standard protocol for users to follow.
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http://dx.doi.org/10.1002/mrc.5089DOI Listing
March 2021

In vivo [U-C]glucose labeling to assess heart metabolism in murine models of pressure and volume overload.

Am J Physiol Heart Circ Physiol 2020 08 10;319(2):H422-H431. Epub 2020 Jul 10.

King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, United Kingdom.

Alterations in the metabolism of substrates such as glucose are integrally linked to the structural and functional changes that occur in the remodeling heart. Assessment of such metabolic changes under in vivo conditions would provide important insights into this interrelationship. We aimed to investigate glucose carbon metabolism in pressure-overload and volume-overload cardiac hypertrophy by using an in vivo [U-C]glucose labeling strategy to enable analyses of the metabolic fates of glucose carbons in the mouse heart. Therefore, [U-C]glucose was administered in anesthetized mice by tail vein infusion, and the optimal duration of infusion was established. Hearts were then excised for C metabolite isotopomer analysis by NMR spectroscopy. [U-C]glucose infusions were performed in mice 2 wk following transverse aortic constriction (TAC) or aortocaval fistula (Shunt) surgery. At this time point, there were similar increases in left ventricular (LV) mass in both groups, but TAC resulted in concentric hypertrophy with impaired LV function, whereas Shunt caused eccentric hypertrophy with preserved LV function. TAC was accompanied by significant changes in glycolysis, mitochondrial oxidative metabolism, glucose metabolism to anaplerotic substrates, and de novo glutamine synthesis. In contrast to TAC, hardly any metabolic changes could be observed in the Shunt group. Taken together, in vivo [U-C]glucose labeling is a valuable method to investigate the fate of nutrients such as glucose in the remodeling heart. We find that concentric and eccentric cardiac remodeling are accompanied by distinct differences in glucose carbon metabolism. This study implemented a method for assessing the fate of glucose carbons in the heart in vivo and used this to demonstrate that pressure and volume overload are associated with distinct changes. In contrast to volume overload, pressure overload-induced changes affect the tricarboxylic acid cycle, glycolytic pathways, and glutamine synthesis. A better understanding of cardiac glucose metabolism under pathological conditions in vivo may provide new therapeutic strategies specific for different types of hemodynamic overload.
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http://dx.doi.org/10.1152/ajpheart.00219.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473922PMC
August 2020

Backbone resonance assignments of the catalytic and regulatory domains of Ca/calmodulin-dependent protein kinase 1D.

Biomol NMR Assign 2020 10 13;14(2):221-225. Epub 2020 Jun 13.

Department of Biochemistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.

The CaMK subfamily of Ser/Thr kinases are regulated by calmodulin interactions with their C-terminal regions. They are exemplified by Ca/calmodulin dependent protein kinase 1δ which is known as CaMK1D, CaMKIδ or CKLiK. CaMK1D mediates intracellular signalling downstream of Ca influx and thereby exhibits amplifications of Casignals and polymorphisms that have been implicated in breast cancer and diabetes. Here we report the backbone H, C, N assignments of the 38 kDa human CaMK1D protein in its free state, including both the canonical bi-lobed kinase fold as well as the autoinhibitory and calmodulin binding domains.
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http://dx.doi.org/10.1007/s12104-020-09950-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462902PMC
October 2020

The effect of sodium hydroxide on Al uptake by calcium silicate hydrates (CSH).

J Colloid Interface Sci 2020 Jul 20;572:246-256. Epub 2020 Mar 20.

École Polytechnique Fédéral de Lausanne (EPFL), ENAC IIE GR-LUD, CH-1015 Lausanne, Switzerland; Paul Scherrer Institute (PSI), ENE LBK CPM, 5232 Villigen PSI, Switzerland. Electronic address:

To reduce the CO emissions from cement production, Portland cement (PC) is partially replaced by supplementary cementitious materials (SCM). Reactions of SCM with PC during hydration leads to the formation of CSH with more silicon and aluminum than in PC, which affects the stability and durability of such concrete. Therefore, it is crucial to determine the role of aluminum on CSH properties to predict the formed hydrate phase assemblages and their effects on durability. Aluminum sorption isotherms including very low Al concentrations have been determined for CSH with Ca/Si ratios from 0.6 to 1.4. Elemental measurements were performed with ICP-MS and ICP-OES. The presence of secondary phases was investigated by using thermogravimetric analysis and XRD. Higher dissolved concentrations of Al were observed at increased alkali hydroxide concentrations and thus higher pH values. High alkali hydroxide led to an increased Al(OH) formation, which reduced the Al uptake in CSH. This comparable behavior of Al and Si towards changes in pH values, points toward the uptake of aluminum within the silica chain both at low and high Ca/Si ratios. A higher Al uptake in CSH was observed at higher Ca/Si ratios, which indicates a stabilizing effect of calcium in the interlayer on Al uptake.
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http://dx.doi.org/10.1016/j.jcis.2020.03.057DOI Listing
July 2020

Evaporation of Metals during the Thermal Treatment of Oxide Nanomaterials in Cellulose-Based Matrices.

Environ Sci Technol 2020 04 19;54(7):4504-4514. Epub 2020 Mar 19.

Bioenergy and Catalysis Laboratory (CPM-LBK), Energy and Environment Research Division (ENE), Paul Scherrer Institut (PSI), CH 5232 Villigen PSI, Switzerland.

Like conventional material products, waste is the last stage of the life cycle of engineered nanomaterials, which are then incinerated or stabilized before disposal. However, because of their special physical characteristics, the fate of the thermally treated nanomaterials may differ or not from the conventional ones. In this study the thermal release of metals from three nanomaterials, namely CuO, ZnO, and TiO, embedded in matrices containing organic and inorganic compounds was investigated by using an in-house developed setup. The latter, which combines a TGA (Thermogravimetric Analyzer) and an ICP-OES (Inductively Coupled Plasma Optical Emission Spectrometer), offers the possibility to gain simultaneously thermogravimetric and elemental information. It is shown that the matrix composition, such as chlorine and silicon, plays a key role in the evaporation of Cu and Zn at temperatures above 700 °C, while at relatively low temperatures (250 to 450 °C) the nanomaterials are most probably entrained in the flue gas independently of their chemical properties. Incineration experiments using a tubular furnace and subsequent ICP-MS (ICP Mass Spectrometry) analysis of the obtained residues allowed for quantification of the metal evaporation from the three nanomaterials.
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http://dx.doi.org/10.1021/acs.est.9b06359DOI Listing
April 2020

Brief O uploading during continuous hypothermic machine perfusion is simple yet effective oxygenation method to improve initial kidney function in a porcine autotransplant model.

Am J Transplant 2020 08 21;20(8):2030-2043. Epub 2020 Feb 21.

Surgery and Abdominal Transplant Unit, University Clinics Saint Luc, Université Catholique de Louvain, Brussels, Belgium.

With oxygenation proposed as a resuscitative measure during hypothermic models of preservation, the aim of this study was to evaluate the optimal start time of oxygenation during continuous hypothermic machine perfusion (HMP). In this porcine ischemia-reperfusion autotransplant model, the left kidney of a ±40 kg pig was exposed to 30 minutes of warm ischemia prior to 22 hours of HMP and autotransplantation. Kidneys were randomized to receive 2 hours of oxygenation during HMP either at the start (n = 6), or end of the perfusion (n = 5) and outcomes were compared to standard, nonoxygenated HMP (n = 6) and continuous oxygenated HMP (n = 8). The brief initial and continuous oxygenated HMP groups were associated with superior graft recovery compared to either standard, nonoxygenated HMP or kidneys oxygenated at the end of HMP. This correlated with significant metabolic differences in perfusate (eg, lactate, succinate, flavin mononucleotide) and tissues (eg, succinate, adenosine triphosphate, hypoxia-inducible factor-1α, nuclear factor erythroid 2-related factor 2) suggesting superior mitochondrial preservation with initial oxygenation. Brief initial O uploading during HMP at procurement site might be an easy and effective preservation strategy to maintain aerobic metabolism, protect mitochondria, and achieve an improved early renal graft function compared with standard HMP or oxygen supply shortly at the end of HMP preservation.
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http://dx.doi.org/10.1111/ajt.15800DOI Listing
August 2020

Real-Time Detection of Aerosol Metals Using Online Extractive Electrospray Ionization Mass Spectrometry.

Anal Chem 2020 01 26;92(1):1316-1325. Epub 2019 Dec 26.

Engineering (ENAC) , École Polytechnique Fédérale de Lausanne (EPFL) , CH 1015 Lausanne , Switzerland.

Metal emissions are of major environmental and practical concern because of their highly toxic effects on human health and ecosystems. Current technologies available in the market for their detection are typically limited by a time resolution of 1 h or longer (e.g., via semicontinuous X-ray fluorescence measurements) or are nonquantitative (e.g., laser ablation mass spectrometry). In this work, we report the development of a novel technique for the real-time detection and monitoring of metal particles in situ using an extractive electrospray ionization (EESI) source coupled to a high-resolution time-of-flight mass spectrometer (TOF-MS). The experiments were conducted in negative ionization mode using disodium ethylenediamine tetraacetic acid (EDTA) dihydrate to chelate with metals and form stable metal complexes. Results for water-soluble metal compounds were obtained. The following representative metal ions were examined: Pb, Cd, Zn, Ce (III), Ba, Ni, Fe(II), Fe(III), Cu(II), Cr, Mo, Co(II), Mg, Nd, Li, Ti, Ca, Cs, Ag, Tm, Er(III), La(III), Yb(III), Eu(III), Pr(III), Gd(III), Lu(III), Dy(III), Tb(III), Ho, and Ru(III). The results showed a very good linear mass response ( = 0.9983), low ng/m limits of detection (LoD), and a fast response time (1 s). The stability and repeatability of the developed EESI-TOF-MS were tested under complex dynamic and periodic experimental conditions, and negligible matrix effects were measured for internally and externally mixed metal particles. Benchmark testing against inductively coupled plasma-mass spectrometry (ICP-MS) was also performed, highlighting the online measurement capabilities of aerosol metals with a LoD lower than those of ICP-MS. Proof-of-concept ambient measurements were performed in New Delhi, India, and very promising results were obtained, allowing further exploitation elsewhere.
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http://dx.doi.org/10.1021/acs.analchem.9b04480DOI Listing
January 2020

Siloxane compounds in biogas from manure and mixed organic waste: Method development and speciation analysis with GC-ICP-MS.

Talanta 2020 Feb 2;208:120398. Epub 2019 Oct 2.

Bioenergy and Catalysis Laboratory (LBK), Energy and Environment Research Division (ENE), Paul Scherrer Institut (PSI), CH 5232, Villigen, PSI, Switzerland; Environmental Engineering Institute (IIE), School of Architecture, Civil and Environmental Engineering (ENAC), École Polytechnique Fédérale de Lausanne (EPFL), CH 1015, Lausanne, Switzerland. Electronic address:

A novel method for the determination of linear and cyclic siloxane compounds (L2, L3, D3, D4, D5, and D6) in biogas was developed by combining gas chromatography (GC) with inductively coupled plasma mass spectrometry (ICP-MS). Using a continuous liquid quench sampling system, biogas samples were collected from a Swiss biogas production plant processing manure and mixed organic wastes. Although significant concentrations of siloxanes are normally linked to biogas from wastewater treatment plants (WWTP) or landfill gas, manure and mixed organic waste samples also showed values in the range of 0.1 mg Nm, which would be particularly critical for appliances such as solid oxide fuel cells (SOFC). The GC-ICP-MS method showed very good linearity for all the investigated compounds (R between 0.999 and 1.000). The limits of detection and quantification (LOD and LOQ) in the gas for cyclic compounds, such as D5, vary based upon the used sampling conditions (approximate range of 0.002-0.004 mg Nm and 0.007-0.014 mg Nm, respectively). To the best of our knowledge, these LOD and LOQ values are by far among the lowest reported in literature and they satisfy the EURAMET (the European Association of National Metrology Institutes) requirements, which fix recommended levels for Si total amounts between 0.1 and 0.3 mg Nm for measurement in biogas or bio-methane. The GC-ICP-MS method was evaluated by comparing its performances with a flame ionization detector (FID), operated in parallel with ICP-MS, and with GC-MS (gas chromatography - mass spectrometry). The GC-FID showed higher detection limits and matrix effects than GC-ICP-MS. Nevertheless, it can still be suitable for an initial estimation of the siloxane compounds present in the biogas, at least for samples having relatively high concentration, by following some data treatment optimization. The GC-MS analyses were considered here as a further confirmation of the accuracy of the GC-ICP-MS results.
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http://dx.doi.org/10.1016/j.talanta.2019.120398DOI Listing
February 2020

Influence of Different Partial Pressures of Oxygen During Continuous Hypothermic Machine Perfusion in a Pig Kidney Ischemia-reperfusion Autotransplant Model.

Transplantation 2020 04;104(4):731-743

Department of Surgery, Surgery and Abdominal Transplant Unit, University Clinics Saint Luc, Université catholique de Louvain, Brussels, Belgium.

Background: The optimal perfusate partial pressure of oxygen (PO2) during hypothermic machine perfusion (HMP) is unknown. The aims of the study were to determine the functional, metabolic, structural, and flow dynamic effects of low and high perfusate PO2 during continuous HMP in a pig kidney ischemia-reperfusion autotransplant model.

Methods: The left kidneys of a ±40 kg pigs were exposed to 30 minutes of warm ischemia and randomized to receive 22-hour HMP with either low perfusate PO2 (30% oxygen, low oxygenated HMP [HMPO2]) (n = 8) or high perfusate PO2 (90% oxygen, HMPO2high) (n = 8), before autotransplantation. Kidneys stored in 22-hour standard HMP (n = 6) and 22-hour static cold storage (n = 6) conditions served as controls. The follow-up after autotransplantation was 13 days.

Results: High PO2 resulted in a 3- and 10-fold increase in perfusate PO2 compared with low HMPO2 and standard HMP, respectively. Both HMPO2 groups were associated with superior graft recovery compared with the control groups. Oxygenation was associated with a more rapid and sustained decrease in renal resistance. While there was no difference in functional outcomes between both HMPO2 groups, there were clear metabolic differences with an inverse correlation between oxygen provision and the concentration of major central metabolites in the perfusion fluid but no differences were observed by oxidative stress and metabolic evaluation on preimplantation biopsies.

Conclusions: While this animal study does not demonstrate any advantages for early graft function for high perfusate PO2, compared with low perfusate PO2, perfusate metabolic profile analysis suggests that aerobic mechanism is better supported under high perfusate PO2 conditions.
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http://dx.doi.org/10.1097/TP.0000000000003051DOI Listing
April 2020

Supercritical water anomalies in the vicinity of the Widom line.

Sci Rep 2019 Oct 31;9(1):15731. Epub 2019 Oct 31.

Laboratory for Scientific Computing and Modelling (LSM), NES Division, Paul Scherrer Institute, 5232, Villigen PSI, Switzerland.

Supercritical water is used in a variety of chemical and industrial applications. As a consequence, a detailed knowledge of the structure-properties correlations is of uttermost importance. Although supercritical water was considered as a homogeneous fluid, recent studies revealed an anomalous behaviour due to nanoscale density fluctuations (inhomogeneity). The inhomogeneity is clearly demarked through the Widom line (maxima in response factions) and drastically affect the properties. In the current study the physical properties of supercritical water have been determined by classical molecular dynamics simulations using a variety of polarized and polarizable interatomic potentials. Their validity which was not available at supercritical conditions has been assessed based on the ability to reproduce experimental data. Overall, the polarized TIP4P/2005 model accurately predicted the properties of water in both liquid-like and gas-like regions. All interatomic potentials captured the anomalous behaviour providing a direct evidence of molecular-scale inhomogeneity.
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http://dx.doi.org/10.1038/s41598-019-51843-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823507PMC
October 2019

Metabolic tracing reveals novel adaptations to skeletal muscle cell energy production pathways in response to NAD depletion.

Wellcome Open Res 2018 17;3:147. Epub 2019 Sep 17.

Institute of Metabolism and Systems Research, University of Birmingham, UK, Birmingham, B15 2TT, UK.

Skeletal muscle is central to whole body metabolic homeostasis, with age and disease impairing its ability to function appropriately to maintain health. Inadequate NAD availability is proposed to contribute to pathophysiology by impairing metabolic energy pathway use. Despite the importance of NAD as a vital redox cofactor in energy production pathways being well-established, the wider impact of disrupted NAD homeostasis on these pathways is unknown. We utilised skeletal muscle myotube models to induce NAD depletion, repletion and excess and conducted metabolic tracing to provide comprehensive and detailed analysis of the consequences of altered NAD metabolism on central carbon metabolic pathways. We used stable isotope tracers, [1,2-13C] D-glucose and [U- C] glutamine, and conducted combined 2D-1H,13C-heteronuclear single quantum coherence (HSQC) NMR spectroscopy and GC-MS analysis. NAD excess driven by nicotinamide riboside (NR) supplementation within skeletal muscle cells resulted in enhanced nicotinamide clearance, but had no effect on energy homeostasis or central carbon metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) inhibition induced NAD depletion and resulted in equilibration of metabolites upstream of glyceraldehyde phosphate dehydrogenase (GAPDH). Aspartate production through glycolysis and TCA cycle activity was increased in response to low NAD , which was rapidly reversed with repletion of the NAD pool using NR. NAD depletion reversibly inhibits cytosolic GAPDH activity, but retains mitochondrial oxidative metabolism, suggesting differential effects of this treatment on sub-cellular pyridine pools. When supplemented, NR efficiently reversed these metabolic consequences. However, the functional relevance of increased aspartate levels after NAD depletion remains unclear, and requires further investigation. These data highlight the need to consider carbon metabolism and clearance pathways when investigating NAD precursor usage in models of skeletal muscle physiology.
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http://dx.doi.org/10.12688/wellcomeopenres.14898.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305244PMC
September 2019

Visualization of supercritical water pseudo-boiling at Widom line crossover.

Nat Commun 2019 Sep 17;10(1):4114. Epub 2019 Sep 17.

Laboratory for Bioenergy and Catalysis (LBK), ENE Division, Paul Scherrer Institute, 5232, Villigen PSI, Switzerland.

Supercritical water is a green solvent used in many technological applications including materials synthesis, nuclear engineering, bioenergy, or waste treatment and it occurs in nature. Despite its relevance in natural systems and technical applications, the supercritical state of water is still not well understood. Recent theories predict that liquid-like (LL) and gas-like (GL) supercritical water are metastable phases, and that the so-called Widom line zone is marking the crossover between LL and GL behavior of water. With neutron imaging techniques, we succeed to monitor density fluctuations of supercritical water while the system evolves rapidly from LL to GL as the Widom line is crossed during isobaric heating. Our observations show that the Widom line of water can be identified experimentally and they are in agreement with the current theory of supercritical fluid pseudo-boiling. This fundamental understanding allows optimizing and developing new technologies using supercritical water as a solvent.
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http://dx.doi.org/10.1038/s41467-019-12117-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748934PMC
September 2019

Detecting acetylated aminoacids in blood serum using hyperpolarized C-Η-2D-NMR.

J Magn Reson 2019 08 5;305:175-179. Epub 2019 Jul 5.

HWB-NMR, University of Birmingham, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. Electronic address:

Dynamic Nuclear Polarization (DNP) can substantially enhance the sensitivity of NMR experiments. Among the implementations of DNP, ex-situ dissolution DNP (dDNP) achieves high signal enhancement levels owing to a combination of a large temperature factor between 1.4 and 300 K with the actual DNP effect in the solid state at 1.4 K. For sufficiently long T relaxation times much of the polarization can be preserved during dissolution with hot solvent, thus enabling fast experiments during the life time of the polarization. Unfortunately, for many metabolites found in biological samples such as blood, relaxation times are too short to achieve a significant enhancement. We have therefore introduced C-carbonyl labeled acetyl groups as probes into amino acid metabolites using a simple reaction protocol. The advantage of such tags is a sufficiently long T relaxation time, the possibility to enhance signal intensity by introducing C, and the possibility to identify tagged metabolites in NMR spectra. We demonstrate feasibility for mixtures of amino acids and for blood serum. In two-dimensional dDNP-enhanced HMQC experiments of these samples acquired in 8 s we can identify acetylated amino acids and other metabolites based on small differences in chemical shifts.
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http://dx.doi.org/10.1016/j.jmr.2019.07.003DOI Listing
August 2019

Mechanical factors in the prediction of integrity of the gastrojejunal anastomosis in ex-vivo RYGB models.

Surg Obes Relat Dis 2019 Jun 22;15(6):887-893. Epub 2019 Mar 22.

Bariatric Unit, Birmingham Heartlands Hospital, University Hospitals Birmingham, Birmingham, United Kingdom.

Background: Surgical staplers represent one of the important instruments in modern surgery. Laparoscopic Roux-en-Y gastric bypass is one of the most commonly performed bariatric procedures. Various techniques have been described for performing gastrojejunal (GJ) anastomosis, including linear stapled anastomosis (LSA), circular stapled anastomosis (CSA) and hand-sewn anastomosis (HSA).

Objectives: An ex-vivo porcine-based experiment was designed to compare the mechanical integrity of the GJ anastomosis among the 3 different techniques by measuring burst pressure (BP).

Setting: Laboratory-based study conducted at the clinical skills laboratory at Birmingham Heartlands Hospitals, Birmingham, United Kingdom.

Methods: Porcine stomachs and small bowels were used to create a GJ model. Four GJ anastomosis models each were created using circular stapler (CSA group) and hand-sewn techniques (HSA group). Stomach and small bowel thickness were recorded. BP was measured by sequential injections of methylene-blue diluted saline until a leak was detected. Total volume until leak is recorded. Compliance (C) was calculated using the formula C = ΔP/ΔV.

Results: Results from our previous experiment for the LSA group are included. One model was excluded from the CSA and the HSA groups due to technical errors. Results were presented as mean ± standard deviation. Total volume in LSA, CSA, and HSA groups was 60 ± 4.08 mL, 73.67 ± 3.22 mL, and 51.67 ± 20.21 mL, respectively. BP in LSA, CSA, and HSA groups was 18 ± 4.69 mm Hg, 20.33 ± 5.77 mm Hg, and 9.67 ± 3.79 mm Hg, respectively. There was a statistically significant difference in BP among the 3 groups (P = .033; Kruskal-Wallis test). C in LSA, CSA, and HSA were 3.50 ± .88 mm Hg/mL, 3.78 ± .85 mm Hg/mL, and 5.39 ± 1.34 mm Hg/mL, respectively (P = .064).

Conclusion: BP was higher in CSA and LSA groups compared with the HSA group, suggesting a mechanically stronger anastomosis. Despite the lack of statistical significance, higher BP recorded in the CSA group than in the LSA group suggests better anastomotic integrity.
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http://dx.doi.org/10.1016/j.soard.2019.03.007DOI Listing
June 2019

PhenoMeNal: processing and analysis of metabolomics data in the cloud.

Gigascience 2019 02;8(2)

Cheminformatics and Computational Metabolomics, Institute for Analytical Chemistry, Lessingstr. 8, 07743 Jena, Germany.

Background: Metabolomics is the comprehensive study of a multitude of small molecules to gain insight into an organism's metabolism. The research field is dynamic and expanding with applications across biomedical, biotechnological, and many other applied biological domains. Its computationally intensive nature has driven requirements for open data formats, data repositories, and data analysis tools. However, the rapid progress has resulted in a mosaic of independent, and sometimes incompatible, analysis methods that are difficult to connect into a useful and complete data analysis solution.

Findings: PhenoMeNal (Phenome and Metabolome aNalysis) is an advanced and complete solution to set up Infrastructure-as-a-Service (IaaS) that brings workflow-oriented, interoperable metabolomics data analysis platforms into the cloud. PhenoMeNal seamlessly integrates a wide array of existing open-source tools that are tested and packaged as Docker containers through the project's continuous integration process and deployed based on a kubernetes orchestration framework. It also provides a number of standardized, automated, and published analysis workflows in the user interfaces Galaxy, Jupyter, Luigi, and Pachyderm.

Conclusions: PhenoMeNal constitutes a keystone solution in cloud e-infrastructures available for metabolomics. PhenoMeNal is a unique and complete solution for setting up cloud e-infrastructures through easy-to-use web interfaces that can be scaled to any custom public and private cloud environment. By harmonizing and automating software installation and configuration and through ready-to-use scientific workflow user interfaces, PhenoMeNal has succeeded in providing scientists with workflow-driven, reproducible, and shareable metabolomics data analysis platforms that are interfaced through standard data formats, representative datasets, versioned, and have been tested for reproducibility and interoperability. The elastic implementation of PhenoMeNal further allows easy adaptation of the infrastructure to other application areas and 'omics research domains.
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http://dx.doi.org/10.1093/gigascience/giy149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377398PMC
February 2019

The Effects of Oxygenation on Ex Vivo Kidneys Undergoing Hypothermic Machine Perfusion.

Transplantation 2019 02;103(2):314-322

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Background: Supplemental oxygenation of the standard hypothermic machine perfusion (HMP) circuit has the potential to invoke favorable changes in metabolism, optimizing cadaveric organs before transplantation.

Methods: Eight pairs of porcine kidneys underwent 18 hours of either oxygenated (HMP/O2) or aerated (HMP/Air) HMP in a paired donation after circulatory death model of transplantation. Circulating perfusion fluid was supplemented with the metabolic tracer universally labeled glucose.Perfusate, end-point renal cortex, and medulla samples underwent metabolomic analysis using 1-dimension and 2-dimension nuclear magnetic resonance experiments in addition to gas chromatography-mass spectrometry. Analysis of C-labeled metabolic products was combined with adenosine nucleotide levels and differences in tissue architecture.

Results: Metabolomic analysis revealed significantly higher concentrations of universally labeled lactate in the cortex of HMP/Air versus HMP/O2 kidneys (0.056 mM vs 0.026 mM, P < 0.05). Conversely, newly synthesized [4,5-C] glutamate concentrations were higher in the cortex of HMP/O2 kidneys inferring relative increases in tricarboxylic acid cycle activity versus HMP/Air kidneys (0.013 mmol/L vs 0.003 mmol/L, P < 0.05). This was associated with greater amounts of adenoside triphosphate in the cortex HMP/O2 versus HMP/Air kidneys (19.8 mmol/mg protein vs 2.8 mmol/mg protein, P < 0.05). Improved flow dynamics and favorable ultrastructural features were also observed in HMP/O2 kidneys. There were no differences in thiobarbituric acid reactive substances and reduced glutathione levels, tissue markers of oxidative stress, between groups.

Conclusions: The supplementation of perfusion fluid with high-concentration oxygen (95%) results in a greater degree of aerobic metabolism versus aeration (21%) in the nonphysiological environment of HMP, with reciprocal changes in adenoside triphosphate levels.
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http://dx.doi.org/10.1097/TP.0000000000002542DOI Listing
February 2019

Rationalisation of a mechanism for sensing single point variants in target DNA using anthracene-tagged base discriminating probes.

Org Biomol Chem 2018 09;16(35):6576-6585

School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

The labelling of DNA oligonucleotides with signalling groups that give a unique response to duplex formation depending on the target sequence is a highly effective strategy in the design of DNA-based hybridisation sensors. A key challenge in the design of these so-called base discriminating probes (BDPs) is to understand how the local environment of the signalling group affects the sensing response. The work herein describes a comprehensive study involving a variety of photophysical techniques, NMR studies and molecular dynamics simulations, on anthracene-tagged oligonucleotide probes that can sense single base changes (point variants) in target DNA strands. A detailed analysis of the fluorescence sensing mechanism is provided, with a particular focus on rationalising the high dependence of this process on not only the linker stereochemistry but also the site of nucleobase variation within the target strand. The work highlights the various factors and techniques used to respectively underpin and rationalise the BDP approach to point variant sensing, which relies on different responses to duplex formation rather than different duplex binding strengths.
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http://dx.doi.org/10.1039/c8ob01710gDOI Listing
September 2018

Formation and transformation of calcium phosphate phases under biologically relevant conditions: Experiments and modelling.

Acta Biomater 2018 07 18;74:478-488. Epub 2018 May 18.

Paul Scherrer Institut (PSI), ENE, CH-5232 Villigen PSI, Switzerland. Electronic address:

The experimental data on calcium phosphates formation were collected in dilute solution at constant pH (7.40) and temperature (37.0 °C) at different levels of ionic strength (IS). The evolution of the solid phase formation is described in detail using a thermodynamic-kinetic model. The thermodynamic model takes into account all relevant chemical species as well as Posner's clusters; the kinetic model, based on the discretized population balance approach, accounts for the solid formation from solution. The experimental data are consistent with an initial formation of dicalcium phosphate dihydrate (DCPD, brushite), which dominates the nucleation rate, and its rapid transformation into octacalcium phosphate (OCP) or hydroxyapatite (HA), which dominates the growth rate. Depending on the experimental conditions and, including the influence of the IS level, OCP may be further transformed into apatite. The classical nucleation theory is able to describe the experimental results very well and the solid phase growth is limited by the diffusion of Ca ions. The precipitation pathway described by a complete thermodynamic-kinetic model is expected to contribute to the understating of the in vivo osteogenesis.

Statement Of Significance: The formation mechanism of calcium phosphates under biomimetic conditions is unraveled. The formation pathway is mathematically described based on a thermodynamic-kinetic model in which (i) the nucleation stages (primary and secondary) are dominated by the formation of dicalcium phosphate dihydrate (DCPD) and (ii) the fast growth stage is limited by the diffusion of Ca ions under the driving force of octacalcium phosphate (OCP), or hydroxyapatite (HA), solubility. The obtained solid phase seems correlated to the activity coefficient of phosphate ions, thus to the ionic strength and local phosphate speciation. The model, being able to highlight the details of the precipitation pathway, is expected to contribute to the understanding of the apatitic phase formation in the biomineralization-biodemineralization processes under in-vivo conditions.
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http://dx.doi.org/10.1016/j.actbio.2018.05.027DOI Listing
July 2018

Roux-en-Y Gastric Bypass: Does the Direction of Staples Matter?

Obes Surg 2018 09;28(9):2868-2873

General Surgery Department, Heartlands Hospital, Birmingham, UK.

Purpose: Mechanical gastro-intestinal anastomosis using stapler is a critical step in laparoscopic Roux-en-Y gastric bypass (RYGB). To date the effect of the direction of staples on anastomotic leak has not been investigated. The study aim was to investigate the impact of the direction of staples on the integrity of the gastro-jejunal anastomosis.

Materials And Methods: Eight gastro-jejunostomy (GJ) models were performed using porcine stomach and small intestine. Specimens were divided into group A where the cartridge was in the gastric lumen with the anvil in the jejunal lumen and vice versa in group B. Enterotomy was closed and gastric and jejunal ends were stapled off. Burst pressure (BP) was measured by infusion of methylene blue saline into the GJ model until leak occurred. Site of leak, BP, and total volume (TV) infused were recorded. Compliance (C) was calculated from the equation ΔTV/ΔBP.

Results: The BP was greater in group A compared to group B (18 mmHg (range 15-25) versus 11 mmHg (range 8-15); p = 0.045) despite similar TV between the groups 60.00 mL (range 55.00-65.00) versus 51.25 mL (range 40.00-60.00); p = 0.11). The compliance did not significantly differ between groups A and B (6.38 mL/mmHg (range 4.34-8.59) versus 5.61 mL/mmHg (range 3.93-7.21); p = 0.48).

Conclusion: BP recorded when the stapler cartridge was introduced in the gastric lumen was higher than when it was introduced from the jejunal lumen. The lack of difference in compliance between groups suggests that the difference in BP was due to the difference in the direction of staples.
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http://dx.doi.org/10.1007/s11695-018-3275-zDOI Listing
September 2018

Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis.

Cell Rep 2018 03;22(12):3107-3114

Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address:

Since the discovery of mutations in isocitrate dehydrogenase 1 (IDH1) in gliomas and other tumors, significant efforts have been made to gain a deeper understanding of the consequences of this oncogenic mutation. One aspect of the neomorphic function of the IDH1 R132H enzyme that has received less attention is the perturbation of cellular redox homeostasis. Here, we describe a biosynthetic pathway exhibited by cells expressing mutant IDH1. By virtue of a change in cellular redox homeostasis, IDH1-mutated cells synthesize excess glutamine-derived proline through enhanced activity of pyrroline 5-carboxylate reductase 1 (PYCR1), coupled to NADH oxidation. Enhanced proline biosynthesis partially uncouples the electron transport chain from tricarboxylic acid (TCA) cycle activity through the maintenance of a lower NADH/NAD ratio and subsequent reduction in oxygen consumption. Thus, we have uncovered a mechanism by which tumor cell survival may be promoted in conditions associated with perturbed redox homeostasis, as occurs in IDH1-mutated glioma.
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http://dx.doi.org/10.1016/j.celrep.2018.02.084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883319PMC
March 2018

High-Speed Tracer Analysis of Metabolism (HS-TrAM).

Wellcome Open Res 2018 12;3. Epub 2018 Jan 12.

Institute of Metabolism and Systems Research, University of Birmingham, West Midlands, UK.

Tracing the fate of stable isotopically-enriched nutrients is a sophisticated method of describing and quantifying the activity of metabolic pathways. Nuclear Magnetic Resonance (NMR) offers high resolution data, yet is under-utilised due to length of time required to collect the data, quantification requiring multiple samples and complicated analysis. Here we present two techniques, quantitative spectral filters and enhancement of the splitting due to J-coupling in H, C-HSQC NMR spectra, which allow the rapid collection of NMR data in a quantitative manner on a single sample. The reduced duration of HSQC spectra data acquisition opens up the possibility of real-time tracing of metabolism including the study of metabolic pathways . We show how these novel techniques can be used to trace the fate of labelled nutrients in a whole organ model of kidney preservation prior to transplantation using a porcine kidney as a model organ, and also show how the use of multiple nutrients, differentially labelled with C and N, can be used to provide additional information with which to profile metabolic pathways.
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http://dx.doi.org/10.12688/wellcomeopenres.13387.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811808PMC
January 2018

Emissions of Secondary Formed ZnO Nano-Objects from the Combustion of Impregnated Wood. An Online Size-Resolved Elemental Investigation.

Environ Sci Technol 2018 01 4;52(2):895-903. Epub 2018 Jan 4.

Environmental Engineering Institute (IIE), School of Architecture, Civil and Environmental Engineering (ENAC), École Polytechnique Fédérale de Lausanne (EPFL) , CH 1015 Lausanne, Switzerland.

The release of secondary nano-objects formed during waste combustion processes is becoming a matter of concern, considering their known toxicity and the fact that the 100% efficiency of filtering systems is not always ensured. An increased cytotoxicity and genotoxicity on human peripheral blood lymphocytes is known particularly in the case of ZnO, which is often contained in paints and waterproof agents, heading to a relevant quantity present in the waste wood material. In this study, the behavior of ZnO nanoparticles during wood combustion and the effect of the reduction potential of generated carbon species on the release of secondarily formed ZnO-containing nano-objects were investigated. By hyphenating a modified scanning mobility particle sizer (SMPS) and inductively coupled mass spectrometry (ICP-MS), it was possible to obtain simultaneously size-resolved and chemical information on the emitted nanoparticles. Through the established correlation between SMPS and ICP-MS signals, Zn-containing particles were efficiently resolved from the combustion generated particles. Transmission electron microscopy (TEM) and energy-dispersive X-ray spectroscopy (EDS) on size-selected particles confirmed the SMPS and ICP-MS data. The use of electron diffraction allowed determining the structure of the crystalline materials as hexagonal ZnO. A possible mechanism of reduction of ZnO to Zn and further reformation as secondary nano-objects is proposed.
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http://dx.doi.org/10.1021/acs.est.7b03584DOI Listing
January 2018

nmrML: A Community Supported Open Data Standard for the Description, Storage, and Exchange of NMR Data.

Anal Chem 2018 01 14;90(1):649-656. Epub 2017 Dec 14.

Leibniz Institute of Plant Biochemistry , Department of Stress and Developmental Biology, Weinberg 3, 06120 Halle, Germany.

NMR is a widely used analytical technique with a growing number of repositories available. As a result, demands for a vendor-agnostic, open data format for long-term archiving of NMR data have emerged with the aim to ease and encourage sharing, comparison, and reuse of NMR data. Here we present nmrML, an open XML-based exchange and storage format for NMR spectral data. The nmrML format is intended to be fully compatible with existing NMR data for chemical, biochemical, and metabolomics experiments. nmrML can capture raw NMR data, spectral data acquisition parameters, and where available spectral metadata, such as chemical structures associated with spectral assignments. The nmrML format is compatible with pure-compound NMR data for reference spectral libraries as well as NMR data from complex biomixtures, i.e., metabolomics experiments. To facilitate format conversions, we provide nmrML converters for Bruker, JEOL and Agilent/Varian vendor formats. In addition, easy-to-use Web-based spectral viewing, processing, and spectral assignment tools that read and write nmrML have been developed. Software libraries and Web services for data validation are available for tool developers and end-users. The nmrML format has already been adopted for capturing and disseminating NMR data for small molecules by several open source data processing tools and metabolomics reference spectral libraries, e.g., serving as storage format for the MetaboLights data repository. The nmrML open access data standard has been endorsed by the Metabolomics Standards Initiative (MSI), and we here encourage user participation and feedback to increase usability and make it a successful standard.
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http://dx.doi.org/10.1021/acs.analchem.7b02795DOI Listing
January 2018

A Practical Guide on Coupling a Scanning Mobility Sizer and Inductively Coupled Plasma Mass Spectrometer (SMPS-ICPMS).

J Vis Exp 2017 07 11(125). Epub 2017 Jul 11.

Bioenergy and Catalysis Laboratory (LBK), Energy and Environment Research Division (ENE), Paul Scherrer Institute; Environmental Engineering Institute (IIE), School of Architecture, Civil and Environmental Engineering (ENAC), École; Polytechnique Fédérale de Lausanne (EPFL).

A large variety of analytical methods are available to characterize particles in aerosols and suspensions. The choice of the appropriate technique depends on the properties to be determined. In many fields information about particle size and chemical composition are of great importance. While in aerosol techniques particle size distributions of gas-borne particles are determined online, their elemental composition is commonly analyzed offline after an appropriate sampling and preparation procedure. To obtain both types of information online and simultaneously, a hyphenated setup was recently developed, including a Scanning Mobility Particle Sizer (SMPS) and an Inductively Coupled Plasma Mass Spectrometer (ICPMS). This allows first to classify the particles with respect to their mobility diameter, and then to determine their number concentration and elemental composition in parallel. A Rotating Disk Diluter (RDD) is used as the introduction system, giving more flexibility regarding the use of different aerosol sources. In this work, a practical guide is provided describing the different steps for establishing this instrumentation, and how to use this analysis tool. The versatility of this hyphenated technique is demonstrated in example measurements on three different aerosols generated out of a) a salt solution, b) a suspension, and c) emitted by a thermal process.
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http://dx.doi.org/10.3791/55487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612223PMC
July 2017

Dopant-Free Hole-Transporting Materials for Stable and Efficient Perovskite Solar Cells.

Adv Mater 2017 Sep 17;29(35). Epub 2017 Jul 17.

Group for Molecular Engineering of Functional Materials, École Polytechnique Fédérale de Lausanne, CH-1951, Sion, Switzerland.

Molecularly engineered novel dopant-free hole-transporting materials for perovskite solar cells (PSCs) combined with mixed-perovskite (FAPbI ) (MAPbBr ) (MA: CH NH , FA: NH=CHNH ) that exhibit an excellent power conversion efficiency of 18.9% under AM 1.5 conditions are investigated. The mobilities of FA-CN, and TPA-CN are determined to be 1.2 × 10 cm V s and 1.1 × 10 cm V s , respectively. Exceptional stability up to 500 h is measured with the PSC based on FA-CN. Additionally, it is found that the maximum power output collected after 1300 h remained 65% of its initial value. This opens up new avenue for efficient and stable PSCs exploring new materials as alternatives to Spiro-OMeTAD.
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http://dx.doi.org/10.1002/adma.201606555DOI Listing
September 2017

Iron phosphate nanoparticles for food fortification: Biological effects in rats and human cell lines.

Nanotoxicology 2017 May 20;11(4):496-506. Epub 2017 Apr 20.

a Department of Health Sciences and Technology , ETH Zürich , Switzerland.

Nanotechnology offers new opportunities for providing health benefits in foods. Food fortification with iron phosphate nanoparticles (FePO NPs) is a promising new approach to reducing iron deficiency because FePO NPs combine high bioavailability with superior sensory performance in difficult to fortify foods. However, their safety remains largely untested. We fed rats for 90 days diets containing FePO NPs at doses at which iron sulfate (FeSO), a commonly used food fortificant, has been shown to induce adverse effects. Feeding did not result in signs of toxicity, including oxidative stress, organ damage, excess iron accumulation in organs or histological changes. These safety data were corroborated by evidence that NPs were taken up by human gastrointestinal cell lines without reducing cell viability or inducing oxidative stress. Our findings suggest FePO NPs appear to be as safe for ingestion as FeSO.
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http://dx.doi.org/10.1080/17435390.2017.1314035DOI Listing
May 2017