42 research outputs found

    'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'

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    Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure

    CPT correlations for thermal properties of soils

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    Obtaining in situ thermal properties of soils is often difficult and time-consuming. Here, cone penetration test (CPT) correlations are proposed and validated for thermal properties of saturated ground, i.e. thermal conductivity and volumetric heat capacity, giving continuous profiles of the parameters, in a substantially reduced time. The proposed correlations utilise the characteristics of existing CPT correlations. The volumetric heat capacity correlations show good agreement with laboratory hot disc tests, and the thermal conductivity correlations proved successful for a range of soil types, including organic soils, clays and sands, although with a reasonable scatter. Empirical adjustment was required for the thermal conductivity of soils showing high (normalised) cone resistance. Utilising thermal CPT (T-CPT)-derived thermal conductivity point values in conjunction with the thermal conductivity correlations offers accurate and continuous site-specific profiles.Geo-engineerin

    Interpreting and validating the thermal cone penetration test (T-CPT)

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    The thermal cone penetration test (T-CPT) allows in situ measurement of the thermal properties of soil during a CPT-that is without withdrawing the CPT tool and introducing another tool such as a thermal needle probe. An interpretation method is presented based on one-dimensional axisymmetric analytical solutions. Numerical verification of the method is given and numerical simulations are presented to derive a calibration factor required for the interpretation model. This factor accounts for the temperature sensor location and two-dimensional geometric effects, particularly internal voids and end effects for the cone penetrometer. Finally field data are presented for the T-CPT and compared with results from in situ needle probe tests and laboratory tests on sampled material. The interpretation model is able to provide thermal conductivity values robustly.Geo-engineerin

    Example calculation sheet for Thermal Cone Penetration Test (T-CPT)

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    This is an example calculation sheet for the Thermal Cone Penetration Test (T-CPT), based on the paper tentatively recommended for publication on 22 May 2018: Journal: Geotechnique; Article number: 17-P-214R1; Title: Interpreting and validating the Thermal Cone Penetration Test (T-CPT); Author(s): Philip J Vardon, Dimitris Baltoukas, Joek Peuche

    CPT based unit weight estimation extended to soft organic soils and peat

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    A reliable estimate of the saturated soil weight from CPT analysis can be useful for various purposes. An often used relation that gives a reasonable first approximation is presented by Robertson & Cabal (2010). In The Netherlands very soft and highly organic soils are omnipresent and these types of soil are absent in the aforementioned relation. In this paper a new relation is proposed that can be used to estimate the saturated soil unit weight for a wider range of soils, from sands to highly organic soils

    Surface-Confined Aqueous Reversible Addition–Fragmentation Chain Transfer (SCARAFT) Polymerization Method for Preparation of Coated Capillary Leads to over 10 000 Peptides Identified from 25 ng HeLa Digest by Using Capillary Zone Electrophoresis-Tandem Mass Spectrometry

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    A surface-confined aqueous reversible addition–fragmentation chain transfer (SCARAFT) polymerization method was developed to coat capillaries for use in capillary zone electrophoresis (CZE). SCARAFT polymerization primarily takes place on the inner surface of the capillary instead of in solution, which greatly improves the homogeneity of the coating. Capillaries treated with this coating produced an electroosmotic mobility of 2.8 ± 0.2 × 10<sup>–6</sup> cm<sup>2</sup>·V<sup>–1</sup>·s<sup>–1</sup> (<i>N</i> = 3), which is roughly an order of magnitude lower than that of commercial linear polyacrylamide (LPA)-coated capillaries. Coated capillaries were evaluated for bottom-up proteomic analysis using CZE. The very low electroosmotic mobility results in a 200 min separation and improved single-shot analysis. An average of 977 protein groups and 5605 unique peptides were identified from 50 ng of an E. coli digest, and 2158 protein groups and 10 005 peptides were identified from 25 ng of a HeLa digest using single-shot analysis with a SCARAFT-acrylamide capillary coupled to a Q Exactive HF mass spectrometer. The coating is stable. A single capillary was used for over 200 h (8.4 days) of continuous operation. RSD in migration time was between 2 and 3% for selected ion electropherograms (SIEs) generated for six ions; median theoretical plate counts ranged from 240 000 to 600 000 for these SIEs. Various types of coatings could be prepared by simply changing the functional vinyl monomers in the polymerization mixture. Positively charged coatings using direct attachment and formation of a block copolymer were prepared and demonstrated for the separation of mixtures of intact proteins

    CPT based settlement prediction of shallow footings on granular soils

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    Van Oord DMC executed a large land reclamation project, where requirements had to be met concerning the settlement of shallow foundations to be placed on the sand fill. CPT based settlement predictions performed in the design phase had to be verified with zone load testing. After completing the project, all measurement data were analysed to gain insight into the accuracy of existing correlations between CPT data and settlement of a sand fill. The correlations by De Beer &amp; Martens (1957), Schmertmann (1978), Peck et al. (1996) and Robertson (1990) were considered. From the total number of zone load tests, 43 test were selected which allowed for comparison of the results with the predictions using the mentioned correlations. It was concluded that the CPT to stiffness correlation of Robertson combined with the analytical model of Schmertmann corresponds very well with the measurements, consistently showing only small deviations from the measured settlement

    A probabilistic tool for geotechnical assessment of Jack-Up leg penetration

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    Prediction of jack-up leg penetration behaviour requires assessment of uncertainties in calculation models and their input parameter values, including quality and extent of site investigation information. Commonly, uncertainty assessment is achieved by sensitivity analysis. This publication presents a probabilistic tool (JURIG4) for more rigorous prediction of jack-up leg penetration behaviour, as an add-on for conventional SNAME (2002) calculation methods. JURIG4 allows systematic input of expected variability of the important input parameters: (1) soil layer thickness, (2) trends in clay strength versus depth, (3) angle of internal friction of sand, (4) submerged unit weight and (5) lateral continuity of soil characteristics. Probabilistic calculations are performed by Monte Carlo simulation. Important output consists of probability of punch-through failure for any of the legs, as a function of distance between the geotechnical borehole and the leg. Probability density functions are provided for leg penetration and leg plunge in case of punch-through conditions
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