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Lost in translocation: the functions of the 18-kD translocator protein
No full textResearch spanning nearly four decades has assigned to the translocator protein (18 kDa) (TSPO) a critical role, among others, in the mitochondrial import of cholesterol, the subsequent steps of (neuro)steroid production, and systemic endocrine regulation, with implications for the pathophysiology of immune, inflammatory, neurodegenerative, and psychiatric as well as neoplastic diseases. Recent knockout studies in mice unexpectedly report normal or latent phenotypes, raising doubts about the protein's role in steroidogenesis and other previously postulated functions and challenging the validity of earlier data on the selectivity of TSPO-binding drugs. Here we provide a synthesis of the current debate from a structural and molecular biology perspective, discuss the limits of inference in loss-of-function (gene knockout) studies, and suggest new functions of TSPO. © 2015 Elsevier Inc
Defect evolution in a NiMoCrFe alloy subjected to high-dose Kr ion irradiation at elevated temperature
No full textA candidate NiMoCrFe alloy (GH3535) for application as a structural material in a molten salt nuclear reactor was irradiated with 1 MeV Kr2+ ions (723 K, max dose of 100 dpa) at the IVEM-Tandem facility. The evolution of defects like dislocation loops and vacancy- and self-interstitial clusters was examined in-situ. For obtaining a deeper insight into the true nature of these defects, the irradiated sample was further analysed under a TEM post-facto. The results show that there is a range of different types of defects formed under irradiation. Interaction of radiation defects with each other and with pre-existing defects, e.g., linear dislocations, leads to the formation of complex microstructures. Molecular dynamics simulations used to obtain a greater understanding of these defect transformations showed that the interaction between linear dislocations and radiation induced dislocation loops could form faulted structures that explain the fringed contrast of these defects observed in TEM. © 2016 Elsevier B.V
Mitigating cutting-induced plasticity in the contour method, part 1: Experimental
No full textApplication of the contour method for the measurement of weld residual stresses (WRS) is prone to inaccuracy due to plastic deformation resulting from the redistribution of typically high (close to yield) WRS during the cutting process. The current work, seeks ways to mitigate cutting-induced plasticity by controlling stress redistribution through optimisation of the contour cutting configuration. The idea of using a stress-informed fracture mechanics approach to find the optimal cutting configuration is introduced. The level of plasticity associated with different cutting configurations is then assessed, allowing control of the location and magnitude of cutting-induced plasticity to occur during the cutting process. A conventional edge-crack cutting configuration is compared with a proposed double-embedded cutting configuration by measuring the longitudinal WRS in two three-pass slot weld specimens (NeT TG4) produced using identical weld procedures. The experimental results show that a novel double-embedded cutting configuration leads to greater accuracy in WRS measurements relative to conventional edge-crack cutting configurations at the expense of higher levels of plasticity being introduced local to small ligaments. © 2016 Published by Elsevier Ltd
Hierarchical multivariate covariance analysis of metabolic connectivity
No full textConventional brain connectivity analysis is typically based on the assessment of interregional correlations. Given that correlation coefficients are derived from both covariance and variance, group differences in covariance may be obscured by differences in the variance terms. To facilitate a comprehensive assessment of connectivity, we propose a unified statistical framework that interrogates the individual terms of the correlation coefficient. We have evaluated the utility of this method for metabolic connectivity analysis using [18F]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. As an illustrative example of the utility of this approach, we examined metabolic connectivity in angular gyrus and precuneus seed regions of mild cognitive impairment (MCI) subjects with low and high β-amyloid burdens. This new multivariate method allowed us to identify alterations in the metabolic connectome, which would not have been detected using classic seed-based correlation analysis. Ultimately, this novel approach should be extensible to brain network analysis and broadly applicable to other imaging modalities, such as functional magnetic resonance imaging (MRI).© 2014,SAGE Publication
Microfluidics in radiopharmaceutical chemistry
No full textThe increased demand for molecular imaging tracers useful in assessing and monitoring diseases has stimulated research towards more efficient and flexible radiosynthetic routes, including newer technologies. The traditional vessel-based approach suffers from limitations concerning flexibility, reagent mass needed, hardware requirements, large number of connections and valves, repetitive cleaning procedures and overall big footprint to be shielded from radiation. For these reasons, several research groups have started to investigate the application of the fast growing field of microfluidic chemistry to radiosynthetic procedures. After the first report in 2004, many scientific papers have been published and demonstrated the potential for increased process yields, reduced reagent use, improved flexibility and general ease of setup. This review will address definitions occurring in microfluidics as well as analyze the different approaches under two macro-categories: microvessel and microchannel. In this perspective, several works will be collected, involving the use of positron emitting species (11C, 18F, 64Cu) and the fewer examples of gamma emitting radionuclides (99mTc, 125/131I). New directions in microfluidic research applied to PET radiochemistry, future developments and challenges are also discussed. © 2013 Elsevier Inc
Different radiolabelling methods alter the pharmacokinetic and biodistribution properties of Plasminogen Activator Inhibitor Type 2 (PAI-2) forms
No full textIntroduction
Tumour-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, and it is recognised as having strong prognostic relevance as well as being a therapeutic target. The specific uPA inhibitor plasminogen activator inhibitor type-2 (PAI-2, SerpinB2) specifically targets cell bound uPA and is internalised. Furthermore, preclinical studies have established the “proof-of-principle” of uPA-targeting by PAI-2-cytotoxin conjugates in human carcinoma models. However, these studies also suggest that PAI-2 is rapidly cleared via the renal system with low total dose reaching the tumour. In this study, a comparative single photon emission computed tomography (SPECT) and biodistribution (BD) analysis of different forms of PAI-2 labelled with the radioisotopes iodine-123 (123I) and technetium-99m (99mTc) was undertaken.
Methods
The pharmacokinetic (PK) properties and BD of wild-type, ΔCD-loop and PEGylated ΔCD-loop PAI-2 labelled with the commonly used diagnostic SPECT radioisotopes 99mTc or 123I were compared in mouse models of human prostate carcinoma. Whole body SPECT imaging was also performed.
Results
Both wild-type and the shorter but active ΔCD-loop form of PAI-2 123I-labelled indirectly via conjugation to free amine groups (termed 123I-Bn-PAI-2) exhibited low tumour uptake, rapid excretion and similar PK profiles. Preliminary studies with a short branched-chain PEGylated 123I-Bn-PAI-2 ΔCD-loop indicated an increase in blood retention time and tumour uptake. All 123I-Bn-labelled radiotracers were largely excreted through the kidneys. By comparison, both wild-type 123I-PAI-2 (labelled directly via tyrosine residues) and 99mTc-PAI-2 displayed different PK/BD patterns compared to 123I-Bn-PAI-2, suggesting greater liver based catabolism and thus slower elimination. SPECT imaging mimicked the BD results of all radiotracers. © 2020 Elsevier B.V.
Conclusion
The different labelling methods gave distinct PAI-2 BD and tumour uptake profiles, with radioiodination resulting in the best non-tumour organ clearance profiles. Preliminary analyses with short branched-chain PEGylated 123I-Bn-PAI-2 ΔCD-loop suggest that further investigations with other PEGylation reagents are required to optimise this approach for tumour imaging. These findings impact on the use of PAI-2 for drug delivery and/or diagnostic development. © 2012 Published by Elsevier Inc
Radiation dosimetry of the translocator protein ligands [18F]PBR111 and [18F]PBR102
No full textIntroduction
The translocator protein (TSPO) ligands [18F]PBR111 and [18F]PBR102 show promise for imaging neuroinflammation. Our aim was to estimate the radiation dose to humans from primate positron emission tomography (PET) studies using these ligands and compare the results with those obtained from studies in rodents.
Methods
[18F]PBR111 and [18F]PBR102 PET–computed tomography studies were carried out in baboons. The cumulated activity in the selected source organs was obtained from the volume of interest time–activity curves drawn on coronal PET slices and adjusted for organ mass relative to humans. Radiation dose estimates were calculated in OLINDA/EXM Version 1.1 from baboon studies and compared with those calculated from Sprague–Dawley rat tissue concentration studies, also adjusted for relative organ mass.
Results
In baboons, both ligands cleared rapidly from brain, lung, kidney and spleen and more slowly from liver and heart. For [18F]PBR111, the renal excretion fraction was 6.5% and 17% for hepatobiliary excretion; for [18F]PBR102, the renal excretion was 3.0% and 15% for hepatobiliary excretion. The estimated effective dose in humans from baboon data was 0.021 mSv/MBq for each ligand, whilst from rat data, the estimates were 0.029 for [18F]PBR111 and 0.041 mSv/MBq for [18F]PBR102.
Conclusion
Biodistribution in a nonhuman primate model is better suited than the rat model for the calculation of dosimetry parameters when translating these ligands from preclinical to human clinical studies. Effective dose calculated from rat data was overestimated compared to nonhuman primate data. The effective dose coefficient for both these TSPO ligands determined from PET studies in baboons is similar to that for [18F]FDG.
© 2012 Elsevier Inc
Groundwater mean residence times of a subtropical barrier sand island
Get PDFFresh groundwater on barrier islands is affected by changing sea levels and precipitation variability due to climate change and is also vulnerable to anthropogenic processes, such as contamination and groundwater over-abstraction. Constraining groundwater mean residence times (MRTs) and flow paths is essential for understanding and managing these resources.
This study uses tritium (3H) and carbon-14 (14C) to determine the MRTs of groundwater along a transect across subtropical North Stradbroke Island, south-east Queensland, Australia. Hydraulic properties, major ion geochemistry and stable isotopes are used to validate residence times and to identify the processes responsible for their variability. 3H activities range from less than 0.01 to 1 TU (tritium units), which are values lower than those of local average rainfall (1.6–2.0 TU). 14C concentrations range from 62.5 to 111 pMC (percent modern carbon). Estimated MRTs determined using lumped parameter models and 3H activities range from 37 to more than 50 years. Recharge occurs over the entire island, and groundwater MRTs generally increase vertically and laterally towards the coastal discharge areas, although no systematic pattern is observed. MRTs estimated from 14C concentrations display similar spatial relationships but have a much greater range (from modern to approximately 5000 years). Water diversion and retention by lower-permeability units in the unsaturated parts of the dune systems are the most likely course for relatively long MRTs to date. The results indicate that the internal structures within the dune systems increase MRTs in the groundwater system and potentially divert flow paths. The structures produce perched aquifer systems that are wide-spread and have a significant influence on regional recharge. The geochemical composition of groundwater remains relatively consistent throughout the island, with the only irregularities attributed to old groundwater stored within coastal peat.
The outcomes of this study enhance the understanding of groundwater flow, recharge diversion and inhibition for large coastal sand masses in general, especially for older sand masses that have developed structures from pedogenesis and dune movement. With respect to south-east Queensland, it allows the existing regional groundwater flow model to be refined by incorporating independent MRTs to test models' validity. The location of this large fresh groundwater reservoir, in dry and populous south-east Queensland, means that its potential to be used as a water source is always high. Background information on aquifer distribution and groundwater MRTs is crucial to better validate impact assessment for water abstraction. © Author(s) 202
Spatial and temporal variation in carbon storage in subtropical seagrass meadows
No full textSeagrass meadows are one of three habitats that serve as marine carbon sinks, preserving up to thousands of years of carbon stored in their sediments. However, seagrass meadows are highly threatened and are continuing to decline worldwide. Seagrass management and conservation initiatives require adequate understanding of the spatial and temporal variability of carbon storage in these ecosystems, which is currently limited. This study aimed to identify how varying environmental and biological conditions influence spatial and temporal variability of carbon storage in subtropical seagrass meadows. Seagrass biomass and sediment cores were collected between the years 2012 and 2013 at multiple locations across a water quality gradient within Moreton Bay, Australia. The number of cores collected were 298 biomass cores, 298 shallow sediment cores, and 20 deeper sediment cores of up to 2 m sediment depth. Sediment carbon content and seagrass structural complexitywere determined for each location. Environmental variables were determined from field data (water quality) and modelled data (wave height). Spatial variability of carbon content was found among sites and linked to variations in seagrass canopy complexity, water turbidity, depth and wave energy. Sediment isotopic composition varied among locations, indicating variations in the contribution of carbon sources. Seasonal variability was limited and overshadowed by spatial variability. Millennial variation was observed, by dating the deeper sediment cores using 210PB and 14C. Carbon content, vertical accretion, isotopic composition, and carbon accumulation rates varied through the sediment column in Moreton Bay and were higher following European settlement. This study provides comprehensive results on spatial and temporal variability of seagrass sediments in Moreton Bay, which provides useful information for the developmentand implementation of blue carbon conservation and management initiatives
Testicular translocator protein expression is differentially altered by synthetic cannabinoid HU210 in adult and adolescent Rats
Get PDFObjective: The translocator protein (TSPO) has been implicated in numerous functions including steroid production and regulation of stress and anxiety. Cannabinoids have been shown to reduce plasma testosterone levels and alter anxiety levels. The aim of the present study was to determine whether the synthetic cannabinoid HU210 is able to regulate TSPO expression in several peripheral organs.
Methods: HU210 (100 μg/kg) was administered intraperitoneally to both adult and adolescent male ratsfor 14 days. TSPO receptor expression in several organs, including the liver, spleen, kidneys and testes, was quantified by membrane receptor binding using the selective radiolig and, PK11195. In cases where receptor binding data indicated significant cannabinoid-induced differences, further RT-qPCR was carried out to determine the transcriptional regulation of the TSPO gene. Additionally, film-autography was used to identify potential changes in the spatial distribution of the TSPO tissue binding sites.
Results: Results indicate that HU210 induces significant reductions in testicular TSPO expression in adult but not adolescent rats. No changes were found in other organs examined. These results are consistent with the previously observed effects of cannabinoids on testosterone production and a presumed role for TSPO in steroidogenesis.
Conclusions: Overall, these results suggest that cannabinoids may alter testosterone production by altering the expression of testicular TSPO and that the alteration of TSPO occurs in an age-dependent manner.© 2014 Chan RHY, et al