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Up-regulation of matrix metallopeptidase 12 in motor neurons undergoing synaptic stripping
No full textAxotomy of the rodent facial nerve represents a well-established model of synaptic plasticity. Post-traumatic “synaptic stripping” was originally discovered in this system. We report upregulation of matrix metalloproteinase MMP12 in regenerating motor neurons of the mouse and rat facial nucleus. Matrix metalloproteinases (matrix metallopeptidases, MMPs) are zinc-binding proteases capable of degrading components of the extracellular matrix and of regulating extracellular signaling networks including within synapses. MMP12 protein expression in facial motor neurons was enhanced following axotomy and peaked at day 3 after the operation. The peak of neuronal MMP12 expression preceded the peak of experimentally induced synaptic plasticity. At the same time, MMP12 redistributed intracellularly and became predominantly localized beneath the neuronal somatic cytoplasmic membrane. Both findings point to a role of MMP12 in the neuronal initiation of the synaptic stripping process. MMP12 is the first candidate molecule for such a trigger function and has potential as a therapeutic target. Moreover, since statins have been shown to increase the expression of MMP12, interference with synaptic stability may represent one mechanism by which these widely used drugs exert their side effects on higher CNS functions. © 2014 by Elsevier Ltd
Attenuation correction for freely moving small animal brain PET studies based on a virtual scanner geometry
No full textAttenuation correction in positron emission tomography brain imaging of freely moving animals is a very challenging problem since the torso of the animal is often within the field of view and introduces a non negligible attenuating factor that can degrade the quantitative accuracy of the reconstructed images. In the context of unrestrained small animal imaging, estimation of the attenuation correction factors without the need for a transmission scan is highly desirable. An attractive approach that avoids the need for a transmission scan involves the generation of the hull of the animal’s head based on the reconstructed motion corrected emission images. However, this approach ignores the attenuation introduced by the animal’s torso. In this work, we propose a virtual scanner geometry which moves in synchrony with the animal’s head and discriminates between those events that traversed only the animal’s head (and therefore can be accurately compensated for attenuation) and those that might have also traversed the animal’s torso. For each recorded pose of the animal’s head a new virtual scanner geometry is defined and therefore a new system matrix must be calculated leading to a time-varying system matrix. This new approach was evaluated on phantom data acquired on the microPET Focus 220 scanner using a custom-made phantom and step-wise motion. Results showed that when the animal’s torso is within the FOV and not appropriately accounted for during attenuation correction it can lead to bias of up to 10% . Attenuation correction was more accurate when the virtual scanner was employed leading to improved quantitative estimates (bias < 2%), without the need to account for the attenuation introduced by the extraneous compartment. Although the proposed method requires increased computational resources, it can provide a reliable approach towards quantitatively accurate attenuation correction for freely moving animal studies. © 2014 Institute of Physic
Bardoxolone methyl prevents mesenteric fat deposition and inflammation in high-fat diet mice
Full text linkMesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue. © 2015 Chi H. L. Dinh et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Guwiyang Wurra–‘Fire Mouse’: a global gene knockout model for TSPO/PBR drug development, loss-of-function and mechanisms of compensation studies.
No full textThe highly conserved 18-kDa translocator protein (TSPO) or peripheral benzodiazepine receptor (PBR), is being investigated as a diagnostic and therapeutic target for disease conditions ranging from inflammation to neurodegeneration and behavioural illnesses. Many functions have been attributed to TSPO/PBR including a role in the mitochondrial permeability transition pore (MPTP), steroidogenesis and energy metabolism. In this review, we detail the recent developments in determining the physiological role of TSPO/PBR, specifically based on data obtained from the recently generated Tspo knockout mouse models. In addition to defining the role of TSPO/PBR, we also describe the value of Tspo knockout mice in determining the selectivity, specificity and presence of any off-target effects of TSPO/PBR ligands. © 2015 Author
Synthesis and in vivo evaluation of [123I]melanin-targeted agents
No full textThis study reports the synthesis, [123I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [131I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60–90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [123I]4 (ICF01012). The most favorable compounds ([123I]20, [123I]23, [123I]41, and [123I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [123I]20 and [123I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [123I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [123I]41 and [123I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [123I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [131I] therapeutic evaluation. ©2015, American Chemical Societ
Lanthanoid “bottlebrush” clusters: remarkably elongated metal–oxo core structures with controllable lengths
Full text linkLarge metal–oxo clusters consistently assume spherical or regular polyhedral morphologies rather than high-aspect-ratio structures. Access to elongated core structures has now been achieved by the reaction of lanthanoid salts with a tetrazole-functionalized calixarene in the presence of a simple carboxylate co-ligand. The resulting Ln19 and Ln12 clusters are constructed from apex-fused Ln5O6 trigonal bipyramids and are formed consistently under a range of reaction conditions and reagent ratios. Altering the carboxylate co-ligand structure reliably controls the cluster length, giving access to a new class of rod-like clusters of variable length. © 2014 American Chemical SocietyACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Terms of use can be found here: https://pubs.acs.org/page/policy/authorchoice_termsofuse.htm
Reciting the layers: evidence for past tsunamis at Mataora-Wairau Lagoon, Aotearoa-New Zealand
No full textSedimentary, geochemical, microfossil and geochronological analyses were carried out on 10 sediment cores across the south-eastern corner of Mataora-Wairau Lagoon (M-WL), South Island, Aotearoa-New Zealand. This multi-proxy approach provides strong evidence for three late Holocene palaeotsunamis (two previously unreported) and a historical tsunami generated by rupture of the Wairarapa Fault in 1855 CE. The main scientific evidence for these events consists of anomalous, high-energy marine sediment layers that overlie material of contrasting composition. These layers coincide with peaks in planktonic and benthic marine to brackish-marine diatoms and geochemical signatures indicative of sudden changes in environmental conditions. Palaeotsunami I (maximum date 2095 cal. BP) and Palaeotsunami II (maximum date 915 cal. BP - previously identified by Clark et al., 2015) appear to represent large events contemporaneous with major earthquakes inducing tectonic uplift and coseismic subsidence around the Cook Strait region. Palaeotsunami II is close to the date of the earliest settlement of the M-WL area by Māori, and a traditional narrative that references loss of life following waves over-washing the Wairau boulder bank. Given the boulder bank was likely to have been seaward of its current position during events I and II, we surmise that the inundation distances would have been greater than the most landward extent (340 m) inferred from the deposits found in this study. Palaeotsunami III (maximum date 525 cal. BP) was associated with tectonic subsidence across the study site, most likely associated with rupture of the southern Hikurangi subduction zone. We expect the ongoing refinement of the methods used in this study, and the results from future studies of analogue sites and offshore fault systems, will improve our understanding of the significant tsunami hazard facing this region. © 2017 Elsevier B.V
Fully automated one-pot radiosynthesis of O-(2-[18F]fluoroethyl)-L-tyrosine on the TracerLab FXFN module
No full textIntroduction: An efficient fully automated method for the radiosynthesis of enantiomerically pure O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) using the GE TracerLab FXFN synthesis module via the O-(2-tosyloxyethyl)-N-trityl-L-tyrosine tert-butylester precursor has been developed. Methods: The radiolabelling of [18F]FET involved a classical [18F]fluoride nucleophilic substitution performed in acetonitrile using potassium carbonate and Kryptofix 222, followed by acid hydrolysis using 2N hydrochloric acid. Results: [18F]FET was produced in 35±5% (n=22) yield non-decay-corrected (55±5% decay-corrected) and with radiochemical and enantiomeric purity of >99% with a specific activity of >90 GBq/μmol after 63 min of radiosynthesis including HPLC purification and formulation. Conclusion: The automated radiosynthesis provides high and reproducible yields suitable for routine clinical use. © 2011 Elsevier Inc
From solid solution to cluster formation of Fe and Cr in α-Zr
No full textTo understand the mechanisms by which the re-solution of Fe and Cr additions increase the corrosion rate of irradiated Zr alloys, the solubility and clustering of Fe and Cr in model binary Zr alloys was investigated using a combination of experimental and modelling techniques — atom probe tomography (APT), x-ray diffraction (XRD), thermoelectric power (TEP) and density functional theory (DFT). Cr occupies both interstitial and substitutional sites in the α-Zr lattice; Fe favours interstitial sites, and a low-symmetry site that was not previously modelled is found to be the most favourable for Fe. Lattice expansion as a function of Fe and Cr content in the α-Zr matrix deviates from Vegard's law and is strongly anisotropic for Fe additions, expanding the c-axis while contracting the a-axis. Matrix content of solutes cannot be reliably estimated from lattice parameter measurements, instead a combination of TEP and APT was employed. Defect clusters form at higher solution concentrations, which induce a smaller lattice strain compared to the dilute defects. In the presence of a Zr vacancy, all two-atom clusters are more soluble than individual point defects and as many as four Fe or three Cr atoms could be accommodated in a single Zr vacancy. The Zr vacancy is critical for the increased apparent solubility of defect clusters; the implications for irradiation induced microstructure changes in Zr alloys are discussed. © 2015 Elsevier B.V
Formation and structure of V–Zr amorphous alloy thin films
No full textAlthough the equilibrium phase diagram predicts that alloys in the central part of the V–Zr system should consist of V2Zr Laves phase with partial segregation of one element, it is known that under non-equilibrium conditions these materials can form amorphous structures. Here we examine the structures and stabilities of thin film V–Zr alloys deposited at room temperature by magnetron sputtering. The films were characterized by X-ray diffraction, transmission electron microscopy and computational methods. Atomic-scale modelling was used to investigate the enthalpies of formation of the various competing structures. The calculations confirmed that an amorphous solid solution would be significantly more stable than a random body-centred solid solution of the elements, in agreement with the experimental results. In addition, the modelling effort provided insight into the probable atomic configurations of the amorphous structures allowing predictions of the average distance to the first and second nearest neighbours in the system. © 2014 Elsevier Ltd