365 research outputs found

    Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice

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    Background: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a cognitive enhancer and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Methodology/Principal Findings: Through the use of stereological counting methods, we observed a significant reduction (~20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing. Conclusion: Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences

    A thermostatically controlled miniature glass-house

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    Simulation of flow diversion in cerebral aneurysms

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    Intracranial aneurysms are abnormal focal enlargements of the vascular walls that necessitate surgical intervention once detected. Emerging stent technology involves an innovative type of finely-braided stents, called flow diverters, which abruptly impede the arterial flow into the aneurysm, upon deployment, and induce thrombosis, vascular remodelling and complete aneurysm occlusion in under a year [1]. The understanding of the dynamics of blood flow within this radically modified environment is thought to be pivotal in increasing the efficacy of both stent design and prolonged treatment. The aim of this study is to numerically simulate the blood flow within stented arterial segments and to evaluate critical hemodynamic factors around the aneurysm neck, validated with clinical and experimental data [1,2]. These objectives create many geometric challenges around the flow diverter due to the tessellation and resolution of features with very large ratio (artery-to-stent) in the input i.e., medical images and stent models. Following a novel Body-Centric Cubic (BCC) mesh generation method [2], high-fidelity tetrahedral meshes of aneurysmal dilatations that incorporate flow diverters across the aneurysm neck are now possible with an accurate image- to-mesh (I2M) conversion scheme from micro-CT images (Fig. 1a,b). Preliminary results involve arterial segments both with and without flow diverters (Fig.1c), utilising the CFD software OpenFOAM® to solve the incompressible Navier-Stokes equations, under steady and physiologically-correct pulsatile flow conditions

    Manganese exposure in juvenile C57BL/6 mice increases glial inflammatory responses in the substantia nigra following infection with H1N1 influenza virus.

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    Infection with Influenza A virus can lead to the development of encephalitis and subsequent neurological deficits ranging from headaches to neurodegeneration. Post-encephalitic parkinsonism has been reported in surviving patients of H1N1 infections, but not all cases of encephalitic H1N1 infection present with these neurological symptoms, suggesting that interactions with an environmental neurotoxin could promote more severe neurological damage. The heavy metal, manganese (Mn), is a potential interacting factor with H1N1 because excessive exposure early in life can induce long-lasting effects on neurological function through inflammatory activation of glial cells. In the current study, we used a two-hit model of neurotoxin-pathogen exposure to examine whether exposure to Mn during juvenile development would induce a more severe neuropathological response following infection with H1N1 in adulthood. To test this hypothesis, C57BL/6 mice were exposed to MnCl2 in drinking water (50 mg/kg/day) for 30 days from days 21-51 postnatal, then infected intranasally with H1N1 three weeks later. Analyses of dopaminergic neurons, microglia and astrocytes in basal ganglia indicated that although there was no significant loss of dopaminergic neurons within the substantia nigra pars compacta, there was more pronounced activation of microglia and astrocytes in animals sequentially exposed to Mn and H1N1, as well as altered patterns of histone acetylation. Whole transcriptome Next Generation Sequencing (RNASeq) analysis was performed on the substantia nigra and revealed unique patterns of gene expression in the dual-exposed group, including genes involved in antioxidant activation, mitophagy and neurodegeneration. Taken together, these results suggest that exposure to elevated levels of Mn during juvenile development could sensitize glial cells to more severe neuro-immune responses to influenza infection later in life through persistent epigenetic changes

    Photon Beam Asymmetry Σ for η and η′ Photoproduction From the Proton

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    Measurements of the linearly-polarized photon beam asymmetry Σ for photoproduction from the proton of η and η ′ mesons are reported. A linearly-polarized tagged photon beam produced by coherent bremsstrahlung was incident on a cryogenic hydrogen target within the CEBAF Large Acceptance Spectrometer. Results are presented for the γ p → η p reaction for incident photon energies from 1.070 to 1.876 GeV, and from 1.516 to 1.836 GeV for the γ p → η ′ p reaction. For γ p → η p , the data reported here considerably extend the range of measurements to higher energies, and are consistent with the few previously published measurements for this observable near threshold. For γ p → η ′ p , the results obtained are consistent with the few previously published measurements for this observable near threshold, but also greatly expand the incident photon energy coverage for that reaction. Initial analysis of the data reported here with the Bonn–Gatchina model strengthens the evidence for four nucleon resonances – the N (1895) 1/2− , N (1900) 3/2+ , N(2100) 1/2+ and N (2120) 3/2− resonances – which presently lack the four-star status in the current Particle Data Group compilation, providing examples of how these new measurements help refine models of the photoproduction process

    Photon beam asymmetry Sigma for eta and eta \u27 photoproduction from the proton

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    Measurements of the linearly-polarized photon beam asymmetry Sigma for photoproduction from the proton of eta and eta \u27 mesons are reported. A linearly-polarized tagged photon beam produced by coherent bremsstrahlung was incident on a cryogenic hydrogen target within the CEBAF Large Acceptance Spectrometer. Results are presented for the gamma p -\u3e eta p reaction for incident photon energies from 1.070 to 1.876 GeV, and from 1.516 to 1.836 GeV for the gamma p -\u3e eta \u27 p reaction. For gamma p -\u3e eta p, the data reported here considerably extend the range of measurements to higher energies, and are consistent with the few previously published measurements for this observable near threshold. For gamma p -\u3e eta \u27 p, the results obtained are consistent with the few previously published measurements for this observable near threshold, but also greatly expand the incident photon energy coverage for that reaction. Initial analysis of the data reported here with the Bonn-Gatchina model strengthens the evidence for four nucleon resonances - the N(1895)1/2(-), N(1900)3/2(+), N(2100)1/2(+) and N(2120)3/2(-) resonances which presently lack the four-star status in the current Particle Data Group compilation, providing examples of how these new measurements help refine models of the photoproduction process. (C) 2017 The Authors. Published by Elsevier B.V

    Biosynthesis of HLA-C heavy chains in melanoma cells with multiple defects in the expression of HLA-A, -B, -C molecules

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    Recent investigations have shown that malignant transformation may down-regulate the expression of class I HLA molecules, beta(2)-microglobulin (beta(2)m) and members of the antigen-processing machinery. In the present study, we HLA-genotyped and identified at a biochemical level the three (HLA-A25, -B8, -Cw7) class I alleles expressed by the previously described [D'Urso CM et al (1992) J Clin Invest 87: 284-292] beta(2)m-defective human melanoma FO-1 cell line and tested their ability to interact with calnexin, calreticulin and the TAP (transporter associated with antigen processing) complex. Ail these alleles were found to bind calnexin, but not calreticulin or the poorly expressed TAP complex, both in parental and beta(2)m-transfected FO-1 cells, demonstrating a complex defect of class I expression in FO-1 cells. In these conditions, Cw7 heavy chains interacted with calnexin more strongly than A25 and B8, and preferentially accumulated in the endoplasmic reticulum, in both a calnexin-associated and a calnexin-free form. In addition, they could be transported to the cell surface at low levels even in the absence of beta(2)m, without undergoing terminal glycosylation. These results establish a parallel between HLA-C and the murine D-b and L-d molecules which have been found to be surface expressed and functional in beta(2)m-defective cells. They also demonstrate distinctive features of HLA-C molecules. We propose that the accumulation of several assembly intermediates of HLA-C might favour the binding of peptide antigens not readily bound by HLA-A and -B molecules in neoplastic cells with suboptimal class I expression

    Molecular dynamics simulation of the early stages of the synthesis of periodic mesoporous silica

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    We present results of detailed atomistic modeling of the early stages of the synthesis of periodic mesoporous silica using molecular dynamics. Our simulations lead to the proposal of a mechanism that validates several previous experimental and modeling studies and answers many controversial issues regarding the synthesis of mesoporous silicas. In particular, we show that anionic silicates interact very strongly with cationic surfactants and, significantly adsorb on the surface of micelles, displacing a fraction of previously bound bromide counterions. This induces an increase in micelle size and also enhances silica condensation at the micelle surface. The presence of larger silica aggregates in solution further promotes the growth of micelles and, by binding to surfactant molecules in different micelles, their aggregation. This work demonstrates the crucial role played by silica in influencing, by way of a cooperative templating mechanism, the structure of the eventual liquid-crystal phase, which in turn determines the structure of the porous material

    Loss of heterozygosity (LOH), malignancy grade and clonality in microdissected prostate cancer

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    The aim of the present study was to find out whether increasing malignancy of prostate carcinoma correlates with an overall increase of loss of heterozygosity (LOH), and whether LOH typing of microdissected tumour areas can help to distinguish between multifocal or clonal tumour development. In 47 carcinomas analysed at 25 chromosomal loci, the overall LOH rate was found to be significantly lower in grade 1 areas (2.2%) compared with grade 2 (9.4%) and grade 3 areas (8.3%, P = 0.007). A similar tendency was found for the mean fractional allele loss (FAL, 0.043 for grade 1, 0.2 for grade 2 and 0.23 for grade 3, P = 0.0004). Of 20 tumours (65%) with LOH in several microdissected areas, 13 had identical losses at 1–4 loci within two or three areas, suggesting clonal development of these areas. Markers near RB, DCC, BBC1, TP53 and at D13S325 (13q21–22) showed higher loss rates in grades 2 and 3 (between 25% and 44.4%) compared with grade 1 (0–6.6%). Tumour-suppressor genes (TSGs) near these loci might, thus, be important for tumour progression. TP53 mutations were detected in 27%, but BBC1 mutations in only 7%, of samples with LOH. Evaluation of all 25 loci in every tumour made evident that each prostate cancer has its own pattern of allelic losses. © 1999 Cancer Research Campaig

    Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice

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    Background: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a ‘‘cognitive enhancer’ ’ and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Methodology/Principal Findings: Through the use of stereological counting methods, we observed a significant reduction (,20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChipH HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigr
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