1,996 research outputs found

    The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy Bodies in Parkinson’s disease

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    Parkinson’s disease (PD) is characterized by intracellular, insoluble Lewy bodies composed of highly stable α-synuclein (α-syn) amyloid fibrils. α-synuclein is an intrinsically disordered protein that has the capacity to assemble to form ÎČ-sheet rich fibrils. Oxidiative stress and metal rich environments have been implicated in triggering assembly. Here, we have explored the composition of Lewy bodies in post-mortem tissue using electron microscopy and immunogold labeling and revealed dityrosine crosslinks in Lewy bodies in brain tissue from PD patients. In vitro, we show that dityrosine cross-links in α-syn are formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress by fluorescence and confirmed using mass-spectrometry. A covalently cross-linked dimer isolated by SDS-PAGE and mass analysis showed that dityrosine dimer was formed via the coupling of Y39-Y39 to give a homo dimer peptide that may play a key role in formation of oligomeric and seeds for fibril formation. Atomic force microscopy analysis reveals that the covalent dityrosine contributes to the stabilization of α-syn assemblies. Thus, the presence of oxidative stress induced dityrosine could play an important role in assembly and toxicity of α-syn in PD

    Alzheimer's disease-like paired helical filament assembly from truncated tau protein is independent of disulphide cross-linking

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    Abstract Alzheimer's disease is characterised by the self-assembly of tau and amyloid ÎÂČ proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into {PHFs} is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fibre diffraction, we have characterised the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulphide formation to fibril formation, we have compared the assembly of tau(297-391) under reduced and non-reducing conditions and for truncated tau carrying a {C322A} substitution. We show that disulphide bond formation inhibits assembly and that the {C322A} variant rapidly forms long and highly ordered PHFs

    Tau (297‐391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer’s disease brain

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    The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer’s disease (AD) and other tauopathies. Full‐length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297‐391 known as ‘dGAE’, spontaneously forms cross‐ÎČ‐containing PHFs and straight filaments under physiological conditions. Here, we have analysed and compared the structures of the filaments formed by dGAE in vitro with those deposited in the brains of individuals diagnosed with AD. We show that dGAE forms PHFs that share a macromolecular structure similar to those found in brain tissue. Thus, dGAEs may serve as a model system for studying core domain assembly and for screening for inhibitors of tau aggregation

    Exact Kohn-Sham exchange kernel for insulators and its long-wavelength behavior

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    We present an exact expression for the frequency-dependent Kohn-Sham exact-exchange (EXX) kernel for periodic insulators, which can be employed for the calculation of electronic response properties within time-dependent (TD) density-functional theory. It is shown that the EXX kernel has a long-wavelength divergence behavior of the exact full exchange-correlation kernel and thus rectifies one serious shortcoming of the adiabatic local-density approximation and generalized-gradient approximations kernels. A comparison between the TDEXX and the GW-approximation-Bethe-Salpeter-equation approach is also made.Comment: two column format 6 pages + 1 figure, to be publisehd in Physical Review

    Risk factors for pre-term birth in Iraq: a case-control study

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    BACKGROUND: Preterm birth (PTB)is a major clinical problem associated with perinatal mortality and morbidity. The aim of the present study is to identify risk factors associated with PTB in Mosul, Iraq. METHODS: A case-control study was conducted in Mosul, Iraq, from 1(st )September, 2003 to 28(th )February, 2004. RESULTS: A total of 200 cases of PTB and 200 controls of full-term births were screened and enrolled in the study. Forward logistic regression analysis was used in the analysis. Several significant risk associations between PTB and the following risk factors were identified: poor diet (OR = 4.33), heavy manual work (OR = 1.70), caring for domestic animals (OR = 5.06), urinary tract infection (OR = 2.85), anxiety (OR = 2.16), cervical incompetence (OR = 4.74), multiple pregnancies (OR = 7.51), direct trauma to abdomen (OR = 3.76) and abortion (OR = 6.36). CONCLUSION: The main determinants of PTB in Iraq were low socio-economic status and factors associated with it, such as heavy manual work and caring for domestic animals, in addition to urinary tract infections and poor obstetric history

    Chemical abundances of late-type pre-main sequence stars in the σ\sigma-Orionis cluster

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    The young σ\sigma-Orionis cluster is an important location for understanding the formation and evolution of stars, brown dwarfs, and planetary-mass objects. Its metallicity, although being a fundamental parameter, has not been well determined yet. We present the first determination of the metallicity of nine young late-type stars in σ\sigma-Orionis. Using the optical and near-infrared broadband photometry available in the literature we derive the effective temperatures for these nine cluster stars, which lie in the interval 4300--6500 K (1--3 \Msuno). These parameters are employed to compute a grid of synthetic spectra based on the code MOOG and Kurucz model atmospheres. We employ a χ2\chi^2-minimization procedure to derive the stellar surface gravity and atmospheric abundances of Al, Ca, Si, Fe, Ni and Li, using multi-object optical spectroscopy taken with WYFFOS+AF2 at at the William Herschel Telescope (λ/Ύλ∌7500\lambda/\delta\lambda\sim7500). The average metallicity of the σ\sigma-Orionis cluster is [Fe/H] =−0.02±0.09±0.13 = -0.02\pm0.09\pm0.13 (random and systematic errors). The abundances of the other elements, except lithium, seem to be consistent with solar values. Lithium abundances are in agreement with the "cosmic" 7^7Li abundance, except for two stars which show a logâĄÏ”(Li)\log \epsilon(\mathrm{Li}) in the range 3.6--3.7 (although almost consistent within the error bars). There are also other two stars with logâĄÏ”(Li)∌2.75\log \epsilon(\mathrm{Li})\sim 2.75. We derived an average radial velocity of the σ\sigma-Orionis cluster of 28±428\pm4km/s. The σ\sigma-Orionis metallicity is roughly solar.Comment: Accepted for publication in Astronomy and Astrophysic

    Efficiency of closed loop geothermal heat pumps: A sensitivity analysis

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    Geothermal heat pumps are becoming more and more popular as the price of fossil fuels is increasing and a strong reduction of anthropogenic CO2 emissions is needed. The energy performances of these plants are closely related to the thermal and hydrogeological properties of the soil, but a proper design and installation also plays a crucial role. A set of flow and heat transport simulations has been run to evaluate the impact of different parameters on the operation of a GHSP. It is demonstrated that the BHE length is the most influential factor, that the heat carrier fluid also plays a fundamental role, and that further improvements can be obtained by using pipe spacers and highly conductive grouts. On the other hand, if the physical properties of the soil are not surveyed properly, they represent a strong factor of uncertainty when modelling the operation of these plants. The thermal conductivity of the soil has a prevailing importance and should be determined with in-situ tests (TRT), rather than assigning values from literature. When groundwater flow is present, the advection should also be considered, due to its positive effect on the performances of BHEs; by contrast, as little is currently known about thermal dispersion, relying on this transport mechanism can lead to an excessively optimistic desig
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