The Modulation of Tau Aggregation in a Cell Model of Alzheimer’s Disease by the Proteasome Adaptor Protein NUB1

Neurofibrillary tangles (NFT) in Alzheimer’s disease (AD) are mainly composed of hyperphosphorylated and aggregated wild-type tau. NFTs are decorated by the ubiquitin-like modifier NEDD8, a protein targeted for proteasomal degradation by the NEDD8 Ultimate Buster 1 (NUB1). NUB1 has been shown to reduce synphilin-1 positive inclusions in a model of Parkinson’s disease. Therefore, this study examined the subcellular localisation of NUB1 as well as the effect of NUB1 on tau phosphorylation and aggregation. Furthermore, the effect of reducing NUB1 expression by RNA interference was investigated. Brain sections from AD patients showed that NUB1 and NEDD8 were expressed in the pyramidal neurons of the hippocampus, where the accumulation of NFTs is most abundant. In rat primary cortical neurons, NUB1 and tau co-localised in neurites and signalling structures such as varicosities, suggesting a functional interaction between them. The upregulation of the tau kinase GSK3β in AD leads to increased tau hyperphosphorylation and accumulation. In SK-N-SH neuroblastoma cells, which lack endogenous tau, ectopic wild-type tau formed inclusions when it was co-expressed with GSK3β, and this was enhanced by proteasome inhibition. NUB1 co-localised with both tau and GSK3β and significantly reduced tau inclusion formation. In neuroblastoma cells, NUB1 could interact with both tau and GSK3β, disrupt their interaction, and decrease the GSK3β-dependent phosphorylation of tau. NUB1 can directly bind synphilin-1 and induce its proteasomal degradation. Therefore, the ability of NUB1 to regulate GSK3β degradation was investigated in neuroblastoma cells. The upregulation of NUB1 accelerated the turnover of GSK3β, and the ubiquitin-associated (UBA) domains of NUB1 were necessary for NUB1 to exert its effect. Conversely, the downregulation of endogenous NUB1 by RNA interference increased the stability of endogenous GSK3β. Thus, NUB1 might have a role in tau inclusion formation by modulating GSK3β levels

Pressure-induced amorphization, crystal-crystal transformations and the memory glass effect in interacting particles in two dimensions

We study a model of interacting particles in two dimensions to address the relation between crystal-crystal transformations and pressure-induced amorphization. On increasing pressure at very low temperature, our model undergoes a martensitic crystal-crystal transformation. The characteristics of the resulting polycrystalline structure depend on defect density, compression rate, and nucleation and growth barriers. We find two different limiting cases. In one of them the martensite crystals, once nucleated, grow easily perpendicularly to the invariant interface, and the final structure contains large crystals of the different martensite variants. Upon decompression almost every atom returns to its original position, and the original crystal is fully recovered. In the second limiting case, after nucleation the growth of martensite crystals is inhibited by energetic barriers. The final morphology in this case is that of a polycrystal with a very small crystal size. This may be taken to be amorphous if we have only access (as experimentally may be the case) to the angularly averaged structure factor. However, this `X-ray amorphous' material is anisotropic, and this shows up upon decompression, when it recovers the original crystalline structure with an orientation correlated with the one it had prior to compression. The memory effect of this X-ray amorphous material is a natural consequence of the memory effect associated to the underlying martensitic transformation. We suggest that this kind of mechanism is present in many of the experimental observations of the memory glass effect, in which a crystal with the original orientation is recovered from an apparently amorphous sample when pressure is released.Comment: 13 pages, 13 figures, to be published in Phys. Rev.

Revisiting the seasonal cycle of the Timor throughflow: impacts of winds, waves and eddies

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Peña‐Molino, B., Sloyan, B., Nikurashin, M., Richet, O., & Wijffels, S. Revisiting the seasonal cycle of the Timor throughflow: impacts of winds, waves and eddies. Journal of Geophysical Research: Oceans, 127, (2022): e2021JC018133, https://doi.org/10.1029/2021jc018133.The tropical Pacific and Indian Oceans are connected via a complex system of currents known as the Indonesian Throughflow (ITF). More than 30% of the variability in the ITF is linked to the seasonal cycle, influenced by the Monsoon winds. Despite previous efforts, a detailed knowledge of the ITF response to the components of the seasonal forcing is still lacking. Here, we describe the seasonal cycle of the ITF based on new observations of velocity and properties in Timor Passage, satellite altimetry and a high-resolution regional model. These new observations reveal a complex mean and seasonally varying flow field. The amplitude of the seasonal cycle in volume transport is approximately 6 Sv. The timing of the seasonal cycle, with semi-annual maxima (minima) in May and December (February and September), is controlled by the flow below 600 m associated with semi-annual Kelvin waves. The transport of thermocline waters (<300 m) is less variable than the deep flow but larger in magnitude. This top layer is modulated remotely by cycles of divergence in the Banda Sea, and locally through Ekman transport, coastal upwelling, and non-linearities of the flow. The latter manifests through the formation of eddies that reduce the throughflow during the Southeast Monsoon, when is expected to be maximum. While the reduction in transport associated with the eddies is small, its impact on heat transport is large. These non-linear dynamics develop over small scales (<10 km), and without high enough resolution, both observations and models will fail to capture them adequately.B. Peña-Molino, B. M. Sloyan, M. Nikurashin, and O. Richet were supported by the Centre for Southern Hemisphere Oceans Research (CSHOR). CSHOR is a joint research Centre for Southern Hemisphere Ocean Research between QNLM and CSIRO. S. E. Wijffels was supported by the US National Science Foundation Grant No. OCE-1851333

Compressibility of titanosilicate melts

The effect of composition on the relaxed adiabatic bulk modulus (K0) of a range of alkali- and alkaline earth-titanosilicate [X 2 n/n+ TiSiO5 (X=Li, Na, K, Rb, Cs, Ca, Sr, Ba)] melts has been investigated. The relaxed bulk moduli of these melts have been measured using ultrasonic interferometric methods at frequencies of 3, 5 and 7 MHz in the temperature range of 950 to 1600°C (0.02 Pa s < s < 5 Pa s). The bulk moduli of these melts decrease with increasing cation size from Li to Cs and Ca to Ba, and with increasing temperature. The bulk moduli of the Li-, Na-, Ca- and Ba-bearing metasilicate melts decrease with the addition of both TiO2 and SiO2 whereas those of the K-, Rb- and Cs-bearing melts increase. Linear fits to the bulk modulus versus volume fraction of TiO2 do not converge to a common compressibility of the TiO2 component, indicating that the structural role of TiO2 in these melts is dependent on the identity of the cation. This proposition is supported by a number of other property data for these and related melt compositions including heat capacity and density, as well as structural inferences from X-ray absorption spectroscopy (XANES). The compositional dependence of the compressibility of the TiO2 component in these melts explains the difficulty incurred in previous attempts to incorporate TiO2 in calculation schemes for melt compressibility. The empirical relationship KV-4/3 for isostructural materials has been used to evaluate the compressibility-related structural changes occurring in these melts. The alkali metasilicate and disilicate melts are isostructural, independent of the cation. The addition of Ti to the metasilicate composition (i.e. X2TiSiO5), however, results in a series of melts which are not isostructural. The alkaline-earth metasilicate and disilicate compositions are not isostructural, but the addition of Ti to the metasilicate compositions (i.e. XTiSiO5) would appear, on the basis of modulus-volume systematics, to result in the melts becoming isostructural with respect to compressibility

Mechanical versus thermodynamical melting in pressure-induced amorphization: the role of defects

We study numerically an atomistic model which is shown to exhibit a one--step crystal--to--amorphous transition upon decompression. The amorphous phase cannot be distinguished from the one obtained by quenching from the melt. For a perfectly crystalline starting sample, the transition occurs at a pressure at which a shear phonon mode destabilizes, and triggers a cascade process leading to the amorphous state. When defects are present, the nucleation barrier is greatly reduced and the transformation occurs very close to the extrapolation of the melting line to low temperatures. In this last case, the transition is not anticipated by the softening of any phonon mode. Our observations reconcile different claims in the literature about the underlying mechanism of pressure amorphization.Comment: 7 pages, 7 figure

Post-operative Aspergillus mediastinitis in a man who was immunocompetent: a case report

<p>Abstract</p> <p>Introduction</p> <p><it>Aspergillus </it>spp. infections mainly affect patients who are immunocompromised, and are extremely rare in immunocompetent individuals.</p> <p>Case presentation</p> <p><it>Aspergillus </it>post-operative mediastinitis is considered to be a devastating infection, usually affecting patients undergoing cardiothoracic surgery with specific predisposing factors. We describe the case of an immunocompetent 68-year-old Caucasian man with severe chronic thromboembolic pulmonary hypertension, who underwent pulmonary thromboendarterectomy and developed post-operative mediastinitis due to <it>Aspergillus flavus</it>. The environmental control did not reveal the source of <it>A. flavus </it>infection and, despite combined antifungal therapy, our patient died as a result of septic shock and multiple organ failure.</p> <p>Conclusion</p> <p><it>Aspergillus </it>mediastinitis mainly affects patients after cardiosurgery operations with predisposing factors, and it is unusual in patients who are immunocompetent. The identification of the <it>Aspergillus </it>spp. source is often difficult, and there are no guidelines for the administration of pre-emptive therapy in this population of at-risk patients.</p

Differential Expression of the Demosponge (Suberites domuncula) Carotenoid Oxygenases in Response to Light: Protection Mechanism Against the Self-Produced Toxic Protein (Suberitine)

The demosponge Suberites domuncula has been described to contain high levels of a proteinaceous toxin, Suberitine, that displays haemolytic activityIn the present study this 7–8 kDa polypeptide has been isolated and was shown to exhibit also cytotoxic effects on cells of the same species. Addition of retinal, a recently identified metabolite of β-carotene that is abundantly present in S. domuncula was found to reduce both the haemolytic and the cell toxic activity of Suberitine at a molar ratio of 1:1. Spectroscopic analyses revealed that the interaction between β-carotene and Suberitine can be ascribed to a reversible energy transfer reaction. The enzyme that synthesises retinal in the sponge system is the β,β-carotene-15,15′-dioxygenase [carotene dioxygenase]. In order to clarify if this enzyme is the only β-carotene-metabolizing enzyme a further oxygenase had been identified and cloned, the (related) carotenoid oxygenase. In contrast to the dioxygenase, the carotenoid oxygenase could not degrade β-carotene or lycopene in Escherichia coli strains that produced these two carotenoids; therefore it had been termed related-carotenoid oxygenase. Exposure of primmorphs to light of different wavelengths from the visible spectrum resulted after 3 days in a strong upregulation of the dioxygenase in those 3D-cell aggregates that had been incubated with β-carotene. The strongest effect is seen with blue light at a maximum around 490 nm. It is concluded that the toxin Suberitine is non-covalently modified by retinal, the cleavage product from β-carotene via the enzyme carotene dioxygenase, a light inducible oxygenase. Hence, this study highlights that in S. domuncula the bioactive metabolite, retinal, has the property to detoxify its homologous toxin

Structural study of alpha-Bi2O3 under pressure

An experimental and theoretical study of the structural properties of monoclinic bismuth oxide (alpha-(BiO3)-O-2) under high pressures is here reported. Both synthetic and mineral bismite powder samples have been compressed up to 45 GPa and their equations of state have been determined with angle-dispersive x-ray diffraction measurements. Experimental results have been also compared with theoretical calculations which suggest the possibility of several phase transitions below 10 GPa. However, experiments reveal only a pressure-induced amorphization between 15 and 25 GPa, depending on sample quality and deviatoric stresses. The amorphous phase has been followed up to 45 GPa and its nature discussed.Financial support from the Spanish Consolider Ingenio 2010 Program (MALTA Project No. CSD2007-00045) is acknowledged. This work was also supported by Brazilian Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) under project 201050/2012-9, Spanish MICINN under projects MAT2010-21270-C04-01/03/04, Spanish MINECO under project CTQ2012-36253-C03-02, by Generalitat Valenciana through project GVA-ACOMP2013- 012 and from Vicerrectorado de Investigaci on dePereira, ALJ.; Errandonea, D.; Beltrán, A.; Gracia, L.; Gomis Hilario, O.; Sans, JA.; García-Domene, B.... (2013). Structural study of alpha-Bi2O3 under pressure. Journal of Physics: Condensed Matter. 25(47):475402-1-475402-12. https://doi.org/10.1088/0953-8984/25/47/475402S475402-1475402-12254