Inhibition of AMPA receptor trafficking at hippocampal synapses by β-amyloid oligomers: the mitochondrial contribution

<p>Abstract</p> <p>Background</p> <p>Synaptic defects represent a major mechanism underlying altered brain functions of patients suffering Alzheimer's disease (AD) <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr></abbrgrp>. An increasing body of work indicates that the oligomeric forms of β-amyloid (Aβ) molecules exert profound inhibition on synaptic functions and can cause a significant loss of neurotransmitter receptors from the postsynaptic surface, but the underlying mechanisms remain poorly understood. In this study, we investigated a potential contribution of mitochondria to Aβ inhibition of AMPA receptor (AMPAR) trafficking.</p> <p>Results</p> <p>We found that a brief exposure of hippocampal neurons to Aβ oligomers not only led to marked removal of AMPARs from postsynaptic surface but also impaired rapid AMPAR insertion during chemically-induced synaptic potentiation. We also found that Aβ oligomers exerted acute impairment of fast mitochondrial transport, as well as mitochondrial translocation into dendritic spines in response to repetitive membrane depolarization. Quantitative analyses at the single spine level showed a positive correlation between spine-mitochondria association and the surface accumulation of AMPARs. In particular, we found that spines associated with mitochondria tended to be more resistant to Aβ inhibition on AMPAR trafficking. Finally, we showed that inhibition of GSK3β alleviated Aβ impairment of mitochondrial transport, and effectively abolished Aβ-induced AMPAR loss and inhibition of AMPAR insertion at spines during cLTP.</p> <p>Conclusions</p> <p>Our findings indicate that mitochondrial association with dendritic spines may play an important role in supporting AMPAR presence on or trafficking to the postsynaptic membrane. Aβ disruption of mitochondrial trafficking could contribute to AMPAR removal and trafficking defects leading to synaptic inhibition.</p

Forecasting return of used products for remanufacturing using graphical evaluation and review technique (GERT)

This research develops a forecasting model that can predict the quantity, time and probability of product return, recyclable parts/components/materials and disposal. It adopts the Graphical Evaluation and Review Technique (GERT) by translating the remanufacturing operational process into a stochastic network. This stochastic network possesses two characteristics: activities having a probability of occurrence associated with them; and time to perform an activity. Together with the GERT method, Mason’s rule is applied to calculate the equivalence transfer function of the system, therefore predicting the desired outcomes. A generic eight-step process on how to implement this method in any structure of return products and remanufacturing network is provided. A numerical example is presented to demonstrate the result of using GERT on forecasting printer remanufacturing outcomes. The main contribution of this research is: Instead of giving one result such as either return quantity, or time, or probability, our research can forecast three of these outcomes simultaneously, and the algorithm is generalised to be applicable to any product structure and remanufacturing network

Modifying Cement Hydration with NS@PCE Core-Shell Nanoparticles

It is generally accepted that fine particles could accelerate cement hydration process, or, more specifically, this accelerating effect can be attributed to additional surface area introduced by fine particles. In addition to this view, the surface state of fine particles is also an important factor, especially for nanoparticles. In the previous study, a series of nano-SiO2-polycarboxylate superplasticizer core-shell nanoparticles (NS@PCE) were synthesized, which have a similar particle size distribution but different surface properties. In this study, the impact of NS@PCE on cement hydration was investigated by heat flow calorimetry, mechanical property measurement, XRD, and SEM. Results show that, among a series of NS@PCE, NS@PCE-2 with a moderate shell-core ratio appeared to be more effective in accelerating cement hydration. As dosage increases, the efficiency of NS@PCE-2 would reach a plateau which is quantified by various characteristic values. Compressive strength results indicate that strength has a linear correlation with cumulative heat release. A hypothesis was proposed to explain the modification effect of NS@PCE, which highlights a balance between initial dispersion and pozzolanic reactivity. This paper provides a new understanding for the surface modification of supplementary cementitious materials and their application and also sheds a new light on nano-SiO2 for optimizing cement-based materials

Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy

BACKGROUND: A few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures. RESULTS: Surprisingly, we here show that one antibody, 4E6, which has low affinity for most forms of tau acutely improved cognition and reduced soluble phospho-tau, whereas another antibody, 6B2, which has high affinity for various tau species was ineffective. Concurrently, we confirmed and clarified these efficacy differences in an ex vivo model of tauopathy. Alzheimer’s paired helical filaments (PHF) were toxic to the neurons and increased tau levels in remaining neurons. Both toxicity and tau seeding were prevented by 4E6 but not by 6B2. Furthermore, 4E6 reduced PHF spreading between neurons. Interestingly, 4E6’s efficacy relates to its high affinity binding to solubilized PHF, whereas the ineffective 6B2 binds mainly to aggregated PHF. Blocking 4E6's uptake into neurons prevented its protective effects if the antibody was administered after PHF had been internalized. When 4E6 and PHF were administered at the same time, the antibody was protective extracellularly. CONCLUSIONS: Overall, these findings indicate that high antibody affinity for solubilized PHF predicts efficacy, and that acute antibody-mediated improvement in cognition relates to clearance of soluble phospho-tau. Importantly, both intra- and extracellular clearance pathways are in play. Together, these results have major implications for understanding the pathogenesis of tauopathies and for development of immunotherapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0126-z) contains supplementary material, which is available to authorized users

Nonlinear dynamic analysis of large scale structures

The nonlinear dynamic analysis to obtain the response of whole building structures or structural components under blast loading can be computationally prohibitive. Two approaches have been considered in this study to improve the efficiency of such analyses: i) to employ an appropriate time integration scheme and, ii) to employ accurate simplified models of structural components. A new implicit-explicit time integration scheme has been developed and implemented with a novel automatic element-based mesh partitioning approach. The scheme allows simultaneous execution of implicit integration and explicit integration in different parts of a system to maximise computational efficiency. The developed scheme has also been notably incorporated to the novel domain decomposition approach developed previously at Imperial College London. The scheme is also successfully incorporated with the mixed-dimensional coupling technique included in the domain decomposition approach. Simplified models of structural components have been improved for a better representation of responses under blast loading. Mechanical models of fin plate connections have been modified by including material nonlinearity and material strain rate effect in the coupled axial and shear response of bolt rows. The flat shell elements have been verified in their ability to capture the influence of transverse damage in floor slabs due to uplift on the in-plane diaphragm stiffness and strength. These simplified models have been incorporated in the global model of a reference building, which has been analysed and assessed under characteristic blast loading. Typical masonry cavity cladding has been investigated as a case study. The failure mode and the interaction between the cladding and the structural frame have been successfully obtained from mesoscale models employing the mixed-dimensional domain decomposition approach and the implicit-explicit time integration scheme. A SDOF model based on the results of the detailed model has been constructed and incorporated in the global model of the reference building.Open Acces

Aramid Fibers Modulated Polyethylene Separator as Efficient Polysulfide Barrier for High-Performance Lithium-Sulfur Batteries

The separators with high absorbability of polysulfides are essential for improving the electrochemical performance of lithium–sulfur (Li–S) batteries. Herein, the aramid fibers coated polyethylene (AF-PE) films are designed by roller coating, the high polarity of AFs can strongly increase the binding force at AF/PE interfaces to guarantee the good stability of the hybrid film. As confirmed by the microscopic analysis, the AF-PE-6 film with the nanoporous structure exhibits the highest air permeability by the optimal coating content of AFs. The high absorbability of polysulfides for AF-PE-6 film can effectively hinder the migration of polysulfides and alleviate the shuttle effect of the Li–S battery. AF-PE-6 cell shows the specific capacity of 661 mAh g−1 at 0.1 C. After 200 charge/discharge cycles, the reversible specific capacity is 542 mAh g−1 with the capacitance retention of 82%, implying the excellent stability of AF-PE-6. The enhanced cell performance is attributed to the porous architecture of the aramid layer for trapping the dissolved sulfur-containing species and facilitating the charge transfer, as confirmed by SEM and EDS after 200 cycles. This work provides a facile way to construct the aramid fiber-coated separator for the inhibition of polysulfides in the Li–S battery

Dynamic assessment of tau immunotherapies in the brains of live animals by two-photon imagingResearch in context

Our original findings, showing the effectiveness of active and passive tau immunizations in mouse models, have now been confirmed and extended by many groups, with several clinical trials underway in Alzheimer's disease and progressive supranuclear palsy. Here, we report on a unique and sensitive two-photon imaging approach to concurrently study the dynamics of brain and neuronal uptake and clearance of tau antibodies as well as the acute removal of their pathological target in live animals. This in vivo technique is more sensitive to detect clearance of pathological tau protein than western blot tau analysis of brain tissue. In addition to providing an insight into the mechanisms involved, it allows for an efficient in vivo assessment of the therapeutic potential of tau antibodies, and may be applied to related protein misfolding diseases. Keywords: Tau protein, Alzheimer's disease, Tauopathy, Antibody, Immunotherapy, Two-photon imagin