Numerical analysis of seismic wave amplification in Nice (France) and comparisons with experiments

The analysis of site effects is very important since the amplification of seismic motion in some specific areas can be very strong. In this paper, the site considered is located in the centre of Nice on the French Riviera. Site effects are investigated considering a numerical approach (Boundary Element Method) and are compared to experimental results (weak motion and microtremors). The investigation of seismic site effects through numerical approaches is interesting because it shows the dependency of the amplification level on such parameters as wave velocity in surface soil layers, velocity contrast with deep layers, seismic wave type, incidence and damping. In this specific area of Nice, a one-dimensional (1D) analytical analysis of amplification does not give a satisfactory estimation of the maximum reached levels. A boundary element model is then proposed considering different wave types (SH, P, SV) as the seismic loading. The alluvial basin is successively assumed as an isotropic linear elastic medium and an isotropic linear viscoelastic solid (standard solid). The thickness of the surface layer, its mechanical properties, its general shape as well as the seismic wave type involved have a great influence on the maximum amplification and the frequency for which it occurs. For real earthquakes, the numerical results are in very good agreement with experimental measurements for each motion component. Two-dimensional basin effects are found to be very strong and are well reproduced numerically

Glycosylated clusterin species facilitate Aβ toxicity in human neurons

We thank members of Synthego Corporation generating the CLU exon 2 knockout iPSC lines and their support in this research. This work was supported by AstraZeneca as part of a CASE studentship and the Valat-Jones Foundation (Nigel and Françoise Jones).Clusterin (CLU) is one of the most significant genetic risk factors for late onset Alzheimer’s disease (AD). However, the mechanisms by which CLU contributes to AD development and pathogenesis remain unclear. Studies have demonstrated that the trafficking and localisation of glycosylated CLU proteins is altered by CLU-AD mutations and amyloid-β (Aβ), which may contribute to AD pathogenesis. However, the roles of non-glycosylated and glycosylated CLU proteins in mediating Aβ toxicity have not been studied in human neurons. iPSCs with altered CLU trafficking were generated following the removal of CLU exon 2 by CRISPR/Cas9 gene editing. Neurons were generated from control (CTR) and exon 2 −/− edited iPSCs and were incubated with aggregated Aβ peptides. Aβ induced changes in cell death and neurite length were quantified to determine if altered CLU protein trafficking influenced neuronal sensitivity to Aβ. Finally, RNA-Seq analysis was performed to identify key transcriptomic differences between CLU exon 2 −/− and CTR neurons. The removal of CLU exon 2, and the endoplasmic reticulum (ER)-signal peptide located within, abolished the presence of glycosylated CLU and increased the abundance of intracellular, non-glycosylated CLU. While non-glycosylated CLU levels were unaltered by Aβ25–35 treatment, the trafficking of glycosylated CLU was altered in control but not exon 2 −/− neurons. The latter also displayed partial protection against Aβ-induced cell death and neurite retraction. Transcriptome analysis identified downregulation of multiple extracellular matrix (ECM) related genes in exon 2 −/− neurons, potentially contributing to their reduced sensitivity to Aβ toxicity. This study identifies a crucial role of glycosylated CLU in facilitating Aβ toxicity in human neurons. The loss of these proteins reduced both, cell death and neurite damage, two key consequences of Aβ toxicity identified in the AD brain. Strikingly, transcriptomic differences between exon 2 −/− and control neurons were small, but a significant and consistent downregulation of ECM genes and pathways was identified in exon 2 −/− neurons. This may contribute to the reduced sensitivity of these neurons to Aβ, providing new mechanistic insights into Aβ pathologies and therapeutic targets for AD.Peer reviewe

Clusterin in Alzheimer’s Disease: Mechanisms, Genetics, and Lessons From Other Pathologies

Clusterin (CLU) or APOJ is a multifunctional glycoprotein that has been implicated in several physiological and pathological states, including Alzheimer’s disease (AD). With a prominent extracellular chaperone function, additional roles have been discussed for clusterin, including lipid transport and immune modulation, and it is involved in pathways common to several diseases such as cell death and survival, oxidative stress, and proteotoxic stress. Although clusterin is normally a secreted protein, it has also been found intracellularly under certain stress conditions. Multiple hypotheses have been proposed regarding the origin of intracellular clusterin, including specific biogenic processes leading to alternative transcripts and protein isoforms, but these lines of research are incomplete and contradictory. Current consensus is that intracellular clusterin is most likely to have exited the secretory pathway at some point or to have re-entered the cell after secretion. Clusterin’s relationship with amyloid beta (Aβ) has been of great interest to the AD field, including clusterin’s apparent role in altering Aβ aggregation and/or clearance. Additionally, clusterin has been more recently identified as a mediator of Aβ toxicity, as evidenced by the neuroprotective effect of CLU knockdown and knockout in rodent and human iPSC-derived neurons. CLU is also the third most significant genetic risk factor for late onset AD and several variants have been identified in CLU. Although the exact contribution of these variants to altered AD risk is unclear, some have been linked to altered CLU expression at both mRNA and protein levels, altered cognitive and memory function, and altered brain structure. The apparent complexity of clusterin’s biogenesis, the lack of clarity over the origin of the intracellular clusterin species, and the number of pathophysiological functions attributed to clusterin have all contributed to the challenge of understanding the role of clusterin in AD pathophysiology. Here, we highlight clusterin’s relevance to AD by discussing the evidence linking clusterin to AD, as well as drawing parallels on how the role of clusterin in other diseases and pathways may help us understand its biological function(s) in association with AD

A new fast multi-domain BEM to model seismic wave propagation and amplification in 3D geological structures

International audienceThe analysis of seismic wave propagation and amplification in complex geological structures raises the need for efficient and accurate numerical methods. The solution of the elastodynamic equations using traditional boundary element methods (BEMs) is greatly hindered by the fully-populated nature of the matrix equations arising from the discretization. In a previous study limited to homogeneous media, the present authors have established that the Fast Multipole (FM) method reduces the complexity of a 3-D elastodynamic BEM to $N \log N$ per GMRES iteration and demonstrated its effectiveness on 3-D canyon configurations. In this article, the frequency-domain FM-BEM methodology is extented to 3-D elastic wave propagation in piecewise-homogeneous domains in the form of a FM-accelerated multi-region BE-BE coupling approach. This new method considerably enhances the capability of the BEM for studying the propagation of seismic waves in 3-D alluvial basins of arbitrary geometry embedded in semi-infinite media. Several fully 3-D examples (oblique SV-waves) representative of such configurations validate and demonstrate the capabilities of the multi-domain fast multipole approach. They include comparisons with available (low-frequency) results for various types of incident wavefields, and time-domain results obtained by means of Fourier synthesis

Clusterin Is Required for β-Amyloid Toxicity in Human iPSC-Derived Neurons

Our understanding of the molecular processes underlying Alzheimer’s disease (AD) is still limited, hindering the development of effective treatments, and highlighting the need for human-specific models. Advances in identifying components of the amyloid cascade are progressing, including the role of the protein clusterin in mediating β-amyloid (Aβ) toxicity. Mutations in the clusterin gene (CLU), a major genetic AD risk factor, are known to have important roles in Aβ processing. Here we investigate how CLU mediates Aβ-driven neurodegeneration in human induced pluripotent stem cell (iPSC)-derived neurons. We generated a novel CLU-knockout iPSC line by CRISPR/Cas9-mediated gene editing to investigate Aβ-mediated neurodegeneration in cortical neurons differentiated from wild type and CLU knockout iPSCs. We measured response to Aβ using an imaging assay and measured changes in gene expression using qPCR and RNA sequencing. In wild type neurons imaging indicated that neuronal processes degenerate following treatment with Aβ25-35 peptides and Aβ1-42 oligomers, in a dose dependent manner, and that intracellular levels of clusterin are increased following Aβ treatment. However, in CLU knockout neurons Aβ exposure did not affect neurite length, suggesting that clusterin is an important component of the amyloid cascade. Transcriptomic data were analyzed to elucidate the pathways responsible for the altered response to Aβ in neurons with the CLU deletion. Four of the five genes previously identified as downstream to Aβ and Dickkopf-1 (DKK1) proteins in an Aβ-driven neurotoxic pathway in rodent cells were also dysregulated in human neurons with the CLU deletion. AD and lysosome pathways were the most significantly dysregulated pathways in the CLU knockout neurons, and pathways relating to cytoskeletal processes were most dysregulated in Aβ treated neurons. The absence of neurodegeneration in the CLU knockout neurons in response to Aβ compared to the wild type neurons supports the role of clusterin in Aβ-mediated AD pathogenesis

On-chip pressure measurements and channel deformation after oil absorption

Microfluidic channels moulded from the soft polymer poly(dimethylsiloxane) (PDMS) are widely used as a platform for mimicking biological environments, and can be used for the simulation of fluid filled structures such as blood and lung vessels. The control of pressure and flow rate within these structures is vital to mimic physiological conditions. The flexibility of PDMS leads to pressure-induced deformation under flow, leading to variable flow profiles along a device. Here, we investigate the change in Young’s modulus of microfluidic channels due to infiltration of mineral oil, a PDMS permeable fluid, and how this affects the resulting pressure profile using a novel pressure measurement method. We found a 53% decrease in Young’s modulus of PDMS due to mineral oil absorption over the course of 3 h accounted for lower internal pressure and larger channel deformation compared to fresh PDMS at a given flow rate. Confocal fluorescence microscopy used to image channel profiles before and after the introduction of mineral oil showed a change in pressure-induced deformation after infiltration of the oil. Atomic force microscopy (AFM) nanoindentation was used to measure Young’s modulus of PDMS before (2.80±0.032.80±0.03 MPa) and after (1.32±0.041.32±0.04 MPa) mineral oil absorption. Raman spectroscopy showed the infiltration of mineral oil into PDMS from channel walls and revealed the diffusion coefficient of mineral oil in PDMS

Hybrid HBT oscillator and mixer

The HBT presents inherent low 1/f noise characteristic, which makes HBT a very promising candidate, compared to GaAs MESFET or Silicon BJT, for these high frequency low phase noise applications [1,2,3]. In this paper, the preliminary measured results on the conversion factor of low frequency noise to the phase noise of HBT oscillator will be presented, together with the first results of our HBT mixer