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The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the "C" or "T" allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the "C" allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk "C" allele carriers.

Nerve growth factor (NGF) is the best-characterized neurotrophin and is primarily recognized for its key role in the embryonic development of the nervous system and neuronal cell survival/differentiation. Recently, unexpected actions of NGF in bone regeneration have emerged as NGF is able to enhance the osteogenic differentiation of mesenchymal stem cells. However, little is known regarding how NGF signaling regulates osteogenic differentiation through epigenetic mechanisms. In this study, using human dental mesenchymal stem cells (DMSCs), we demonstrated that NGF mediates osteogenic differentiation through p75NTR, a low-affinity NGF receptor. P75NTR-mediated NGF signaling activates the JNK cascade and the expression of KDM4B, an activating histone demethylase, by removing repressive H3K9me3 epigenetic marks. Mechanistically, NGF-activated c-Jun binds to the KDM4B promoter region and directly upregulates KDM4B expression. Subsequently, KDM4B directly and epigenetically activates DLX5, a master osteogenic gene, by demethylating H3K9me3 marks. Furthermore, we revealed that KDM4B and c-Jun from the JNK signaling pathway work in concert to regulate NGF-mediated osteogenic differentiation through simultaneous recruitment to the promoter region of DLX5. We identified KDM4B as a key epigenetic regulator during the NGF-mediated osteogenesis both in vitro and in vivo using the calvarial defect regeneration mouse model. In conclusion, our study thoroughly elucidated the molecular and epigenetic mechanisms during NGF-mediated osteogenesis.

Osteoporosis is a highly prevalent public health burden associated with an increased risk of bone fracture, particularly in aging women. Estrogen, an important medicinal component for the preventative and therapeutic treatment of postmenopausal osteoporosis, induces osteogenesis by activating the estrogen receptor signaling pathway and upregulating the expression of osteogenic genes, such as bone morphogenetic proteins (BMPs). The epigenetic regulation of estrogen-mediated osteogenesis, however, is still unclear. In this report, we found that estrogen significantly induced the expression of lysine-specific demethylase 6B (KDM6B) and that KDM6B depletion by shRNAs led to a significant reduction in the osteogenic potential of DMSCs. Mechanistically, upon estrogen stimulation, estrogen receptor-α (ERα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. Subsequently, KDM6B was recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 marks and activating the transcription of BMP2 and HOXC6, the master genes of osteogenic differentiation. Furthermore, we found that estrogen enhanced DMSC osteogenesis during calvarial bone regeneration and that estrogen's pro-osteogenic effect was dependent on KDM6B in vivo. Taken together, our results demonstrate the vital role of the ERα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response.

Air refractive index alteration is an important research technique used to examine blast density and pressure. However, precise time-course measurements of refractive index changes at a fixed point caused by air blast waves are challenging due to the necessity for high precision and noise immunity. This study proposes a dual-probe, dual-frequency fiber-optic displacement interferometer that achieves nanometer-level accuracy and can tolerate light intensity fluctuations and transmission-fiber interference. The specially designed sensor enables the measurement of refractive index at a fixed point resulting from explosive-driven air blast waves, further allowing for obtaining the pressure and density information. [ABSTRACT FROM AUTHOR]

This study focuses on the impact mechanism of non‐state shareholder governance on technological innovation in state‐owned enterprises (SOEs) from the perspective of executive compensation incentives, using listed manufacturing companies of SOEs from 2014 to 2020 as research samples. The research findings indicate that the mere ownership of shares by non‐state shareholders has no significant impact on technological innovation. However, the delegation of executives by non‐state shareholders contributes to enhancing technological innovation in SOEs. So Improving technological innovation in SOEs is a crucial objective in the ongoing deepening and enhancing actions of the new round of state‐owned enterprise reforms. [ABSTRACT FROM AUTHOR]

The existence of water-filled barriers alters the cross-sectional shape of the main girder, which may lead to vortex-induced vibrations (VIVs) in suspension bridges. However, the mechanism and occurrence conditions of VIVs in the main girder that is affected by water-filled barriers are still unclear. To this end, this study investigates the effect of water-filled barriers on the VIV performance of suspension bridges. The evolution of the vortex structure during one VIV cycle and the corresponding pressure variations, including the average and fluctuating values on the surface, were analyzed. Additionally, the spatiotemporal distribution of the surface pressure was studied using proper orthogonal decomposition (POD). The results show that VIV occurs in the main girder when the height of the water-filled barriers exceeds a threshold value of 0.317. Moreover, a significant negative pressure vortex occurred when the barriers were installed. The vortex underwent the following distinct phases in one VIV cycle: generation, separation, reattachment, and shedding. However, the negative pressure vortex behind the barrier did not vary substantially when the water-filled barriers were installed without VIV. Additionally, the average pressure on the surface of the main girder remained constant regardless of the occurrence of VIVs. In the presence of VIVs, the pressure fluctuations became much more pronounced and were mainly concentrated on the top surface and leading edge of the main girder. Additionally, the dominant modes of the pressure variations correlated with the evolution of the vortices and pressure distribution. [ABSTRACT FROM AUTHOR]

Offshore floating wind turbines may undergo swaying motions, resulting in significant changes in the wake wind field characteristics of the wind turbine, which can seriously affect the applicability and accuracy of existing wake models. This paper systematically investigates the turbulent wake flows of floating wind turbine with swaying motion based on an improved actuator disk method (ADM). The improved ADM is introduced to reproduce the wake flows of wind turbines, and the characteristics of the turbulent wind fields (i.e., mean wind velocity, turbulence intensity and Reynolds stress) are verified by wind tunnel tests. Furthermore, the wind fields of a floating wind turbine with different swaying amplitudes under turbulent atmospheric boundary layer are simulated, and the mean wind fields and turbulent statistics are analyzed. The performance of various existing wake models (i.e., Jensen model, modified Jensen model and Gaussian model) are compared, and a Gaussian-Shear wake model is proposed for floating wind turbines, which can account for non-uniform inflow and accommodate different swaying amplitudes. The results indicate that the proposed Gaussian-Shear wake model outperforms the other three models in describing the wake flows of floating wind turbines with swaying motions, which can be used for layout optimization and yaw control of offshore floating wind turbines. [ABSTRACT FROM AUTHOR]