This paper establishes a three-dimensional symmetrical shield model to investigate the influence of a double-line shield tunnel undercrossing an existing foundation pit and of changed grouting ...pressure on the deformation and mechanical characteristics of both the foundation pit and the tunnel itself, and it proposes a method of symmetrical segmented pressure, in which different grouting pressure is applied in different sections of the tunnel. The monitoring data are used to verify the reliability of the model, and the maximum relative error is 5.44%. The numerical results show that the maximum subsidence of the retaining pile and anchor are 3.76 mm and 10.33 mm, respectively, and the maximum tensile stress of the anchor is increased by 32.4%. The subsidence shape of the foundation pit raft is an arch with four corners warping upward and the maximum subsidence difference is 3.17 mm. Uneven subsidence of the tunnel occurs along the longitudinal direction, and large and small subsidences are located at the outside and underpart of the foundation pit, respectively, and the maximum and minimum values are 11.15 mm and 2.13 mm, respectively, and the maximum subsidence difference is 9.02 mm. The deformation and mechanical characteristics of both the foundation pit and the tunnel are significantly decreased by appropriately increasing the grouting pressure, and it is recommended that the grouting pressure should not exceed 300 kPa. The proposed method of segmented pressure can reduce the differential subsidence by 47.2% and the maximum tensile stress by 27.2%, so it can significantly reduce the uneven subsidence of the tunnel and improve the tunnel stress condition. The research results can provide a theoretical basis for the safe construction of shield tunnels under the existing foundation pit.
Abstract
Background
The aggregation and spread of α-synuclein (α-Syn) protein and related neuronal toxicity are the key pathological features of Parkinson’s disease (PD) and Lewy body dementia (LBD). ...Studies have shown that pathological species of α-Syn and tau can spread in a prion-like manner between neurons, although these two proteins have distinct pathological roles and contribute to different neurodegenerative diseases. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP1) regulates the spread of tau proteins; however, the molecular regulatory mechanisms of α-Syn uptake and spread, and whether it is also regulated by LRP1, remain poorly understood.
Methods
We established
LRP1
knockout (
LRP1
-KO) human induced pluripotent stem cells (iPSCs) isogenic lines using a CRISPR/Cas9 strategy and generated iPSC-derived neurons (iPSNs) to test the role of LRP1 in α-Syn uptake. We treated the iPSNs with fluorescently labeled α-Syn protein and measured the internalization of α-Syn using flow cytometry. Three forms of α-Syn species were tested: monomers, oligomers, and pre-formed fibrils (PFFs). To examine whether the lysine residues of α-Syn are involved in LRP1-mediated uptake, we capped the amines of lysines on α-Syn with sulfo-NHS acetate and then measured the internalization. We also tested whether the N-terminus of α-Syn is critical for LRP1-mediated internalization. Lastly, we investigated the role of Lrp1 in regulating α-Syn spread with a neuronal
Lrp1
conditional knockout (
Lrp1
-nKO) mouse model. We generated adeno-associated viruses (AAVs) that allowed for distinguishing the α-Syn expression versus spread and injected them into the hippocampus of six-month-old
Lrp1
-nKO mice and the littermate wild type (WT) controls. The spread of α-Syn was evaluated three months after the injection.
Results
We found that the uptake of both monomeric and oligomeric α-Syn was significantly reduced in iPSNs with
LRP1
-KO compared with the WT controls. The uptake of α-Syn PFFs was also inhibited in
LRP1
-KO iPSNs, albeit to a much lesser extent compared to α-Syn monomers and oligomers. The blocking of lysine residues on α-Syn effectively decreased the uptake of α-Syn in iPSNs and the N-terminus of α-Syn was critical for LRP1-mediated α-Syn uptake. Finally, in the
Lrp1
-nKO mice, the spread of α-Syn was significantly reduced compared with the WT littermates.
Conclusions
We identified LRP1 as a key regulator of α-Syn neuronal uptake, as well as an important mediator of α-Syn spread in the brain. This study provides new knowledge on the physiological and pathological role of LRP1 in α-Syn trafficking and pathology, offering insight for the treatment of synucleinopathies.
The surface settlement formula of large slope tunnel is derived firstly. Then, the finite element model of shield tunnel is established by using ABAQUS software. Finally, the influences of tunnel ...slope, grouting pressure and shield tail clearance on ground surface settlement, and mechanical properties of surrounding rock and segments are studied by the field measurement and numerical simulation method. The results show that (1) For the slope is less than 4°, the slope increases by 1°, the settlement of ground surface increases by about 2.85 %, the shear stress of surrounding rock increases by about 4.5 kPa, and the tensile and circumferential stresses of segment increase by about 5 % and 3.1 %, respectively. (2) The proper grouting pressure is beneficial to the settlement of ground surface, and the mechanical properties of surrounding rock and segment. (3) For the shield tail clearance is less than 15 cm, the clearance increases by 1 cm, the settlement of ground surface increases by about 0.65 mm, the shear stress of surrounding rock increases by about 4.77 kPa, and the circumferential stress of segment reduces by about 0.02 MPa. Therefore, the grouting pressure with 200 kPa and the shield tail clearance with 10 cm are recommended.
The immunosuppressive tumor microenvironment plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSC). Compared to traditional chemoradiotherapy, immune checkpoint ...inhibitors (ICIs) have become increasingly important in HNSC therapy. Prior studies linked the efficacy of ICIs to PD-L1, microsatellite instability (MSI), HPV infection, tumor mutation burden (TMB), and tumor lymphocyte infiltration in patients with HNSC, but further verification is needed. Additional predictors are needed to recognize HNSC patients with a good response to ICIs. We collected the clinical information and mutation data of HNSC patients from Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA) databases to generate two clinical cohorts. The MSKCC cohort was used to recognize predictors related to the efficacy of ICIs, and the TCGA cohort was used to further examine the immune microenvironment features and signaling pathways that are significantly enriched in the subgroups of predictors. Multivariate Cox regression analysis indicated that age (HR = 0.50,
= 0.014) and ARID1A (HR = 0.13,
= 0.048), PIK3CA (HR = 0.45,
= 0.021), and TP53 (HR = 1.82,
= 0.035) mutations were potential predictors for ICI efficacy in HNSC patients. Age > 65 years and ARID1A or PIK3CA mutations correlated with good overall survival (OS). TP53 mutant-type (MT) patients experienced a worse prognosis than TP53 wild-type (WT) patients. The subgroups associated with a good prognosis (age > 65 years, ARID1A-MT, and PIK3CA-MT) universally had a high TMB and increased expression of immune checkpoint molecules. Although TP53-MT was associated with a high TMB, the expression of most immune checkpoint molecules and immune-related genes was lower in TP53-MT patients than TP53-WT patients, which may reflect low immunogenicity. Pathways related to the immunosuppressive tumor microenvironment were mostly enriched in the subgroups associated with a poor prognosis (age ≤ 65 years, low TMB, ARID1A-WT, PIK3CA-WT, and TP53-MT). In conclusion, the factors age > 65 years, PIK3CA-MT, and ARID1A-MT predicted favorable efficacy for ICI treatment in HNSC patients, and TP53 mutation was a negative predictor.
Alzheimer's disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, ...while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD.
We integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP) via multiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes. The expression patterns and functional relevance of the top sex-specific network driver of AD were further investigated using postmortem human brain samples and gene perturbation experiments in AD mouse models.
Gene expression changes in AD versus control were identified for each sex. Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex. Key network regulators were further identified as potential drivers of sex differences in AD development. LRP10 was identified as a top driver of the sex differences in AD pathogenesis and manifestation. Changes of LRP10 expression at the mRNA and protein levels were further validated in human AD brain samples. Gene perturbation experiments in EFAD mouse models demonstrated that LRP10 differentially affected cognitive function and AD pathology in sex- and APOE genotype-specific manners. A comprehensive mapping of brain cells in LRP10 over-expressed (OE) female E4FAD mice suggested neurons and microglia as the most affected cell populations. The female-specific targets of LRP10 identified from the single cell RNA-sequencing (scRNA-seq) data of the LRP10 OE E4FAD mouse brains were significantly enriched in the LRP10-centered subnetworks in female AD subjects, validating LRP10 as a key network regulator of AD in females. Eight LRP10 binding partners were identified by the yeast two-hybrid system screening, and LRP10 over-expression reduced the association of LRP10 with one binding partner CD34.
These findings provide insights into key mechanisms mediating sex differences in AD pathogenesis and will facilitate the development of sex- and APOE genotype-specific therapies for AD.
Electrocatalytic CO2 reduction reaction (CO2RR) is one of the most effective methods to convert CO2 into useful fuels. Introducing defects into metal nanostructures can effectively improve the ...catalytic activity and selectivity towards CO2RR. This review provides the recent progress on the use of metal nanomaterials with defects towards electrochemical CO2RR and defects engineering methods. Accompanying these ideas, we introduce the structure of defects characterized by electron microscopy techniques as the characterization and analysis of defects are relatively difficult. Subsequently, we present the intrinsic mechanism of how the defects affect CO2RR performance. Finally, to promote a wide and deep study in this field, the perspectives and challenges concerning defects engineering in metal nanomaterials towards CO2RR are put forward.
Compared with large size foam, pressure microfoam has the characteristics of a good pipeline transportation stability, good jet orientation, strong impact force, and strong ability to capture fine ...dust, which is more suitable for dust removal. The traditional foam preparation device has the disadvantages of high-pressure loss, poor foaming effect, and foam uniformity. To overcome the above shortcomings, the annular air supply vertical foam preparation device was proposed in the article. The foaming cylinder of the device adopts a vertical design to avoid the influence of uneven distribution of foam caused by gravity; the spiral nozzle is used to evenly spray the foaming liquid on the foaming mesh to increase the contact area between foam and airflow. The stainless steel wire mesh and cotton wire mesh are adopted to improve the reliability and durability of concave foaming mesh. The performance of the new device was obtained by the self-built experimental system. Finally, the field test shows that the conditions of the heading face could fully meet the requirements of the device for pressure water and compressed air, and the produced pressure microfoam can effectively control dust.
Introduction
Cerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood‐brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) ...cases.
Methods
We performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin‐5 (CLDN5) and occludin (OCLN), and major AD‐related molecules (amyloid beta Aβ40, Aβ42, tau, p‐tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA.
Results
Higher levels of soluble tau, insoluble p‐tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels.
Discussion
Refining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.
Although mounting evidence has demonstrated an important role of Wnt/β-catenin signaling in the development and progression of cancer, the therapeutic potential of small molecules that target this ...pathway for prostate cancer remains largely unknown. We reported herein that the highly invasive androgen-independent PC-3 and DU145 human prostate cancer cells exhibited higher levels of Wnt/β-catenin signaling than the androgen-dependent LNCaP prostate cancer cells and non-cancerous PZ-HPV-7 and PWR-1E prostate cells, and that exogenous Wnt3A treatment exaggerated the difference of the Wnt/β-catenin signaling levels among these prostate cells. Furthermore, we demonstrated that the non-steroidal anti-inflammatory drug, sulindac sulfide, the cyclooxygenase-2 (COX-2) selective inhibitor, celecoxib, and the nitric oxide-donating aspirin derivative, NO-ASA, blocked Wnt/β-catenin signaling in PC-3 and DU145 cells. These effects occurred at concentrations comparable to those required to inhibit cell proliferation, indicating that the inhibitory effect of these drugs on prostate cancer cell proliferation may involve the suppression of Wnt/β-catenin signaling. Finally, we showed that a novel small molecule inhibitor of Wnt/β-catenin signaling, PKF118- 310, inhibited Wnt/β-catenin signaling and proliferation in prostate cancer cells within the same concentration range. Together, these results suggest that small molecules that inhibit Wnt/β-catenin signaling have therapeutic potential for the prevention or treatment of prostate cancer.
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