Characterizing fatigue damage behaviors of concrete beam specimens in varying amplitude load

In this paper, the random and nonlinear mechanical characteristics of the composition distribution of concrete in each phase are investigated to solve the difficulty of fatigue damage test of concrete beam specimens under variable amplitude loading. A three-dimensional (3D) concrete composite random aggregate meso-model of concrete beam specimens is built with Digimat as a composite modeling tool. Subsequently, the bending-tensile strength and fatigue life of the model under four-point bending loading is analyzed and calculated using Abaqus finite element analysis model based on the concrete elastic-plastic damage criterion. The mechanical behaviors of concrete materials under static load failure, multistage fatigue loading, and random fatigue loading are studied. Finally, compared with the test results, the following conclusions are obtained. The random aggregate model and elastoplastic damage mechanics model of concrete composite constructed by concrete in Abaqus and Digimat can better describe the geometric and distribution characteristics of composite structure and aggregate in concrete beams and the mechanical behavior of fatigue and static load failure. The difference is 4.08 % with the experimental results, which verifies the validity and reliability of the numerical simulation model, and the fatigue life of concrete beams under random loading Sra and Srb is 1622 and 164 times, respectively. The research results have certain guiding significance and reference value for accurate calculation of bending and tensile strength of concrete beams under specified raw material and mix ratio and prediction of fatigue damage cracking in airport cement concrete pavement structure

Numerical Analysis on the Mechanical Properties of the Concrete Precast Pavement of Runways under the Wheel Load

This study aims to investigate the mechanical characteristics of precast concrete runway cement pavement under the wheel load of aircraft, and to promote the construction of precast concrete pavement. In this study, based on the elastic layered Boussinesq calculation theory and ABAQUS finite element numerical model, the distribution law of stress, the displacement of the aircraft wheel load acting on different positions of the pavement slab, the influence of the added dowel bar on the pavement slab, and the load transfer between adjacent slabs are obtained. The results revealed that when the wheel load of the aircraft acts on the edge and joint of the slab, the vertical stress of the adjacent slab edge is largest, followed by the middle of the slab, and then the joint; the maximum vertical stress is 0.295 MPa. Furthermore, the aircraft wheel load on the slab edge, and the joint vertical displacement, is larger than that of the slab middle, and the adjacent slab edge transverse displacement attenuation coefficient is approximate. Moreover, the load transfer efficiency of the dowel bar was lower when the wheel load of the aircraft was closer to another unloaded slab. Finally, the validity and sensitivity of the simulation results are verified by laboratory test data. These results can provide a reference and suggestions for the design and production of the precast concrete pavement of airport runways

Numerical Analysis on the Mechanical Properties of the Concrete Precast Pavement of Runways under the Wheel Load

This study aims to investigate the mechanical characteristics of precast concrete runway cement pavement under the wheel load of aircraft, and to promote the construction of precast concrete pavement. In this study, based on the elastic layered Boussinesq calculation theory and ABAQUS finite element numerical model, the distribution law of stress, the displacement of the aircraft wheel load acting on different positions of the pavement slab, the influence of the added dowel bar on the pavement slab, and the load transfer between adjacent slabs are obtained. The results revealed that when the wheel load of the aircraft acts on the edge and joint of the slab, the vertical stress of the adjacent slab edge is largest, followed by the middle of the slab, and then the joint; the maximum vertical stress is 0.295 MPa. Furthermore, the aircraft wheel load on the slab edge, and the joint vertical displacement, is larger than that of the slab middle, and the adjacent slab edge transverse displacement attenuation coefficient is approximate. Moreover, the load transfer efficiency of the dowel bar was lower when the wheel load of the aircraft was closer to another unloaded slab. Finally, the validity and sensitivity of the simulation results are verified by laboratory test data. These results can provide a reference and suggestions for the design and production of the precast concrete pavement of airport runways

Identification of a small molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical models

<p><span>T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC' cleft of Tim-3, a highly conserved binding site of </span><span>phosphatidylserine</span><span> (PtdSer) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of </span><span>primary CD8<sup>+</sup> cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion </span><span>in vitro and in vivo</span><span>. In addition, ML-T7 promoted NK cells' killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3.</span><span> Notably, ML-T7 strengthened DCs' functions through both Tim-3 and Tim-4, consistent with the hypothesis that Tim-4 contains a similar FG-CC' loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to Tim-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wildtype and Tim-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti-PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking Tim-3 and warrants further study.</span></p><p>Funding provided by: National Natural Science Foundation of China<br>Crossref Funder Registry ID: https://ror.org/01h0zpd94<br>Award Number: 81830017</p><p>Funding provided by: National Natural Science Foundation of China<br>Crossref Funder Registry ID: https://ror.org/01h0zpd94<br>Award Number: 31600714</p><p>Funding provided by: National Natural Science Foundation of China<br>Crossref Funder Registry ID: https://ror.org/01h0zpd94<br>Award Number: 81903454</p><p>Funding provided by: National Postdoctoral Program for Innovative Talents<br>Award Number: BX201700147</p><p>Funding provided by: Young Elite Scientist Sponsorship Program by CAST<br>Award Number: YESS20160077</p><p>Funding provided by: Taishan Scholarship<br>Award Number: 20181201</p><p>Funding provided by: Shandong Natural Science Foundation<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100007129<br>Award Number: ZR2020ZD12</p><p>Funding provided by: National Key Research and Development Program<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100012166<br>Award Number: 2021YFC2300603</p><p>Splenocytes from OT-Ι mice were stimulated with 10 nM OVA<sub>257-264</sub> peptide in RPMI 1640 medium containing 10% FBS, 50 U/mL penicillin-streptomycin, 50 μM 2-Mercaptoethanol, 20 U/mL human recombinant IL-2 and 10 μM ML-T7/DMSO for 3 days, followed by 3 days culture in the presence of ML-T7/DMSO to get mature CTLs unless otherwise indicated.Total RNA was isolated from DMSO or ML-T7 treated CD8<sup>+</sup> CTLs using TRIzol reagent (Invitrogen). RNA-Seq analysis was performed with an Illumina HiSeq 2500 or BGISEQ-500 by BGI (Shenzhen, Guangdong, China). Data quality was assessed with fastqc software and aligned to the mouse genome (mm10 build) using TopHat (with Bowtie2), and data was curated and visualized using the BGI Interactive analysis platform.RNAseq detected 1271 differentially expressed transcripts (1.5-fold or more) in ML-T7-treated CD8<sup>+</sup> CTLs. Specifically, ML-T7 treatment upregulated several effector T cell-associated genes, including <em>Lck</em>, <em>Zap70</em>, <em>Erk1</em>, <em>Il-2</em> and <em>Cd69</em>, while downregulated several exhausted T cell-associated genes, including <em>Havcr2, Tigit</em> and <em>Ctla4</em>. Gene set enrichment analysis (GSEA) showed that TCR signaling pathway and IL2-STAT5 pathway were significantly enriched in ML-T7-treated CTLs.</p&gt