Inflammation is an important biological process which contributes to risk for depression, in part as a result of the production of proinflammatory cytokines and of alterations in glutamatergic ...neurotransmission. Ketamine has anti-inflammatory properties which might contribute to its antidepressant effects. This study was designed to clarify mechanisms of action for ketamine and its active metabolites, (2
)-hydroxynorketamine (HNK), which also appear to play a major role in ketamine's rapid antidepressant effects. An HMC3 human microglial cell line was used as a model system to test a possible role for ketamine in immune response regulation that might contribute to its antidepressant effects. Our results highlight the fact that ketamine and its two active metabolites can regulate the type I interferon pathway mediated, at least partially, through signal transducer and activation of transcription 3 (STAT3) which plays a major role in the immune response. Specifically, STAT3 downstream genes that were modulated by either ketamine or its active metabolites were enriched in the "response to type I interferon" pathway. Our data also suggest that STAT3 might play a role in ketamine's antidepressant effects, mediated, at least in part, through eukaryotic elongation factor 2 (EEF2), resulting in the augmentation of brain-derived neurotropic factor (BDNF) expression and promoting the synthesis of synaptic proteins postsynaptic density protein 95 (PSD95) and synapsin I (SYN1).
Mode superposition is a widely used method for solving the dynamic equilibrium equation in structural dynamic analysis. However, the accuracy of this method may be reduced when the dynamic ...equilibrium equations are set up using displacement excitation. A new method for developing solutions for dynamic equilibrium equations based on displacement excitation is introduced. The dynamic equilibrium equation is decomposed into two parts, namely displacement excitation and velocity excitation, and precise integration and mode superposition methods are combined to solve the equation. Ritz vectors are then used to calculate the static response of the truncated modes of the structure, and a method for determining the number of participating modes is obtained. Using multi-degree-of-freedom systems as two computational examples, the differences in the structural responses obtained from the displacement excitation and acceleration excitation are compared and analyzed. It is shown that the new solution method generates consistent accuracy between the displacement excitation and acceleration excitation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Characterized by large plastic deformation and energy-dissipation capacity, low-yield-strength steel shear panel dampers (LYSPDs) are widely used as energy-dissipating members in seismic engineering. ...However, the effect of welding on the properties of LYSPDs remains unclear. Hence, in this study, we investigated the matching performance between low-yield-strength steel (LYS) and two different welding materials. Subsequently, the quality of welding between LYS and dissimilar metals was investigated. Furthermore, the fracture characteristics of the welding seam of LYS under large plastic deformation were explored. Finally, the welding performance of LYSPDs under large plastic deformation was verified under cyclic loading. The results of this study are significant in terms of the effect of welding on the properties of LYSPDs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To select a more suitable turbulence model to study tire aerodynamics, the characteristics of a deformed profile of a 185/65 R14 passenger tire were reproduced using 3D printing technology. Based on ...the distance from automobile chassis to the ground, a partially loaded tire model with a height of 150 mm was selected in this paper, and the surface pressure coefficient of the tire model was determined using a wind tunnel test. A computational fluid dynamics (CFD) model was established according to the tire wind tunnel test. The surface pressure coefficient results of three turbulence models, shear stress transport (SST) k-ω, large eddy simulation (LES), and detached eddy simulation (DES) were obtained. Compared with the wind tunnel test results, the mean relative errors of the surface pressure coefficients predicted using SST, LES, and DES in the longitudinal section were 22.4%, 20.9%, and 14.8%, respectively. The LES and DES can capture details of the unsteady flow field that were not predicted by SST. By synthetically analyzing the results of the surface pressure coefficient and flow fields, the DES model is more advantageous than the other two models in predicting the flow characteristics around a statically loaded tire. This study can help designers in the tire industry to apply these cost-effective tools for minimizing the aerodynamic drag of a new tire design.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose
Anaplastic thyroid carcinoma (ATC) is the most lethal form of thyroid cancer with most patients dying of their disease within a few months. Only a very small percentage of long-term survivors ...(LTS) are alive for 2 years or longer. In this retrospective case-control study, we provided a comprehensive comparison between 46 ATC LTSs and 75 ATC control patients who suffered disease-specific mortality within 2 years, aiming to identify factors that may be associated with prolonged survival in ATC.
Methods
A comprehensive clinicopathologic and molecular comparison was performed between 46 ATC LTSs and 75 ATC control patients. Peripheral neutrophil count and neutrophil-to-lymphocyte ratio (NLR) were recorded. The composition of the tumor microenvironment was compared using immunohistochemistry.
Results
Compared with ATC control patients, ATC LTSs were characterized by 1) higher frequency of (primary) resection as well as clinicopathologic parameters attributed to resectability; 2) lower rate of concurrent
RAS/BRAF
and
TERT
promoter mutations; 3) lower peripheral neutrophil count and NLR; and 4) lower number of tumor-infiltrating neutrophils/myeloid-derived suppressor cells (MDSC). The survival benefits of low peripheral neutrophil counts and low NLR persisted even when controlling for distant metastasis status at presentation.
Conclusions
In addition to traditional beneficial prognostic factors, e.g., surgical resection, factors attributed to resectability, and absence of co-existing
RAS/BRAF
and
TERT
promoter mutations, we herein show that tumor-infiltrating and circulating neutrophils/MDSC are adverse prognostic factors in ATC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Long-span spatial structures are typical city landmarks. Earthquakes can cause serious damage to these structures, leading to tremendous human injury and financial loss. Therefore, it is essential to ...develop effective devices to enhance the performance of spatial structures. This article proposes a new triple-tube glass fiber–reinforced polymer and steel buckling-restrained brace device for reticulated shells, which integrates the light weight and high strength advantages of the composite materials. Specimens of scaled glass fiber–reinforced polymer and steel buckling-restrained braces were designed and produced, and pseudo-static tests were performed on these specimens with an MTS machine. Mechanical performance and damages were examined and compared. An elaborate finite-element model was setup, and the accuracy of this model was verified with the test data. In addition, the model was used to investigate the effect of the Pe/Py ratio on the performance of full-scale triple-tube glass fiber–reinforced polymer and steel buckling-restrained brace devices. Finally, the lower limit of the Pe/Py ratio for this kind of buckling-restrained brace was obtained by theoretical derivation and numerical parametric analysis.
At present, the concrete-filled steel tube structure has been widely used in various practical projects. Due to the low tensile strength of the core concrete of round steel tube concrete (CFST) ...specimens, the axial tensile performance of CFST specimens is far from superior to its compressive performance. However, in practical projects, the concrete-filled steel tube members bearing tensile load often appear. In order to study the axial tensile properties of CFST specimens, the axial tensile tests of 5 CFST specimens and 1 pure steel tube specimen were carried out with steel tube diameter and concrete strength as variation parameters. The results show that the bearing capacity of CFST specimens is increased by 7.5%–16.3% compared with that of pure steel tube specimens with the same cross-sectional area, mainly because the core concrete limits the circumferential shrinkage of the outer steel tube. The larger the cross-sectional area of CFST specimens is, the higher the bearing capacity is. In this paper, the stress-strain relationship and the overall failure mode of CFST members under tensile force are studied, and the deformation characteristics and stress of steel pipe and core concrete are analyzed, which is expected to provide a reference for the application of CFST specimens in practical engineering.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Single nucleotide variants in the open reading frames (ORFs) of pharmacogenes are important causes of interindividual variability in drug response. The functional characterization of variants of ...unknown significance within ORFs remains a major challenge for pharmacogenomics. Deep mutational scanning (DMS) is a high‐throughput technique that makes it possible to analyze the functional effect of hundreds of variants in a parallel and scalable fashion. We adapted a “landing pad” DMS system to study the function of missense variants in the ORFs of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily C member 19 (CYP2C19). We studied 230 observed missense variants in the CYP2C9 and CYP2C19 ORFs and found that 19 of 109 CYP2C9 and 36 of 121 CYP2C19 variants displayed less than ~ 25% of the wild‐type protein expression, a level that may have clinical relevance. Our results support DMS as an efficient method for the identification of damaging ORF variants that might have potential clinical pharmacogenomic application.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
We have recently reported that CXCR7, the alternate high affinity SDF-1 receptor, is induced during monocyte-to-macrophage differentiation, leading to increased macrophage phagocytosis linked to ...atherosclerosis. Statins, the most widely used medications for atherosclerosis, were shown to have pleiotropic beneficial effects independent of their cholesterol-lowering activity. This study aimed to determine whether induction of CXCR7 during macrophage differentiation is inhibited by statins and its significance on macrophage physiology. Here we show for the first time that atorvastatin dose-dependently inhibited CXCR7 mRNA and protein expression in THP-1 macrophages, without affecting the other SDF-1 receptor, CXCR4. Pharmacotherapy relevant dose of atorvastatin affected neither cell viability nor macrophage differentiation. Suppression of CXCR7 expression was completely reversed by supplementation with mevalonate. Inhibition of squalene synthase, the enzyme committed to cholesterol biosynthesis, also decreased CXCR7 induction, albeit not as efficacious as atorvastatin. However, the geranylgeranyl transferase inhibitor, GGTI-286, the farnesyl transferase inhibitor, FTI-276, and the Rho kinase inhibitor, Y-27632, all failed to mimic the effect of atorvastatin, suggesting that the protein prenylation pathways are not critical for atorvastatin inhibition of CXCR7 induction. Interestingly, the dramatic effect of atorvastatin was only partially mimicked by other statins including pravastatin, fluvastatin, mevastatin, and simvastatin. Furthermore, activation of CXCR7 by SDF-1, TC14012, or I-TAC all prompted macrophage migration, which was significantly suppressed by atorvastatin treatment, but not by the CXCR4 antagonist. We conclude that atorvastatin modulates macrophage migration by down-regulating CXCR7 expression, suggesting a new CXCR7-dependent mechanism of atorvastatin to benefit atherosclerosis treatment beyond its lipid lowering effect.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although there is no risk of puncture, the vibration problem caused by discontinuous structures limits nonpneumatic tire development (NPT). The vibration reduction of nonpneumatic tires is a solvable ...urgent problem. This current study analyzed the dynamic grounding characteristics and the vibration reduction mechanism of the cat’s paw pads and then applied the mechanical properties to the bionic design of nonpneumatic tire spokes to solve the vibration problem. Domestic cats’ paw pads’ dynamic grounding characteristics were determined using the pressure-sensitive walkway, high-speed camera, and VIC-2D. The results indicated that the mechanical characteristics of swing deformation of paw pads during the grounding process attenuated the grounding stress and buffered the energy storage to achieve the vibration reduction effect. According to the similarity transformation, a finite element model of NPT that could accurately reconstruct the structure and realistically reflect the load deformation was employed. The structure design of asymmetric arcs on the spokes’ side edges was proposed, and it can effectively reduce the radial excitation force of NPT. The three parameters, the asymmetric arc, the thickness, and the curvature of spokes, were used as design variables to maximize the vibration reduction. The orthogonal experimental, the Kriging approximate model, and the genetic algorithm were carefully selected for optimal solutions. Compared with the original tire, the results showed that peak amplitude 1, peak amplitude 2, and the root square of the optimized tire’s amplitudes were reduced by 76.07%, 52.88%, and 51.65%, respectively. These research results offer great potential guidance in the design of low-vibration NPT.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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