The mechanism by which ECM elasticity induces lineage specification of stem cells has not been clearly understood. Integrins are well-documented mechanosensors that are positioned at the beginning of the sensing pathway. By using an antibody specifically recognizing the active conformation of β1 integrin, we observed that β1 integrin activation in bone marrow mesenchymal stem cells (BMMSCs) was induced by soft substrate to a significantly greater degree than by stiff substrate. In contrast, however, the level of cell surface integrin on soft substrate was significantly lower than that on stiff substrate. Soft substrate markedly enhanced the internalization of integrin, and this internalization was mediated mainly through caveolae/raft-dependent endocytosis. The inhibition of integrin internalization blocked the neural lineage specification of BMMSCs on soft substrate. Furthermore, soft substrate also repressed the bone morphogenetic protein (BMP)/Smad pathway at least partially through integrin-regulated BMP receptor endocytosis. A theoretical analysis based on atomic force microscopy (AFM) data indicated that integrin-ligand complexes are more easily ruptured on soft substrate; this outcome may contribute to the enhancement of integrin internalization on soft substrate. Taken together, our results suggest that ECM elasticity affects integrin activity and trafficking to modulate integrin BMP receptor internalization, thus contributing to stem cell lineage specification.integrin trafficking | mesencymal stem cells | neurogenic lineage | traction force M echanical environment plays an important role in regulating cellular function and behavior, including proliferation, migration, apoptosis, and differentiation (1-3). It has been shown recently that the mechanical properties (e.g., elasticity) of adhesion substrates modulate stem cell fate in both 2D (4, 5) and 3D (6) cultures. However, the mechanism by which mechanical properties of ECM affect the chemical signaling processes has not been clearly understood.Mechanical stimuli induce changes in focal adhesion (FA) protein activities and FA remodeling (7,8). The growth and elongation of FAs vary with changes in substrate stiffness, indicating that ECM elasticity regulates FA assembly (4). FA complexes consist of many signaling molecules (including Src, Cas, vinculin, and integrins), which can undergo tension-dependent conformational changes to affect kinase activity, phosphorylation site availability, intracellular localization, and/or ligand affinity (9-12). Among these molecules, integrins are necessary for most mechanosensing processes and are positioned at the beginning of the sensing pathway (13).We aimed to explore the mechanism by which stem cells sense ECM elasticity, especially the role of β1 integrin in bone marrow mesenchymal stem cells (BMMSCs) (14). Activation of β1 integrin in BMMSCs was significantly greater on softer than on stiffer substrate. Most importantly, the intracellular localization of β1 integrin varied with substrate elasticity, being pres...

S U M M A R YW e present a systematic and efficient approach for computing the dispersion curves (i.e. phase velocities for a given frequency) as well as the eigenfunctions of normal modes in a multilayered half-space medium. Our approach is superior t o previous approaches in the following aspects. First, it is a simple and self-contained algorithm for simultaneously determining both the phase velocities and the corresponding eigenfunctions. From the basic principle that the normal modes are nun-trivial solutions of the free elastodynamic equation under appropriate boundary conditions, we naturally derive the phase velocities and eigenfunctions. Second, because we use the reflection/transmission coefficients of Luco & Apsel's version (Luco & Apse1 1983), which intrinsically exclude the growth terms, our algorithm not only exhibits the physical mechanism of the formation of normal modes, i.e. constructive interference, as Kennett's did (1979,1983), but also is numerically more stable for high-frequency cases. Furthermore, we derive a high-frequency asymptotic solution of the fundamental Rayleigh mode. Therefore, our approach can provide efficient and accurate solutions in any frequency range, and it is expected t o be a powerful and useful tool for simulating the LR and RR phases and complete seismograms a t regional distances.

It has been widely recognized that the cross-correlation function of ambient seismic noise data recorded at two stations approximates to the part of Greens function between two stations. Therefore, the cross-correlation function should include higher modes, aside from the fundamental mode. However, the problem of measuring or extracting overtones from ambient seismic noise data remains. In this paper, we propose the frequency-Bessel transform method (F-J method) for extracting the dispersion curves of higher modes from ambient seismic noise data. We then assess the validity, accuracy, and applicability of the F-J method by conducting extensive numerical simulations and processing the observed ambient seismic noise data of the USArray. As demonstrated in this study, the F-J method is a convenient, practical, and accurate method for extracting the dispersion curves of multimodes from ambient seismic noise data and therefore has significant potentiality in the field of ambient seismic noise tomography.

Benchun Duan et al. "A suite of exercises for verifying dynamic earthquake rupture codes. " Seismological Research Letters 89, no. 3 (2018) We describe a set of benchmark exercises that are designed to test if computer codes that simulate dynamic earthquake rupture are working as intended. These types of computer codes are often used to understand how earthquakes operate, and they produce simulation results that include earthquake size, amounts of fault slip, and the patterns of ground shaking and crustal deformation. The benchmark exercises examine a range of features that scientists incorporate in their dynamic earthquake rupture simulations. These include implementations of simple or complex fault geometry, off-fault rock response to an earthquake, stress conditions, and a variety of formulations for fault friction. Many of the benchmarks were designed to investigate scientific problems at the forefronts of earthquake physics and strong ground motions research. The exercises are freely available on our website for use by the scientific community.

Transition metal dichalcogenides (TMDs) have attracted much attention due to their promising optical, electronic, magnetic, and catalytic properties. Engineering the defects in TMDs represents an effective way to achieve novel functionalities and superior performance of TMDs devices. However, it remains a significant challenge to create defects in TMDs in a controllable manner or to correlate the nature of defects with their functionalities. In this work, taking single-layer MoS 2 as a model system, defects with controlled densities are generated by 500 keV Au irradiation with different ion fluences, and the generated defects are mostly S vacancies. We further show that the defects introduced by ion irradiation can significantly affect the properties of the single-layer MoS 2 , leading to considerable changes in its photoluminescence characteristics and electrocatalytic behavior. As the defect density increases, the characteristic photoluminescence peak of MoS 2 first blueshifts and then redshifts, which is likely due to the electron transfer from MoS 2 to the adsorbed O 2 at the defect sites. The generation of the defects can also strongly improve the hydrogen evolution reaction activity of MoS 2 , attributed to the modified adsorption of atomic hydrogen at the defects.

S U M M A R YIn this study, we propose a new numerical method, named as Traction Image method, to accurately and efficiently implement the traction-free boundary conditions in finite difference simulation in the presence of surface topography. In this algorithm, the computational domain is discretized by boundary-conforming grids, in which the irregular surface is transformed into a 'flat' surface in computational space. Thus, the artefact of staircase approximation to arbitrarily irregular surface can be avoided. Such boundary-conforming gridding is equivalent to a curvilinear coordinate system, in which the first-order partial differential velocity-stress equations are numerically updated by an optimized high-order non-staggered finite difference scheme, that is, DRP/opt MacCormack scheme. To satisfy the free surface boundary conditions, we extend the Stress Image method for planar surface to Traction Image method for arbitrarily irregular surface by antisymmetrically setting the values of normal traction on the grid points above the free surface. This Traction Image method can be efficiently implemented. To validate this new method, we perform numerical tests to several complex models by comparing our results with those computed by other independent accurate methods. Although some of the testing examples have extremely sloped topography, all tested results show an excellent agreement between our results and those from the reference solutions, confirming the validity of our method for modelling seismic waves in the heterogeneous media with arbitrary shape topography. Numerical tests also demonstrate the efficiency of this method. We find about 10 grid points per shortest wavelength is enough to maintain the global accuracy of the simulation. Although the current study is for 2-D P-SV problem, it can be easily extended to 3-D problem.

While radiation therapy is commonly used for treating cancer, radiation resistance can limit long-term control of the disease. In this study, we investigated the reprogramming of the energy metabolism in radiosensitive and radioresistant head and neck squamous cell carcinomas (HNSCC) using a preclinical matched model of radiation resistance. Our investigation found that radioresistant rSCC-61 cells: 1. They display increased glucose uptake and decreased fatty acid uptake; 2. They deviate from the classical Warburg effect by diverting the glycolytic flux into the pentose phosphate pathway; 3. They are more dependent on glucose than glutamine metabolism to support growth; 4. They have decreased mitochondrial oxidative phosphorylation; 5. They have enhanced fatty acid biosynthesis by increasing the expression of fatty acid synthase; and 6. They utilize endogenous fatty acids to meet the energy demands for proliferation. Inhibition of fatty acid synthase with orlistat or FASN siRNA resulted in increased cytotoxicity and sensitivity to radiation in rSCC-61 cells. These results demonstrate the potential of combination therapy using radiation and orlistat or other inhibitors of lipid and energy metabolism for treating radiation resistance in HNSCC.

Lianhuaqingwen (LHQW) capsule, a herb medicine product, has been clinically proved to be effective in coronavirus disease 2019 (COVID-19) pneumonia treatment. However, human exposure to LHQW components and their pharmacological effects remain largely unknown. Hence, this study aimed to determine human exposure to LHQW components and their anti-COVID-19 pharmacological activities. Analysis of LHQW component profiles in human plasma and urine after repeated therapeutic dosing was conducted using a combination of HRMS and an untargeted data-mining approach, leading to detection of 132 LHQW prototype and metabolite components, which were absorbed via the gastrointestinal tract and formed via biotransformation in human, respectively. Together with data from screening by comprehensive 2D angiotensin-converting enzyme 2 (ACE2) biochromatography, 8 components in LHQW that were exposed to human and had potential ACE2 targeting ability were identified for further pharmacodynamic evaluation. Results show that rhein, forsythoside A, forsythoside I, neochlorogenic acid and its isomers exhibited high inhibitory effect on ACE2. For the first time, this study provides chemical and biochemical evidence for exploring molecular mechanisms of therapeutic effects of LHQW capsule for the treatment of COVID-19 patients based on the components exposed to human. It also demonstrates the utility of the human exposure-based approach to identify pharmaceutically active components in Chinese herb medicines.