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Abstract: The current treatment options for multiple myeloma (MM) osteolytic lesions are mainly combinations of chemotherapy and other small-molecule inhibitors, but toxic side effects still remain a major concern. Studies have shown that osteoclast activity is enhanced in MM patients through increased expression of receptor activator of nuclear factor κB ligand (RANKL), triggering RANK signaling on osteoclast precursors, which results in aggressive bone resorption. Furthermore, osteoprotegerin (OPG), a decoy receptor for RANKL, and the osteogenic potential of mesenchymal stem cells (MSCs) are significantly decreased in myeloma patients with multiple bone lesions. Thus, the use of OPG as a therapeutic molecule would greatly decrease osteolytic damage and reduce morbidity. However, in addition to inhibiting osteoclast activation, OPG binds to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), thereby rendering the tumor cells resistant to TRAIL-induced apoptosis and limiting the use of OPG for therapy. The present study developed a bone-disseminated myeloma disease model in mouse and successfully tested a cell therapy approach using MSCs, genetically engineered to express OPG variants that retain the capacity to bind RANKL, but do not bind TRAIL. Our results of skeletal remodeling following this regenerative stem cell therapy with OPG variants indicated a significant protection against myeloma-induced osteolytic bone damage in areas of major myeloma skeletal dissemination, suggesting the potential of this therapy for treating osteolytic damage in myeloma patients.

Abstract Transforming growth factor (TGF)-β1 contributes to autocrine and paracrine functions in the tumor microenvironment (TME). The present study examined the effects of TGF-β1 crosstalk in TME and its role in mediating tumor formation and progression by targeted abrogation of TGF-β1 expression in metastatic cells in situ. Using species-specific primers, we found a significant increase in MMP-9 gene expression in the tumor-reactive stroma during late-stage metastasis in the lung. This effect was also confirmed in cancer-associated fibroblasts (CAFs) when co-cultured with the tumor cells. Knockdown of TGF-β1 expression in the tumor cells negatively affected matrix metalloproteinase (MMP)-9 gene expression. Fibroblasts, cultured in the presence of tumor cells with intact TGF-β1, showed a significant increase in proliferation rate, as well as expression of VEGF, bFGF, and SDF-1, which was not seen when TGF-β1 expression was abrogated in tumor cells. Absence of TGF-β1 in tumor cells also failed to result in myofibroblast differentiation. Co-implantation of CAFs and tumor cells with either intact TGF-β1 expression or devoid of TGF-β1 in vivo showed a significant increase in tumor growth kinetics in both cell types, suggesting a possible activation TGF-β receptor signaling in tumor cells in response to TGF-β from the TME.

Abstract Rational reforming of metal oxide has a potential importance to modulate their inherent properties toward appealing characteristics for various applications. Here, we present a detailed fundamental study of the proton migration phenomena between mediums and propose the methodology for controllable metal oxide hydrogenation through galvanic reactions with metallic cation under ambient atmosphere. As a proof of concept for hydrogenation, we study the role of proton adoption on the structural properties of molybdenum trioxide, as a representative, and its impact on redox characteristics in Li-ion battery (LiB) systems using electrochemical experiments and first-principles calculation. The proton adoption contributes to a lattice rearrangement facilitating the faster Li-ion diffusion along the selected layered and mediates the diffusion pathway that promote the enhancements of high-rate performance and cyclic stability. Our work provides physicochemical insights of hydrogenations and underscores the viable approach for improving the redox characteristics of layered oxide materials.

This paper presents findings of a study on geogrid reinforced flexible pavement in a low volume road through a three-dimensional finite element analysis. A mechanistic model was developed for geogrid reinforced flexible pavement. To analyze the behavior of pavement foundation, stress-dependent resilient modulus models were employed in both base and subgrade layers. The model also incorporated previous research findings to enhance the reliability of the analysis. During the analysis, comparisons were made to contrast the responses of low volume flexible pavement with and without geogrid. The results show geogrid reinforcement reduces critical pavement responses under traffic loading, such as vertical surface deflection, tensile strain in asphalt concrete, and compressive strain in subgrade. The study found up to 18% reduction of vertical strain at the top of subgrade and 68% reduction of tensile strain at the bottom of asphalt concrete. Also, geogrid provides confining stresses in the adjacent aggregate layer, which leads to surrounding layers becoming stiffer. Based on the results of this study, the placement of geogrid reinforcement on top of weak subgrade was found particularly effective compared to that on strong subgrade. First published online: 24 Oct 2013

Anterior Gradient Protein (AGR-2) is reported to be over-expressed in many epithelial cancers and promotes metastasis. A clear-cut mechanism for its observed function(s) has not been previously identified. We found significant upregulation of AGR-2 expression in a bone metastatic prostate cancer cell line, PC3, following culturing in bone marrow-conditioned medium. Substantial AGR-2 expression was also confirmed in prostate cancer tissue specimens in patients with bone lesions. By developing stable clones of PC3 cells with varying levels of AGR-2 expression, we identified that abrogation of AGR-2 significantly reduced cellular attachment to fibronectin, collagen I, collagen IV, laminin I and fibrinogen. Loss of cellular adhesion was associated with sharp decrease in the expression of α4, α5, αV, β3 and β4 integrins. Failure to undergo apoptosis following detachment is a hallmark of epithelial cancer metastasis. The AGR-2-silenced PC3 cells showed higher resistance to Tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) induced apoptosis in vitro. This observation was also supported by significantly reduced Caspase-3 expression in AGR-2-silenced PC3 cells, which is a key effector of both extrinsic and intrinsic death signaling pathways. These data suggest that AGR-2 influence prostate cancer metastasis by regulation of cellular adhesion and apoptosis.

This paper describes numerical analyses on low volume roads (LVRs) using a nonlinear three-dimensional (3D) finite element model (FEM). Various pavement scenarios are analyzed to investigate the effects of pavement layer thicknesses, traffic loads, and material properties on pavement responses, such as surface deflection and subgrade strain. Each scenario incorporates a different combination of wheel/axle configurations and pavement geomaterial properties to analyze the nonlinear behavior of thinly surfaced asphalt pavement. In this numerical study, nonlinear stress-dependent models are employed in the base and subgrade layers to properly characterize pavement geomaterial behavior. Finite element analysis results are then described in terms of the effects of the asphalt pavement thickness, wheel/axle configurations, and geomaterial properties on critical pavement responses. Conclusions are drawn by the comparison of the nonlinear pavement responses in the base and subgrade in association with the effects of multiple wheel/axle load interactions. Santrauka Straipsnyje aprašoma skaitinė mažo intensyvumo kelių analizė, taikant netiesinį—erdvinį baigtinių elementų modelį. Skirtingi dangų paviršiaus variantai analizuojami siekiant ištirti, kokiąįtaką kelio dangos elgsenai, t. y. poslinkiams ir kelio pagrindo deformacijoms, turi dangų sluoksnių storiai, eismo apkrovos ir medžiagų savybės. Kiekvienas kelio dangos variantas turi skirtingas ratų arba ašies ir geometrinių savybių formas, kad būtų galima išanalizuoti netiesinę plonos asfalto dangos paviršiaus elgseną. Šioje skaitinėje analizėje nagrinėjami netiesiniai įtempių modeliai, kurie buvo taikomi pagrindo sluoksniams, siekiant tinkamai apibūdinti geometrinę kelio dangos elgseną. Baigtinių elementų analizės rezultatai toliau nagrinėjami atsižvelgiant į asfalto dangos storį ar ašies formą ir geometrines savybes, priklausomai nuo kritinės kelio dangos būklės. Išvados buvo gautos lyginant netiesines kelių dangos priklausomybes pagrindo sluoksnyje, atsižvelgiant į jų sąveiką su daugkartine ratų apkrova. Reikšminiai žodžiai: mažo intensyvumo kelias, trimatė baigtinio elemento analizė, netiesinės dangos paviršiaus priklausomybės, daugkartinės ratų arba ašies apkrovos, geometrinės savybės

Electric-field-driven phase transformation phenomena in multiferroic BiFeO3 are directly linked to the functionalities of electronic devices based on multiferroic materials. Understanding how the transformation evolves at the nanoscale under the influence of an electric field will provide fascinating insights into key parameters that utilize the transformation features. Here, we report both the electric-field-driven transient and permanent phase transformations in highly strained BiFeO3 thin films and their transformation dynamics at the nanoscale. We found that two distinct transient and permanent phase transformations were triggered below and above a coercive voltage of the polymorphic phase, indicating that ferroelectric polarization switching could promote permanent phase transformations. We also found that the transient transformations evolve via complex phase boundary motions between the coexisting phases, whereas permanent transformations occurred via nucleation of the other phases.

Ammonia (NH3) has been a subject of great interest due to its important roles in diverse technological applications. However, high toxicity and corrosiveness of NH3 has made it an important task to develop an efficient carrier to safely capture NH3 with high capacity. Here, we employ a machine learning (ML) model to discover high-performance metal organic frameworks (MOFs) that will work as efficient NH3 carriers. By constructing databases at two distinct conditions, adsorption and desorption, through Grand Canonical Monte Carlo (GCMC) simulations to train ML models, we identify eight novel MOFs as potentially efficient NH3 carriers through screening the large-scale MOF databases with the trained models and GCMC verification. The identified MOFs exhibit the average NH3 working capacity exceeding 1100 mg/g, and subsequent molecular dynamics simulations demonstrate mechanical stability of the predicted MOFs. Moreover, analyses of the diffusion mechanism within the proposed MOFs underscore the strong dependence of NH₃ gas diffusivity on the structural details of the materials.

As quantum hardware continues to improve, more and more application scientists have entered the field of quantum computing. However, even with the rapid improvements in the last few years, quantum devices, especially for quantum chemistry applications, still struggle to perform calculations that classical computers could not calculate. In lieu of being able to perform specific calculations, it is important have a systematic way of estimating the resources necessary to tackle specific problems. Standard arguments about computational complexity provide hope that quantum computers will be useful for problems in quantum chemistry but obscure the true impact of many algorithmic overheads. These overheads will ultimately determine the precise point when quantum computers will perform better than classical computers. We have developed QREChem to provide logical resource estimates for ground state energy estimation in quantum chemistry through a Trotter-based quantum phase estimation approach. QREChem provides resource estimates which include the specific overheads inherent to problems in quantum chemistry by including heuristic estimates of the number of Trotter steps and number of necessary ancilla, allowing for more accurate estimates of the total number of gates. We utilize QREChem to provide logical resource estimates for a variety of small molecules in various basis sets, obtaining estimates in the range of 107–1015 for total number of T gates. We also determine estimates for the FeMoco molecule and compare all estimates to other resource estimation tools. Finally, we compare the total resources, including hardware and error correction overheads, demonstrating the need for fast error correction cycle times.

To develop single-phase lightweight high-entropy alloys (LWHEAs), we perform massive screening over a vast material space containing more than 560,000 possible compounds by employing thermodynamic principles and examine the mechanical properties of the resulting alloys based on density functional theory (DFT) calculations. Considering LWHEAs composed of five principal elements including light atoms such as Li, Mg and Al, we identify 40 optimal atomic compositions for single-phase solid solutions in body-centered-cubic structure. Combined with DFT calculations, it is demonstrated that the valence electron concentration plays an important role in determining elastic moduli and that the identified LWHEAs are ductile as is evidenced by the satisfied Pugh criteria and positive Cauchy pressure. In cases of shear modulus and yield strength, pd-hybridization between Al and transition metal atoms is shown to make a significant contribution through forming strong directional bonds. Together with an observation that the inclusion of Li and Mg atoms is instrumental in reducing the overall density, the present results provide a valuable guidance to develop novel, low-density high-entropy alloys.