Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments. 相似文献
First examples of multichain (polycatenar) compounds, based on the π-conjugated [1]benzothieno[3,2-b]benzothiophene unit are designed, synthesized, and their soft self-assembly and charge carrier mobility are investigated. These compounds, terminated by the new fan-shaped 2-brominated 3,4,5-trialkoxybenzoate moiety, form bicontinuous cubic liquid crystalline (LC) phases with helical network structure over extremely wide temperature ranges (>200 K), including ambient temperature. Compounds with short chains show an achiral cubic phase with the double network, which upon increasing the chain length, is at first replaced by a tetragonal 3D phase and then by a mirror symmetry is broken triple network cubic phase. In the networks, the capability of bypassing defects provides enhanced charge carrier mobility compared to imperfectly aligned columnar phases, and the charge transportation is non-dispersive, as only rarely observed for LC materials. At the transition to a semicrystalline helical network phase, the conductivity is further enhanced by almost one order of magnitude. In addition, a mirror symmetry broken isotropic liquid phase is formed beside the 3D phases, which upon chain elongation is removed and replaced by a hexagonal columnar LC phase. 相似文献
AbstractBuilding thermal inertia and operation control strategies have impacted on the thermal performance of a radiant floor heating system. This study conducts a two-dimensional numerical analysis of an intermittently operated radiant floor heating system using the Re-Normalization Group model with Discrete Ordinates Radiation model. A detailed numerical simulation setups and various analyses are provided, including grid independency analysis, initial condition, time step sizes and external boundary conditions. Three different weekend day intermittent operation strategies are investigated. The results showed that Case 3 designed with pre-heating of 20?h has better performance compared to Case 1 designed with pre-heating of 8?h and Case 2 designed with pre-heating of 14?h. The average indoor air temperature differences of approximate 2.1, 1.6 and 1.2 K are observed for Case 1, Case 2 and Case 3, respectively, when comparing two-time slot at 8:00am on Friday morning and Monday morning. This significantly highlights the effect of thermal inertia and the potential of energy saving due to the utilization of intermittent operation. Therefore, the current study presents numerical simulation potential in evaluating the radiant floor heating effects on indoor thermal environment, taking into account building thermal inertia and transient external climatic conditions. 相似文献
Multimedia Tools and Applications - The rapid urbanization process is escalating the urban waste problem, and ineffective management has worsened the issue, leading to severe consequences to the... 相似文献
Metals and Materials International - This study investigated the influence of the initial grain size on the plastic deformation and tunnel defects that occurred from friction stir welding of... 相似文献
NaA zeolite membranes were synthesised in the secondary growth hydrothermal method based on the seeding of the inner surface of a ceramic α-alumina tube. The impacts of crystallisation time and zeolite precursor concentration (in H2O) were investigated. The structure and stability of the prepared NaA zeolite membranes were also investigated with operating temperatures, times and pressures. The results indicate that the optimal synthesis gel molar composition was 3Na2O: 2SiO2: Al2O3: 200H2O. This led to cubic-shaped NaA zeolite which showed good stability. The optimal NaA zeolite membrane had H2O and CH3OH fluxes of 2.77 and 0.19 kg/m2h, with H2O/H2 and CH3OH/H2 separation factors of ∞ and 0.09 at a temperature of 30 °C. The NaA zeolite membrane had high thermal stability, but poor separation performance at high temperature (240 °C). The results suggested that the H2 permeation flux is significantly influenced by preferential adsorption of vapour in the NaA zeolite membrane. 相似文献
It has been proposed that Mg2+ and Fe2+ are very similar in interacting with ribozymes and some protein-based enzymes, but their activities with DNAzymes have yet to be studied. Here, the activity of Fe2+ as cofactor for a few RNA-cleaving DNAzymes is investigated. 17E is a well-studied DNAzyme that is active in the presence of many different divalent metal ions; it is highly active with Fe2+ with an apparent Kd of 29.7±2.3 μm and a kobs of 1.12±0.11 min−1 in the presence of 1 mm Fe2+ at pH 7.5. Fe2+ has 21-fold higher activity than Mg2+. Six different DNAzymes are then tested, and only the DNAzymes active with Mg2+ (17E, 8–17, and E5) are active with Fe2+. Fe2+ has 25 and one- to twofold higher activity than Mg2+ for the 8–17 and E5 DNAzymes, respectively. In pH>7 buffer and in presence of air, 1 mm Fe2+ results in a nonspecific degradation of the DNA strand due to reactive oxygen species (ROS). Cleavage reactions in anoxic environment and antioxidant ascorbate can be used to overcome the effect of oxidation. The findings provide insights for potential DNAzyme catalysis in the early Earth, and they further support the similarity between Mg2+ and Fe2+ in enzyme catalysis. 相似文献
In the development of metal-organic frameworks (MOFs), secondary building units (SBUs) have been utilized as molecular modules for the construction of nanoporous materials with robust structures. Under solvothermal synthetic conditions, dynamic changes in the metal coordination environments and ligand coordination modes of SBUs determine the resultant product structures. Alternatively, MOF phases with new topologies can also be achieved by post-synthetic treatment of as-synthesized MOFs via the introduction of acidic or basic moieties that cause the simultaneous cleavage/reformation of coordination bonds in the solid state. In this sense, we studied the solid-state transformation of two ndc-based Zn-MOFs (ndc = 1,4-naphthalene dicarboxylate) with different SBUs but the same pcu topology to another MOF with sev topology. One of the chosen MOFs with pcu nets is [Zn2(ndc)2(bpy)]n (bpy = 4,4′-bipyridine), (6Cbpy-MOF) consisting of a 6-connected pillared-paddlewheel SBU, and the other is IRMOF-7 composed of 6-connected Zn4O(COO)6 SBUs and ndc. Upon post-structural modification, these pcu MOFs were converted into the same MOF with sev topology constructed from the uncommon 7-connected Zn4O(COO)7 SBU (7C-MOF). The appropriate post-synthetic conditions for the transformation of each SBUs were systematically examined. In addition, the effect of the pillar molecules in the pillared-paddlewheel MOFs on the topology conversion was studied in terms of the linker basicity, which determines the inertness during the solid-state phase transformation. This post-synthetic modification approach is expected to expand the available methods for designing and synthesizing MOFs with controlled topologies.