Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases. 相似文献
Multimedia Systems - The preferences of Web information purchasers are changing. Cost-effectiveness (i.e., an emphasis on performance with respect to price) is becoming less regarded than... 相似文献
Large scale wireless sensor networks raise many challenges in the design of efficient and effective routing algorithm due to their complexity and hardware constraints. However, the scalability challenge may be mitigated from a macroscopic perspective. One example is the distributed De la Garza iteration (DDLGI) algorithm for global routing load-balancing, based on a set of partial differential equations iteratively solved by the De la Garza method. We theoretically analyze the parallelism of DDLGI and illustrate that the region of interest may impact the degree of parallelism and error. Furthermore, though DDLGI always converges, the slow convergence and long-range information exchange problems may lead to excess energy consumption in communication. Thus, we propose various enhanced De la Garza routing (E-DLGR) algorithms to alleviate the energy consumption problem by which nodes may exchange less information and only need to exchange information with closer nodes to complete each iteration. Our theoretical analysis and simulation results show that the proposed E-DLGR algorithms may have less transmission overhead, thus further reducing energy consumption, and converge faster while still maintaining adequate accuracy.
We demonstrate the structural evolution of polymorphic phases in Al2O3-inserted SrMnO3 ceramics synthesized by solid state reaction. While the 4H-hexagonal phase is predominant in pure SrMnO3 ceramics, a small amount of 6H-hexagonal polymorph is identified in addition to the primary 4H-hexagonal SrMnO3 and the secondary hexagonal SrAl2O4 phases in the as-sintered ceramics, evidenced by x-ray diffraction and subsequent Rietveld refinement analyses. The existence of the 6H-hexagonal SrMnO3 phase is corroborated using Raman spectroscopy. The chemical compositions and electronic structures of the Al2O3-inserted SrMnO3 compounds are also examined using energy dispersive spectroscopy and x-ray photoelectron spectroscopy, respectively. The first-principles calculations reveal that there is no clear difference between the total energies of 4H- and 6H-hexagonal polymorphs regardless of the presence/absence of Sr and oxygen vacancies. Possible origins are discussed with the estimation of actual strain based on the refined lattice parameter of 6H SrMnO3. 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