Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

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.     

Isolation of antimicrobial agent from the marine algae Cystoseira hakodatensis

Cystoseira hakodatensis is an unutilised brown algae belonging to family Sargassaceae. A crude methanol extract from the algae showed inhibitory effects on the growths of Bacillus cereus and Bacillus licheniformis. To isolate the major antimicrobial agent, a sequential active‐guided isolation procedure was applied: liquid–liquid extraction, column chromatography and bio‐autography. A marked antimicrobial agent (active α) was isolated in hydrophobic fraction and was determined to phenolics without carbohydrates and proteins by phytochemical test. Regarding the antimicrobial potential, the isolated active α showed better inhibitory effects against B. cereus and B. licheniformis at 2 and 4 times of lower concentrations (62.5 and 31.3 μg mL^?1) in comparison with epigallocatechin gallate. These results showed that C. hakodatensis is a potential source of antimicrobial agent capable of preventing the growth of the two bacteria.     

Distributed De La Garza algorithm for load-balancing routing in wireless sensor networks

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.

     

Identification of the adverse effect of nitrate on the phosphate release rate and improvement of EBPR process models.

The adverse effect of nitrate on the phosphate release rate in the anaerobic phase was observed and was hardly explainable with conventional EBPR process models. Four possible mechanisms were proposed including substrate competition, reduced fermentation, parallel reaction and sequential reaction. Batch experiments were designed and conducted to identify the dominant mechanism. Results showed that the sequential reaction was the only possible mechanism where only denitrification occurred if any nitrate existed in the anaerobic phase. Then the phosphate release following after the nitrate was completely removed. Nitrate inhibition effect was added into the PHA storage rate to incorporate the sequential reaction in the conventional ASM3 plus EAWAG bio-P module (ASM3 + P). Nitrate inhibition coefficient, K(I,NO,PAO) was found to be as low as 0.05 mg/L. This correlated well with experimental observation where no also meant that the anaerobic compartment of a continuous flow reactor could be seriously affected by the residual nitrate contained in the sludge recycle flow. This phenomenon caused overestimation of the phosphate uptake rate and consequently underestimation of PO4(3-) -P concentration. This problem was resolved by incorporation of a nitrate inhibition term in the ASM3 + P for more accurate simulation of the EBPR process.     

Ethylene polymerization over MgO‐supported zirconocene catalysts

Supported zirconcene catalysts on a new support, MgO, were prepared and tested in ethylene polymerization. Three types of impregnation methods were employed to find an optimum supporting method for MgO. The direct impregnation of Cp₂ZrCl₂ on MgO showed low metal loading and polymerization activity, while the catalyst had a higher metal loading and polymerization activity when MgO was treated with methylaluminoxane (MAO) before supporting. Treatment of MgO with MAO during the supporting step invoked two types of catalytic sites, which was evidenced by the bimodal molecular weight distribution of the polymer products. MgO is considered to have potential as a support for metallocenes.     

Reducing cycle times in manufacturing and supply chains by input and service rate smoothing

A key performance parameter of a manufacturing network or supply chain is its cycle time; the time that a typical item spends in the network. A previous simulation study on a semiconductor assembly and test facility showed that cycle times could be reduced by having smooth input and service rates. This suggested that there is a “cycle time principle” that, for a system with a specified throughput or input rate, the shortest cycle times are obtained when the input and service rates do not vary over time. We prove that this principle is true for the M/G/1 and M/M/s queueing systems and Jackson networks. The analysis involves establishing several results on the concavity of waiting time probabilities and the convexity of expected waiting times and queue lengths, as functions of input and service rates. These results also have natural uses in other optimization problems.     

Microstructure and mechanical behaviour of 3Y-TZP/Mo nanocomposites possessing a novel interpenetrated intragranular microstructure

Yttria stabilized tetragonal zirconia polycrystal (Y-TZP)/0-100 vol % molybdenum (Mo) composites were fabricated by hot-pressing a mixture of Y-TZP powder containing 3 mol % yttria (Y₂O₃) and a fine Mo powder in vacuum. This composite system possessed a novel microstructural feature composed of an interpenetrated intragranular nanostructure, in which either nanometer sized Mo particles or equivalent sized zirconia (ZrO₂) particles located within the ZrO₂ grains or Mo grains, respectively. The strength and toughness were both greatly enhanced with increasing Mo content for the 3Y-TZP/Mo composites thus breaking through the strength-toughness tradeoff relation in transformation toughened ZrO₂ and its composite materials. They exhibited a maximum strength of 2100 MPa and a toughness of 11.4 MPa·m^1/2 for the composite containing 70 vol % Mo. These simultaneous improvements in strength and toughness were determined to be the result of a decrease in flaw size associated with the interpenetrated intragranular nanostructure, and a stress shielding effect created in the crack tip by the elongated Mo polycrystals bridging the crack tip in addition to the stress induced phase transformation.