A Near-Infrared-Controllable Artificial Metalloprotease Used for Degrading Amyloid-β Monomers and Aggregates

Proteolysis of amyloid-β (Aβ) is a promising approach against Alzheimer's disease. However, it is not feasible to employ natural hydrolases directly because of their cumbersome preparation and purification, poor stability, and hazardous immunogenicity. Therefore, artificial enzymes have been developed as potential alternatives to natural hydrolases. Since specific cleavage sites of Aβ are usually embedded inside the β-sheet structures that restrict access by artificial enzymes, this strongly hinders their efficiency for practical applications. Herein, we construct a NIR (near-IR) controllable artificial metalloprotease (MoS₂-Co) using a molybdenum disulfide nanosheet (MoS₂) and a cobalt complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Codota). Evidenced by detailed experimental and theoretical studies, the NIR-enhanced MoS₂-Co can circumvent the restriction by simultaneously inhibition of β-sheet formation and destroying β-sheet structures of the preformed Aβ aggregates in living cell. Furthermore, our designed MoS₂-Co is an easy to graft Aβ-target agent that prevents misdirected or undesirable hydrolysis reactions, and has been demonstrated to cross the blood brain barrier. This method can be adapted for hydrolysis of other kinds of amyloids.     

联保贷款中的策略性违约规避机制设计

针对联保贷款的策略性违约问题,通过对其产生原因的分析以及对现有文献中解决措施的探讨,设计了一个弹性联保贷款合约。该合约的特点在于,随着企业愿意承担的连带责任的增加,企业可获得的期望收益也随之增加,旨在从正面激励企业主动为同伴承担还款责任,达到规避策略性违约的目的。通过数值分析验证了该弹性合约的特性以及适用范围。并进一步在两企业模式基础上进行拓展,讨论了多于两企业的情况下该弹性合约的适用条件。     

Modeling the Effect of Injection Molding Process Parameters on Warpage Using Neural Network Theory

A back propagation artificial neural network (BPANN) prediction model for warpage of injection-molded polypropylene was developed based on an orthogonal design method. The BPANN model was trained by the input and output data obtained from the moldflow software platform simulations. It is proved that the BPANN model can predict the warpage with reasonable accuracy. Utilizing the BPANN model, the effects of the process parameters, packing pressure (Pp), melt temperature (T_me), mold temperature (T_mo), packing time (t_p), cooling time (t_c), and fill pressure (p_f), on the warpage were investigated. The most important process parameter affecting the warpage was Pp, and the second most important was T_me. The rest of the process parameters, T_mo, t_p, t_c, and p_f, were found to be relatively less influential. Warpage increased with elevating T_mo. In contrast, an increase in Pp and T_me caused the warpage to decrease.     

Neural network modeling of hydrological systems: A review of implementation techniques

This paper presents a review of procedural steps and implementation techniques used in the development of artificial intelligence models, generally referred to as artificial neural networks (ANNs), within the water resources domain. It focusses on identifying different areas wherein ANNs have found application thereby elucidating its advantages and disadvantages as well as various challenges encountered in its use. Results from this review provide useful insights into how the performance of ANNs can be improved and potential areas of application that are yet to be explored in hydrological modeling. Recommendations for Resource Managers

• Development of integrated and hybrid artificial intelligent tools is critical to achieving improved forecasts in hydrological modeling studies.

• Further research into comprehending the internal mechanisms of neural networks is required to obtain a practical meaning of each network component deployed to solve real‐world problems.

• More robust optimization techniques and tools like differential evolution, particle swarm optimization and deep neural nets, are yet to be fully explored in the water resources analysis, and should be given more attention to enhance neural networks aptitude for modeling complex and nonlinear hydrological processes.

     

Strategies Towards Capturing Nitrogenase Substrates and Intermediates via Controlled Alteration of Electron Fluxes

Nitrogenase utilizes an ATP-dependent reductase to deliver electrons to its catalytic component to enable two important reactions: the reduction of N₂ to NH₄⁺, and the reduction of CO to hydrocarbons. The two nitrogenase-based reactions parallel the industrial Haber–Bosch and Fischer–Tropsch processes, yet they occur under ambient conditions. As such, understanding the enzymatic mechanism of nitrogenase is crucial for the future development of biomimetic strategies for energy-efficient production of valuable chemical commodities. Mechanistic investigations of nitrogenase has long been hampered by the difficulty to trap substrates and intermediates relevant to the nitrogenase reactions. Recently, we have successfully captured CO on the Azotobacter vinelandii V-nitrogenase via two approaches that alter the electron fluxes in a controlled manner: one approach utilizes an artificial electron donor to trap CO on the catalytic component of V-nitrogenase in the resting state; whereas the other employs a mismatched reductase component to reduce the electron flux through the system and consequently accumulate CO on the catalytic component of V-nitrogenase. Here we summarize the major outcome of these recent studies, which not only clarified the catalytic relevance of the one-CO (lo-CO) and multi-CO (hi-CO) bound states of nitrogenase, but also pointed to a potential competition between N₂ and CO for binding to the same pair of reactive Fe sites across the sulfur belt of the cofactor. Together, these results highlight the utility of these strategies in poising the cofactor at a well-defined state for substrate- or intermediate-trapping via controlled alteration of electron fluxes, which could prove beneficial for further elucidation of the mechanistic details of nitrogenase-catalyzed reactions.     

Allostatic load as a complex clinical construct: A case‐based computational modeling approach

Allostatic load (AL) is a complex clinical construct, providing a unique window into the cumulative impact of stress. However, due to its inherent complexity, AL presents two major measurement challenges to conventional statistical modeling (the field's dominant methodology): it is comprised of a complex causal network of bioallostatic systems, represented by an even larger set of dynamic biomarkers; and, it is situated within a web of antecedent socioecological systems, linking AL to differences in health outcomes and disparities. To address these challenges, we employed case‐based computational modeling (CBM), which allowed us to make four advances: (1) we developed a multisystem, 7‐factor (20 biomarker) model of AL's network of allostatic systems; (2) used it to create a catalog of nine different clinical AL profiles (causal pathways); (3) linked each clinical profile to a typology of 23 health outcomes; and (4) explored our results (post hoc) as a function of gender, a key socioecological factor. In terms of highlights, (a) the Healthy clinical profile had few health risks; (b) the pro‐inflammatory profile linked to high blood pressure and diabetes; (c) Low Stress Hormones linked to heart disease, TIA/Stroke, diabetes, and circulation problems; and (d) high stress hormones linked to heart disease and high blood pressure. Post hoc analyses also found that males were overrepresented on the High Blood Pressure (61.2%), Metabolic Syndrome (63.2%), High Stress Hormones (66.4%), and High Blood Sugar (57.1%); while females were overrepresented on the Healthy (81.9%), Low Stress Hormones (66.3%), and Low Stress Antagonists (stress buffers) (95.4%) profiles. © 2015 Wiley Periodicals, Inc. Complexity 21: 291–306, 2016     

A new characteristic approach for incompressible thermo‐flow in Cartesian and non‐Cartesian grids

A virtual‐characteristic approach is developed for thermo‐flow with finite‐volume methodology in which a multidimensional characteristic (MC) scheme is applied along with artificial compressibility. To obtain compatibility equations and pseudo‐characteristics, energy equation is taken into account in the MC scheme. With this inherent upwinding of convective fluxes, no artificial viscosity is required even at high Reynolds numbers. Another remarkable advantage of the MC scheme lies in its faster convergence rate with respect to the averaging scheme that is found to exhibit substantial delays in convergence. As benchmarks, forced and mixed convections in a cavity and in flow over cylinder and between parallel plates are examined for a wide range of Reynolds, Grashof, and Prandtl numbers. The MC and averaging schemes are applied for simulation purposes. Results show the better performance of the MC scheme in forced and mixed convections. Results confirm the robustness of the MC scheme in terms of accuracy and convergence. Copyright © 2015 John Wiley & Sons, Ltd.     

Probing the Catalytically Active Species in POM-Catalysed DNA-Model Hydrolysis**

Phosphoester hydrolysis is an important chemical step in DNA repair. One archetypal molecular model of phosphoesters is para-nitrophenylphosphate (pNPP). It has been shown previously that the presence of molecular metal oxide [Mo₇O₂₄]⁶⁻ may catalyse the hydrolysis of pNPP through the partial decomposition of polyoxomolybdate framework resulting in a [(PO₄)₂Mo₅O₁₅]⁶⁻ product. Real-time monitoring of the catalytic system using electrospray ionisation mass spectrometry (ESI-MS) provided a glance into the species present in the reaction mixture and identification of potential catalytic candidates. Following up on the obtained spectrometric data, Density Functional Theory (DFT) calculations were carried out to characterise the hypothetical intermediate [Mo₅O₁₅(pNPP)₂(H₂O)₆]⁶⁻ that would be required to form under the hypothesised transformation. Surprisingly, our results point to the dimeric [Mo₂O₈]⁴⁻ anion resulting from the decomposition of [Mo₇O₂₄]⁶⁻ as the active catalytic species involved in the hydrolysis of pNPP rather than the originally assumed {Mo₅O₁₅} species. A similar study was carried out involving the same species but substituting Mo by W. The mechanism involving W species showed a higher barrier and less stable products in agreement with the non-catalytic effect found in experimental results.     

A note on compressive limiting for two‐material flows

In this short note we describe a simple extension to the multi‐material shock‐capturing algorithm presented in (J. Comput. Phys. 2007; 223 :262–297) that can be used to maintain sharp material interfaces. The method takes the form of an artificial compression which is designed so that the material indicator jumps across only a few cells but which does not excite physical instabilities in the flow. The advantages of the approach include its simplicity and flexibility in that it provides a parameter that effectively determines the captured interface thickness. Copyright © 2009 John Wiley & Sons, Ltd.