Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

Macroscopic and Microscopic Structures of Cesium Lead Iodide Perovskite from Atomistic Simulations

A first‐principles‐based effective Hamiltonian is developed and employed to investigate finite‐temperature structural properties of a prototype of perovskite halides, that is CsPbI₃. Such simulations, when using first‐principles‐extracted coefficients, successfully reproduce the existence of an orthorhombic Pnma state and its iodine octahedral tilting angles around room temperature. However, they also yield a direct transformation from Pnma to cubic $Pm\overline{3}m$ upon heating, unlike measurements that reported the occurrence of an intermediate long‐range‐tilted tetragonal P4/mbm phase in‐between the orthorhombic and cubic phases. Such disagreement, which may cast some doubts about the extent to which first‐principle methods can be trusted to mimic hybrid perovskites, can be resolved by “only” changing one short‐range tilting parameter in the whole set of effective Hamiltonian coefficients. In such a case, some reasonable values of this specific parameter result in the predictions that i) the intermediate P4/mbm state originates from fluctuations over many different tilted states; and ii) the cubic $Pm\overline{3}m$ phase is highly locally distorted and develops strong transverse antiphase correlation between first‐nearest neighbor iodine octahedral tiltings, before undergoing a phase transition to P4/mbm under cooling.     

Calf massager: Intervention for body muscle discomfort during prolonged standing

Many occupations require workers to stand for long periods of time without proper interventions, which causes discomfort in the back and lower limbs. Therefore, this study aims to assess the effectiveness in alleviating body muscle discomfort during prolonged standing through the use of a calf massager. This study was conducted among male workers at a manufacturer with production line workers and the list was obtained from the HR Department and simple random sampling was done by number categorization. A total of 100 respondents (50 respondents for both the control and the experimental groups) participated in this study. The experiment took place in a room with a similar setup for the production line. Each respondent was requested to perform the simulated task for 2 hr. For the experimental group, the calf massager was turned on every 15 min. At every 15‐min interval after turning on the calf massager, respondents from both groups were required to evaluate their discomfort level on a Borg's scale CR‐10 questionnaire. The results showed that the level of body discomfort among respondents in the experimental group reduced (20–30%) compared with that of the control group. Multivariate analysis results revealed that the discomfort rating for the lower back, knees, thighs, calves, and feet was significantly lower (p < .05) among the experimental group compared with the control group. For lower body parts, the lower back region was statistically significant (p < .05) at the 90th, 105th, and 120th min; the thigh region was statistically significant (p < .05) at the 120th min; the knee region was statistically significant (p < .05) at the 105th and 120th min; the calf region was statistically significant (p < .05) at all minute intervals except the 15th and 45th min, while the feet region, was statistically significant at the 105th and 120th min. Therefore, this study indicates that calf massage treatment is capable of reducing body muscle discomfort during prolonged standing and highlights the significance of calf massage.     

Perspectives on Design and Innovation

A series of studies of top European and other firms has revealed patterns of design management associated with commercial success. Firms that invest resources and professional expertise in product and industrial design in traditional and new industries have been commercially more successful than firms that pay less attention to these aspects of design. As an industry matures there is a shift in emphasis from design associated with technological innovation, to designs supporting technical improvements, and then to supporting user needs, fashion and product variants. These issues are illustrated through the history of the evolution of the bicycle.     

High density polyethylene-wood flour composite lumber: efficacy of two proprietary biocides in the control of fungal colonization and discoloration

Two proprietary biocides were compounded and extruded at three concentrations, respectively, into high density polyethylene-maple wood flour lumber (HDPE-MWL) and evaluated for their efficacy to control fungal colonization and discoloration using the ASTM Standard G 21-96. Although the silver biocide used in this study did not control fungal colonization and discoloration of HDPE-MWL, statistically significant difference was observed between the highest silver biocide concentration and those of the two lower silver biocide concentrations. The latter exhibited no significant difference with the controls. In contrast, the three levels of zinc biocides showed significant difference from each other with respect to their efficacy against fungal colonization and discoloration of HDPE-MWL. Overall, only the zinc biocide was efficacious against fungal colonization and discoloration. The biocide containing zinc as an active biocidal agent was most efficacious at 1% (by weight) concentration.     

Global complete observability and output-to-state stability imply the existence of a globally convergent observer

We consider systems which are globally completely observable and output-to-state stable. The former property guarantees the existence of coordinates such that the dynamics can be expressed in observability form. The latter property guarantees the existence of a state norm observer and therefore the possibility of bounding any continuous state functions. Both properties allow to conceptually build an observer from an approximation of an exponentially attractive invariant manifold in the space of the system state and an output driven dynamic extension. The proposed observer provides convergence to zero of the estimation error within the domain of definition of the solutions. The work of A. Astolfi is partly supported by the Leverhulme Trust.     

Cyclosporin A and cyclosporin SDZ PSC 833 enhance anti-CD5 ricin A-chain immunotoxins in human leukemic T cells

Recent studies have shown that cyclosporin A (CsA) may affect ricin A-chain immunotoxin (RTA-IT) therapy. In this study, we evaluated the ability of CsA and its nonimmunosuppressive analog, SDZ PSC 833, to enhance anti-CD5 T101 RTA-ITs in vitro. Both 4 mumol/L CsA and 4 mumol/L SDZ PSC 833 significantly and specifically enhanced the cytotoxic activity of T101 RTA-IT on the human lymphoblastic T-cell line, CEM III (101-fold and 105-fold, respectively). Furthermore, these Cs also enhanced the cytotoxicity of the more potent T101 F(ab')2 RTA-IT (ninefold and eightfold, respectively). The effect of human plasma, originating from four patients enrolled in a phase I high-dose CsA regimen, was examined on T101 RTA-IT cytotoxicity on CEM III cells. In each case, with plasma CsA levels between 3,090 and 4,860 ng/mL (2.5 to 4 mumol/L), a significant increase in T101 RTA-IT-mediated cytotoxicity was observed ranging from 31% to 60%. Neither CsA nor SDZ PSC 833 affected the rate of RTA-IT binding, internalization, intracellular trafficking, or degradation. Analysis of internalized T101 RTA-IT molecules showed that these were essentially intact, which suggests that these enhancers may act only on a small population of RTA-ITs that escapes present investigational techniques. In conclusion, because the concentrations used are clinically achievable, Cs appear to be promising agents for in vivo enhancement of RTA-ITs.