Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering

Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad‐spectrum antibiotic lead was generated with significantly improved activity, including against all Gram‐negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering.     

A Nondifferentiable Optimization Algorithm for Structural Problems with Eigenvalue Inequality Constraints*

This paper presents a nondifferentiable optimization algorithm for solution of structural optimal design problems with eigenvalue inequality constraints. The algorithm is shown to be convergent both in the L _∞ and in the sequence space topologies.     

A Tensile Strain Hardening Test Indicator of Environmental Stress Cracking Resistance

Environmental stress cracking resistance (ESCR) is an important indicator of performance for high density polyethylene (HDPE) in structural and polymer pipe applications. The commonly used test for determining ESCR of HDPE can be time consuming and rather imprecise. A tensile strain hardening test was recently proposed to offer a faster way to characterize ESCR of polyethylene. In this paper, a practical approach is adopted whereby the test is extended to room temperature and shown to relate reliably to the ESCR of HDPE. Several HDPE resins (including pipe‐grade resins) are analyzed at strain rates of 0.5 mm/min and 7 mm/min to compare the effect of strain rate. Comparisons between the conventional ESCR test method and the strain hardening test show that strain hardening can be used to rank ESCR of HDPE in a reliable fashion. In our study the more direct measure of “hardening stiffness” is used to compare resins instead of strain hardening modulus. Because no true stress‐strain measurement is needed, this is a much simpler test method than other methods previously suggested. In addition, the use of the natural drawing ratio (NDR) as ESCR ranking indicator is examined. Results show that NDR can also be employed as a strain rate‐independent indicator of ESCR of HDPE. The test proposed herein is practical, simple and precise, and hence a more reliable indicator of ESCR performance of HDPE.     

On the Perpetual Collision-Free RHC of Fleets of Vehicles

Receding horizon control is emerging as a very promising technique for the centralized control of fleets of vehicles on land, sea, and in the air. We present a sufficient condition for collision avoidance within a fleet under receding horizon control, over an indefinite period of operation.     

An Algorithm Based on Active Sets and Smoothing for Discretized Semi-Infinite Minimax Problems

We present a new active-set strategy which can be used in conjunction with exponential (entropic) smoothing for solving large-scale minimax problems arising from the discretization of semi-infinite minimax problems. The main effect of the active-set strategy is to dramatically reduce the number of gradient calculations needed in the optimization. Discretization of multidimensional domains gives rise to minimax problems with thousands of component functions. We present an application to minimizing the sum of squares of the Lagrange polynomials to find good points for polynomial interpolation on the unit sphere in ℝ³. Our numerical results show that the active-set strategy results in a modified Armijo gradient or Gauss-Newton like methods requiring less than a quarter of the gradients, as compared to the use of these methods without our active-set strategy. Finally, we show how this strategy can be incorporated in an algorithm for solving semi-infinite minimax problems.     

On the Convergence of the Pshenichnyi-Pironneau-Polak Minimax Algorithm with an Active Set Strategy

The purpose of this technical note is to present a proof of convergence of the Pshenichnyi-Pironneau-Polak (PPP) minimax algorithm (see Algorithm 2.4.1 in Polak, Optimization: Algorithms and Consistent Approximations, Springer, [1997]), modified to use an active set strategy. This active set strategy was formally derived in Polak (Optimization: Algorithms and Consistent Approximations, Springer, [1997]) from those used in the methods of feasible directions developed by Zoutendijk (Methods of Feasible Directions, Elsevier, [1960]) and Polak (Computational Methods in Optimization: A Unified Approach, Academic, [1971]). The resulting ε-Active PPP algorithm was presented as Algorithm 2.4.34, in Polak (Optimization: Algorithms and Consistent Approximations, Springer, [1997]), without any proofs.     

Dual-Sampling-Rate Moving-Horizon Control of a Class of Linear Systems with Input Saturation and Plant Uncertainty

Moving-horizon control is a type of sampled-data feedback control in which the control over each sampling interval is determined by the solution of an open-loop optimal control problem. We develop a dual-sampling-rate moving-horizon control scheme for a class of linear, continuous-time plants with strict input saturation constraints in the presence of plant uncertainty and input disturbances. Our control scheme has two components: a slow-sampling moving-horizon controller for a nominal plant and a fast-sampling state-feedback controller whose function is to force the actual plant to emulate the nominal plant. The design of the moving-horizon controller takes into account the nonnegligible computation time required to compute the optimal control trajectory.We prove the local stability of the resulting feedback system and illustrate its performance with simulations. In these simulations, our dual-sampling-rate controller exhibits performance that is considerably superior to its single-sampling-rate moving-horizon controller counterpart.     

Pulverized coal plasma gasification

A number of experiments on the plasma-vapor gasification of brown coals of three types have been carried out using an experimental plant with an electric-arc reactor of the combined type. On the basis of the material and heat balances, process parameters have been obtained: the degree of carbon gasification (_c), the level of sulfur conversion into the gas phase (_s), the synthesis gas concentration (CO+Hz) in the gaseous products, and the specific power consumption for the gasification process. The degree of gasification was 90.5-95.0%, the concentration of the synthesis gas amounted to 84.7–85.7%, and the level of sulfur conversion into the gas phase was 94.3–96.7%. Numerical study of the process of plasma gasification of coals was carried out using a mathematical model of motion, heating, and gasification of polydisperse coal particles in an electric-arc reactor of the combined type with an internal heat source (arc). The initial conditions for a conjugate system of nonlinear differential equations of the gas dynamics and kinetics of a pulverized coal stream interacting with the electric arc and oxidizer (water vapor) agree with the initial conditions of the experiments. The computation results satisfactorily correlate with the experimental data. The mathematical model can be used for the determination of reagent residence time and geometrical dimensions of the plasma reactor for the gasification of coals.Nomenclature c _i volume concentration of components (kmol m^–3) - x longitudinal coordinate (m) - f _i source members, determined by variation of the ith component due to chemical reactions in unit volume in unit time (kmol m^–3s^–1) - velocity (m s^–1) - M _s ash mass in one particle (kg) - C _D particle drag coefficient - 3.14 - r _s particle radius (m) - d particle diameter (m) - density (kg m^–3) - C _p heat capacity of components (J mol^t– K^–1) - Q _j thermal effect of reaction (J kmol^–1) - E_j activation energy of reaction - N _l volume concentration of particles of thelth fraction (m^–3) - T temperature (K) - emissivity factor of coal particles - 5.67 × 10^–8, blackbody emissivity coefficient (W m^–2 K^–4) - P pressure (Pa) - S reactor cross section (m²) - D reactor diameter (m) - V reactor volume (m³) - L _R reactor length (m) - F _W friction force on the wall (N) - f _g friction coefficient - residence time (s) - Nu Nusselt number - Re Reynolds number - Pr Prandtl number - thermal conductivity of gas (J m^– s^–1 K^–1) - R 8.3 × 10³, universal gas constant (J kmol K^–1) - µ _i molecular mass of component (kg kmol^–1) - dynamic viscosity coefficient of gas (kg m^–1 s^–1) - thermal efficiency of plasma reactor - q_arc specific heat flow from arc (W m^–3) - P ₁ heat supplied in vapor at T = 405 K (W) - P ₂ heat loss to wall (W) - P ₃ heat loss in the gas and slag separator chamber (W) - P ₄ heat loss in the synthesis gas oxidation chamber (W) - P ₅ heat loss in the slag catcher (W) - P ₆ heat carried away in the off-gas (W) - P heat input of arc (W) - P _arc electric power of arc (W) - Q_sp specific power consumption (kw Hr kg^–1) - d _w specific heat flow to wall (W m^–2) - _c degree of carbon gasification (%) - _s level of sulfur conversion into gas phase (%)     

Description of oxygen permeability in various high polymers using a graph theoretical approach

Graph theory methods are shown to complement group additivity methods of predicting oxygen permeability in certain types of polymers. Graph theory is a topological approach that assigns a set of indices to a molecule to describe its structure. Since many physical properties of molecules depend upon their structure, graph theory indices can be used to describe important properties of molecules. In this work a set of graph theory indices are used to describe the property of a polymer based on a modified representation of the monomer unit. More specifically, Randic indices are used to describe the log of the oxygen permeability with 3.2% average relative error. Polymers comprising the basis set contain backbones of sp², sp³, or aromatic carbons, oxygen, or silicon and have substituents that contain chloride, fluoride, alkyl groups, hydrogen, oxygen, aromatic carbons, or chloro and/or fluoro substituted alkyl groups. The correlation coefficient (R²) (0 ≤ R² ≤ 1) of a nonlinear model is 0.91. The graph theory method for describing the oxygen permeability of these selected groups of polymers is in good agreement with that predicted by the permachor model. The permachor method makes oxygen permeability predictions based upon group additivity and distinguishes the degree of crystallinity of a polymer by empirically assigning different permachor (π) values to identical groups based upon the polymer crystallinity. The inability of graph theory to explain the remaining 9% of the scatter in the data is probably due to failure to incorporate into the graph theory model terms which quantify crystallinity.