The Value of Modeling and Simulation Standards

In the current economic climate, there is a requirement to justify all government spending by demonstrating the added-value that the expenditure gives. Modeling and Simulation (M&S) community is not exempted from this rule. This paper focuses on attempts to value standards and demonstrates that even though a myriad of different standards exist in the United States today, no one has cracked the nut on determining their value. This does not mean that standards are without value. The paper highlights their importance to our society and human development as a whole. Thus if we cannot give a value to M&S standards, we can at least minimize their cost. The paper concludes with some discussions on cost-savings in the development of standards though a study of organizational misbehavior

2-Sulfonylpyrimidines as Privileged Warheads for the Development of S. aureus Sortase A Inhibitors

Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against S. aureus sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar K(I) values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the S ( N )Ar reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog

Model based process optimisation of an industrial chromatographic process for separation of lactoferrin from bovine milk

Journal articleModel based process development using predictive mechanistic models is a powerful tool for in-silico downstream process development. It allows to obtain a thorough understanding of the process reducing experimental effort. While in pharma industry, mechanistic modeling becomes more common in the last years, it is rarely applied in food industry. This case study investigates risk ranking and possible optimization of the industrial process of purifying lactoferrin from bovine milk using SP Sepharose Big Beads with a resin particle diameter of 200 µm, based on a minimal number of lab-scale experiments combining traditional scale-down experiments with mechanistic modeling. Depending on the location and season, process water pH and the composition of raw milk can vary, posing a challenge for highly efficient process development. A predictive model based on the general rate model with steric mass action binding, extended for pH dependence, was calibrated to describe the elution behavior of lactoferrin and main impurities. The gained model was evaluated against changes in flow rate, step elution conditions, and higher loading and showed excellent agreement with the observed experimental data. The model was then used to investigate the critical process parameters, such as water pH, conductivity of elution steps, and flow rate, on process performance and purity. It was found that the elution behavior of lactoferrin is relatively consistent over the pH range of 5.5 to 7.6, while the elution behavior of the main impurities varies greatly with elution pH. As a result, a significant loss in lactoferrin is unavoidable to achieve desired purities at pH levels below pH 6.0. Optimal process parameters were identified to reduce water and salt consumption and increase purity, depending on water pH and raw milk composition. The optimal conductivity for impurity removal in a low conductivity elution step was found to be 43 mS/cm, while a conductivity of 95 mS/cm leads to the lowest overall salt usage during lactoferrin elution. Further increasing the conductivity during lactoferrin elution can only slightly lower the elution volume thus can also lead to higher total salt usage. Low flow rates during elution of 0.2 column volume per minute are beneficial compared to higher flow rates of 1 column volume per minute. The, on lab-scale, calibrated model allows predicting elution volume and impurity removal for large-scale experiments in a commercial plant processing over 106 liters of milk per day. The successful model extrapolation was possible without recalibration or detailed knowledge of the manufacturing plant. This study therefore provides a possible pathway for rapid process development of chromatographic purification in the food industries combining traditional scale-down experiments with mechanistic modeling.Lukas Gerstweiler, Paulina Schad, Tatjana Trunzer, Lena Enghauser, Max Mayr, Jagan Billakant

Применение метода контрольных возмущений для определения характерных узлов присоединения комплексной нагрузки при расчетах динамической устойчивости

Рассматривается влияние способа замещения комплексной нагрузки на характер электромеханических переходных процессов в электрических системах (ЭС) от действия больших возмущений. Показано, что установить общие рекомендации относительно способа замещения нагрузки в сложных ЭС затруднительно. Предлагается для опреде­ления характерных узлов нагрузки, оказывающих существенное влияние на характер динамического перехода, применять известный метод контрольных возмущений. Приводятся результаты сравнительных расчетов с использованием предлагаемой методики

Magnetic field generation in first order phase transition bubble collisions

We consider the formation of a ring-like magnetic field in collisions of bubbles of broken phase in an abelian Higgs model. Particular attention is paid on multiple collisions. The small collision velocity limit, appropriate to the electroweak phase transition, is discussed. We argue that after the completion of the electroweak phase transition, when averaged over nucleation center distances, there exists a mean magnetic field $B\simeq 2.0\times 10^{20}$ G with a coherence length $9.1 \times 10^3 GeV^{-1}$ (for m_H=68 GeV). Because of the ring-like nature of B, the volume average behaves as $B \sim 1/L$. Taking into account the turbulent enhancement of the field by inverse cascade, we estimate that colliding electroweak bubbles would give rise to a mean field $B_{rms}\simeq 10^{-21}$ G at 10 Mpc comoving scale today.Comment: Latex, 18 pages, 8 figure

The impact of supply chain agility on business performance in a high level customization environment

To improve business performance in rapidly changing environments, supply chain agility can be a crucial requisite to address responsiveness issues, especially in environments with high levels of customization. This paper examines the effect of supply chain agility on customer service, differentiation, and business performance. A survey research methodology was employed using a sample of 156 manufacturing firms that provide high levels of customization. In particular, structural equation modeling (SEM) was employed to evaluate the proposed model. The results suggest that supply chain agility influences customer service and differentiation positively. However, it does not affect business performance directly; instead, better business performance can be achieved and mediated through improved customer service and differentiation. In particular, differentiation through customer service is the most effective way to improve business performance, and supply chain agility can help to achieve high-level customer service. The paper advises managers on details of how to fulfil their business performance ambitions better through suggested key agile supply chain management activities