The role of Computer Aided Process Engineering in physiology and clinical medicine

This paper discusses the potential role for Computer Aided Process Engineering (CAPE) in developing engineering analysis and design approaches to biological systems across multiple levels—cell signalling networks, gene, protein and metabolic networks, cellular systems, through to physiological systems. The 21st Century challenge in the Life Sciences is to bring together widely dispersed models and knowledge in order to enable a system-wide understanding of these complex systems. This systems level understanding should have broad clinical benefits. Computer Aided Process Engineering can bring systems approaches to (i) improving understanding of these complex chemical and physical (particularly molecular transport in complex flow regimes) interactions at multiple scales in living systems, (ii) analysis of these models to help to identify critical missing information and to explore the consequences on major output variables resulting from disturbances to the system, and (iii) ‘design’ potential interventions in in vivo systems which can have significant beneficial, or potentially harmful, effects which need to be understood. This paper develops these three themes drawing on recent projects at UCL. The first project has modeled the effects of blood flow on endothelial cells lining arteries, taking into account cell shape change resulting in changes in the cell skeleton which cause consequent chemical changes. A second is a project which is building an in silico model of the human liver, tieing together models from the molecular level to the liver. The composite model models glucose regulation in the liver and associated organs. Both projects involve molecular transport, chemical reactions, and complex multiscale systems, tackled by approaches from CAPE. Chemical Engineers solve multiple scale problems in manufacturing processes – from molecular scale through unit operations scale to plant-wide and enterprise wide systems – so have an appropriate skill set for tackling problems in physiology and clinical medicine, in collaboration with life and clinical scientists

Economic Benefits of Waste Pickling Solution Valorization

An integrated hybrid membrane process, composed of a diffusion dialysis (DD), a membrane distillation (MD) and a reactive precipitation unit (CSTR), is proposed as a promising solution for the valorization and onsite recycling of pickling waste streams. An economic analysis was performed aiming to demonstrate the feasibility of the developed process with a NPV of about EUR 40,000 and a DPBP of 4 years. The investment and operating costs, as well as the avoided costs and the benefits for the company operating the plant, were analyzed with an extensive cost tracking exercise and through face-to-face contact with manufacturers and sector leaders. A mathematical model was implemented using the gPROMS modelling platform. It is able to simulate steady state operations and run optimization analysis of the process performance. The impact of key operating and design parameters, such as the set-point bath concentration and the DD and MD membrane areas, respectively, was investigated and the optimal arrangement was identified. Finally, operating variables and design parameters were optimized simultaneously in a nonlinear framework as a tradeoff between profitability and environmental impact. We show how the integration of new technologies into the traditional pickling industry could provide a significant benefit for the issues of process sustainability, which are currently pressing

Effects of citric acid and fibronectin and laminin application in treating periodontitis

. To determine the effect on new connective tissue attachment of citric acid conditioning and fibronectin-laminin application in treating naturally occurring periodontitis, all 4 quadrants in each of 2 Beagle dogs were used. Each quadrant included: P 2 , P 3 , P 4 , and M 1 teeth. 2 treatment modalities were employed and comparatively analyzed for differences in histological healing respponses at 120 days after surgery. The treatments were: (1) surgery (mucoperiosteal flaps) plus citric acid; (2) surgery plus citric acid followed by fibronectin-laminin application. After scaling and root planing, coronal and root surface reference notches were placed for histometric measurements. Following each of the randomly assigned treatments, flaps were sutured. After sacrifice, tissue blocks of treated areas were decalcified and serially cut, obtaining bucco-lingual and mesiodistal sections. Using a Filar micrometer. 5 distances were masured on the buccal aspect: (1) from root surface notch to alveolar bone crest; (2) from root surface notch to coronal extent of the cementum; (3) from root surface notch to apical extent of the junctional epithelium; 84) from free gingival margin to apical extent of junctional epithelium; (5) from the coronal notch to the alveolar bone crest. Results showed no differences among the 5 measurements between the 2 treatments tested. On mesiodistal sections, surface area determinations were made in the furcations, evaluating the space occupied by new connective tissue, with or without bone, or by epithelium. For this, images were digitized using a Zeiss IBAS Image analysis system with a 4mB of array processor memory coupled to a Newvicon TV camera and a microcomputer. Significant differences were found, with increased values for both regenerative connective tissue and bone when surgery plus citric acid was followed by fibronectin-laminin application. Often, these tissues filled completely furcation areas above root surface reference notches.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73686/1/j.1600-051X.1987.tb01543.x.pd

Bystander Effects of Hypoxia-Activated Prodrugs: Agent-Based Modeling Using Three Dimensional Cell Cultures

Intra-tumor heterogeneity represents a major barrier to anti-cancer therapies. One strategy to minimize this limitation relies on bystander effects via diffusion of cytotoxins from targeted cells. Hypoxia-activated prodrugs (HAPs) have the potential to exploit hypoxia in this way, but robust methods for measuring bystander effects are lacking. The objective of this study is to develop experimental models (monolayer, multilayer, and multicellular spheroid co-cultures) comprising ‘activator’ cells with high expression of prodrug-activating reductases and reductase-deficient ‘target’ cells, and to couple these with agent-based models (ABMs) that describe diffusion and reaction of prodrugs and their active metabolites, and killing probability for each cell. HCT116 cells were engineered as activators by overexpressing P450 oxidoreductase (POR) and as targets by knockout of POR, with fluorescent protein and antibiotic resistance markers to enable their quantitation in co-cultures. We investigated two HAPs with very different pharmacology: SN30000 is metabolized to DNA-breaking free radicals under hypoxia, while the dinitrobenzamide PR104A generates DNA-crosslinking nitrogen mustard metabolites. In anoxic spheroid co-cultures, increasing the proportion of activator cells decreased killing of both activators and targets by SN30000. An ABM parameterized by measuring SN30000 cytotoxicity in monolayers and diffusion-reaction in multilayers accurately predicted SN30000 activity in spheroids, demonstrating the lack of bystander effects and that rapid metabolic consumption of SN30000 inhibited prodrug penetration. In contrast, killing of targets by PR104A in anoxic spheroids was markedly increased by activators, demonstrating that a bystander effect more than compensates any penetration limitation. However, the ABM based on the well-studied hydroxylamine and amine metabolites of PR104A did not fit the cell survival data, indicating a need to reassess its cellular pharmacology. Characterization of extracellular metabolites of PR104A in anoxic cultures identified more stable, lipophilic, activated dichloro mustards with greater tissue diffusion distances. Including these metabolites explicitly in the ABM provided a good description of activator and target cell killing by PR104A in spheroids. This study represents the most direct demonstration of a hypoxic bystander effect for PR104A to date, and demonstrates the power of combining mathematical modeling of pharmacokinetics/pharmacodynamics with multicellular culture models to dissect bystander effects of targeted drug carriers

The Ethics of Corporate Governance

How should corporate directors determine what is the right decision? For at least the past 30 years the debate has raged as to whether shareholder value should take precedence over corporate social responsibility when crucial decisions arise. Directors face pressure, not least from ethical investors, to do the good thing when they seek to make the right choice. Corporate governance theory has tended to look to agency theory and the need of boards to curb excessive executive power to guide directors' decisions. While useful for those purposes, agency theory provides only limited guidance. Supplementing it with the alternatives - stakeholder theory and stewardship theory - tends to put directors in conflict with their legal obligations to work in the interests of shareholders. This paper seeks to reframe the discussion about corporate governance in terms of the ethical debate between consequential, teleological approaches to ethics and idealist, deontological ones, suggesting that directors are - for good reason - more inclined toward utilitarian judgments like those underpinning shareholder value. But the problems with shareholder value have become so great that a different framework is needed: strategic value, with an emphasis on long-term value creation judged from a decidedly utilitarian standpoint

Unexpected short- and medium-range atomic structure of sputtered amorphous silicon upon thermal annealing

We investigate the structure of magnetron-sputtered (MS) amorphous silicon(a-Si) prepared under standard deposition conditions and compare this to pure ion-implanted (II) a-Si. The structure of both films is characterized in their as-prepared and thermally annealed states. Significant differences are observed in short- and medium-range order following thermal annealing. Whereas II a-Si undergoes structural relaxation toward a continuous random network, MS a-Si exhibits little change. Cross-sectional transmission electron microscopy reveals the presence of nanopores in the MS film consistent with reduced mass-density. Therefore, the short- and medium-range order of annealed, MS a-Si is tentatively attributed to these pores