The ciliary smooth muscle electrotransfer: basic principles and potential for sustained intraocular production of therapeutic proteins.

BACKGROUND: We have developed a nonviral gene therapy method based on the electrotransfer of plasmid in the ciliary muscle. These easily accessible smooth muscle cells could be turned into a biofactory for any therapeutic proteins to be secreted in a sustained manner in the ocular media. METHODS: Electrical conditions, design of electrodes, plasmid formulation, method and number of injections were optimized in vivo in the rat by localizing β-galactosidase expression and quantifying reporter (luciferase) and therapeutic (anti-tumor necrosis factor) proteins secretion in the ocular media. Anatomical measurements were performed via human magnetic resonance imaging to design a human eye-sized prototype that was tested in the rabbit. RESULTS: In the rat, transscleral injection of 30 µg of plasmid diluted in half saline (77 mM NaCl) followed by application of eight square-wave electrical pulses (15 V, 10 ms, 5.3 Hz) using two platinum/iridium electrodes, an internal wire and an external sheet, delivered plasmid efficiently to the ciliary muscle fibers. Gene transfer resulted in a long-lasting (at least 5 months) and plasmid dose-/injection number- dependent secretion of different molecular weight proteins mainly in the vitreous, without any systemic exposure. Because ciliary muscle anatomical measurements remained constant among ages in adult humans, an integrated device comprising needle-electrodes was designed and manufactured. Its usefulness was validated in the rabbit. CONCLUSIONS: Plasmid electrotransfer to the ciliary muscle with a suitable medical device represents a promising local and sustained protein delivery system for treating posterior segment diseases, avoiding repeated intraocular injections.

An application of capital allocation principles to operational risk

The cost of operational risk refers to the capital needed to a fford the loss generated by ordinary activities of a firm. In this work we demonstrate how allocation principles can be used to the subdivision of the aggregate capital so that the firm can distribute this cost across its various constituents that generate operational risk. Several capital allocation principles are revised. Proportional allocation allows to calculate a relative risk premium to be charged to each unit. An example of fraud risk in the banking sector is presented and some correlation scenarios between business lines are compared. Keywords: solvency, quantile, value at risk, copulas

Predicting spinor condensate dynamics from simple principles

We study the spin dynamics of quasi-one-dimensional F=1 condensates both at zero and finite temperatures for arbitrary initial spin configurations. The rich dynamical evolution exhibited by these nonlinear systems is explained by surprisingly simple principles: minimization of energy at zero temperature and maximization of entropy at high temperature. Our analytical results for the homogeneous case are corroborated by numerical simulations for confined condensates in a wide variety of initial conditions. These predictions compare qualitatively well with recent experimental observations and can, therefore, serve as a guidance for ongoing experiments.

Applying the principles of life cycle assessment and costing in process modeling to examine profit-making capability

Static process simulation has traditionally been used to model complex processes for various purposes. However, the use of static processsimulators for the preparation of holistic examinations aiming at improving profit-making capability requires a lot of work because the production of results requires the assessment of the applicability of detailed data which may be irrelevant to the objective. The relevant data for the total assessment gets buried byirrelevant data. Furthermore, the models do not include an examination of the maintenance or risk management, and economic examination is often an extra property added to them which can be performed with a spreadsheet program. A process model applicable to holistic economic examinations has been developed in this work. The model is based on the life cycle profit philosophy developed by Hagberg and Henriksson in 1996. The construction of the model has utilized life cycle assessment and life cycle costing methodologies with a view to developing, above all, a model which would be applicable to the economic examinations of complete wholes and which would require the need for information focusing on aspects essential to the objectives. Life cycle assessment and costing differ from each other in terms of the modeling principles, but the features of bothmethodologies can be used in the development of economic process modeling. Methods applicable to the modeling of complex processes can be examined from the viewpoint of life cycle methodologies, because they involve the collection and management of large corpuses of information and the production of information for the needs of decision-makers as well. The results of the study shows that on the basis of the principles of life cycle modeling, a process model can be created which may be used to produce holistic efficiency examinations on the profit-making capability of the production line, with fewer resources thanwith traditional methods. The calculations of the model are based to the maximum extent on the information system of the factory, which means that the accuracyof the results can be improved by developing information systems so that they can provide the best information for this kind of examinations.

Identifying quantitative operation principles in metabolic pathways: a systematic method for searching feasible enzyme activity patterns leading to cellular adaptive responses

Background: Optimization methods allow designing changes in a system so that specific goals are attained. These techniques are fundamental for metabolic engineering. However, they are not directly applicable for investigating the evolution of metabolic adaptation to environmental changes. Although biological systems have evolved by natural selection and result in well-adapted systems, we can hardly expect that actual metabolic processes are at the theoretical optimum that could result from an optimization analysis. More likely, natural systems are to be found in a feasible region compatible with global physiological requirements. Results: We first present a new method for globally optimizing nonlinear models of metabolic pathways that are based on the Generalized Mass Action (GMA) representation. The optimization task is posed as a nonconvex nonlinear programming (NLP) problem that is solved by an outer- approximation algorithm. This method relies on solving iteratively reduced NLP slave subproblems and mixed-integer linear programming (MILP) master problems that provide valid upper and lower bounds, respectively, on the global solution to the original NLP. The capabilities of this method are illustrated through its application to the anaerobic fermentation pathway in Saccharomyces cerevisiae. We next introduce a method to identify the feasibility parametric regions that allow a system to meet a set of physiological constraints that can be represented in mathematical terms through algebraic equations. This technique is based on applying the outer-approximation based algorithm iteratively over a reduced search space in order to identify regions that contain feasible solutions to the problem and discard others in which no feasible solution exists. As an example, we characterize the feasible enzyme activity changes that are compatible with an appropriate adaptive response of yeast Saccharomyces cerevisiae to heat shock Conclusion: Our results show the utility of the suggested approach for investigating the evolution of adaptive responses to environmental changes. The proposed method can be used in other important applications such as the evaluation of parameter changes that are compatible with health and disease states.

Use of physiological constraints to identify quantitative design principles for gene expression in yeast adaptation to heat shock

Background: Understanding the relationship between gene expression changes, enzyme activity shifts, and the corresponding physiological adaptive response of organisms to environmental cues is crucial in explaining how cells cope with stress. For example, adaptation of yeast to heat shock involves a characteristic profile of changes to the expression levels of genes coding for enzymes of the glycolytic pathway and some of its branches. The experimental determination of changes in gene expression profiles provides a descriptive picture of the adaptive response to stress. However, it does not explain why a particular profile is selected for any given response. Results: We used mathematical models and analysis of in silico gene expression profiles (GEPs) to understand how changes in gene expression correlate to an efficient response of yeast cells to heat shock. An exhaustive set of GEPs, matched with the corresponding set of enzyme activities, was simulated and analyzed. The effectiveness of each profile in the response to heat shock was evaluated according to relevant physiological and functional criteria. The small subset of GEPs that lead to effective physiological responses after heat shock was identified as the result of the tuning of several evolutionary criteria. The experimentally observed transcriptional changes in response to heat shock belong to this set and can be explained by quantitative design principles at the physiological level that ultimately constrain changes in gene expression. Conclusion: Our theoretical approach suggests a method for understanding the combined effect of changes in the expression of multiple genes on the activity of metabolic pathways, and consequently on the adaptation of cellular metabolism to heat shock. This method identifies quantitative design principles that facilitate understating the response of the cell to stress.

Méta-analyses d'essais randomisés sur données individuelles dans le traitement des cancers ORL non métastatiques : principes, résultats, perspectives [Individual patient data meta-analyses of randomized trials for the treatment of non-metastatic head and neck squamous cell carcinomas: Principles, results and perspectives].

Meta-analyses are considered as an important pillar of evidence-based medicine. The aim of this review is to describe the main principles of a meta-analysis and to use examples of head and neck oncology to demonstrate their clinical impact and methodological interest. The major role of individual patient data is outlined, as well as the superiority of individual patient data over meta-analyses based on published summary data. The major clinical breakthrough of head and neck meta-analyses are summarized, regarding concomitant chemotherapy, altered fractionated chemotherapy, new regimens of induction chemotherapy or the use of radioprotectants. Recent methodological developments are described, including network meta-analyses, the validation of surrogate markers. Lastly, the future of meta-analyses is discussed in the context of personalized medicine.

Production Control Principles in Printed Wiring Board Fabrication

Työn tavoitteena oli kuvata piirilevyvalmistaja Aspocomp Oy:n Espoon tehtaan tämän hetkinen tuotannonohjausperiaate ja tunnistaa siinä esiintyvät puutteet sekä kehittää vaihtoehtoinen tuotannonohjausperiaate piirilevyvalmistukseen. Vaihtoehtoisen ohjausperiaatteen lähtökohtana oli tuotannonohjauksen sopeuttaminen vaativaan ja jatkuvasti muuttuvaan liiketoimintaympäristöön. Työn teoreettinen osa keskittyi tuotannonohjauksen eri lähestymistapoihin. Kirjallisuuskatsauksessa esitetään eri tuotannonohjausperiaatteiden keskeiset sisällöt, jotka muodostavat rungon toimivalle tuotannonohjauskäytännölle. Työn kokeellinen osa keskittyi Espoon piirilevytehtaan tuotannonohjausperiaatteen selvittämiseen. Espoon piirilevytehtaan nykyisessä tuotannonohjausperiaatteessa havaittujen ongelmakohtien ja liiketoimintaympäristön vaatimusten perusteella kehitettiin vaihtoehtoinen tuotannonohjaustapa. Vaihtoehtoisen tuotannonohjaustavan päämääränä oli läpimenoajan lyhentäminen sekä tuotannon parempi hallittavuus. Vaihtoehtoinen toimintamalli tavoitteiden saavuttamiseksi perustuu pullonkaulateoriaan, jossa keskeisin muutos nykyiseen toimintamalliin oli puolivalmisteiden varastointi toimitusajan lyhentämiseksi sekä tuotantovolyymin heilahdusten vaikutusten vähentämiseksi. Työn kokeellisessa osassa ilmeni, että kysynnän muutokset ja kapasiteetin suunnittelun puute aiheuttivat ongelmia piirilevytehtaan tuotannonohjauksessa.

First principles analysis of the stability and diffusion of oxygen vacancies in meetal oxides

Oxygen vacancies in metal oxides are known to determine their chemistry and physics. The properties of neutral oxygen vacancies in metal oxides of increasing complexity (MgO, CaO, alpha-Al2O3, and ZnO) have been studied using density functional theory. Vacancy formation energies, vacancy-vacancy interaction, and the barriers for vacancy migration are determined and rationalized in terms of the ionicity, the Madelung potential, and lattice relaxation. It is found that the Madelung potential controls the oxygen vacancy properties of highly ionic oxides whereas a more complex picture arises for covalent ZnO.

MgO/Ag(001) interface structure and STM images from first principles

The interface of MgO/Ag(001) has been studied with density functional theory applied to slabs. We have found that regular MgO films show a small adhesion to the silver substrate, the binding can be increased in off-stoichiometric regimes, either by the presence of O vacancies at the oxide film or by a small excess of O atoms at the interface between the ceramic to the metal. By means of theoretical methods, the scanning tunneling microscopy signatures of these films is also analyzed in some detail. For defect free deposits containing 1 or 2 ML and at low voltages, tunnelling takes place from the surface Ag substrate, and at large positive voltages Mg atoms are imaged. If defects, oxygen vacancies, are present on the surface of the oxide they introduce much easier channels for tunnelling resulting in big protrusions and controlling the shape of the image, the extra O stored at the interface can also be detected for very thin films.