On the optimal ratio of heavy to light chain genes for efficient recombinant antibody production by CHO cells

Monoclonal antibodies (Mab) are heterotetramers consisting of an equimolar ratio of heavy chain (HC) and light chain (LC) polypeptides. Accordingly, most recombinant Mab expression systems utilize an equimolar ratio of heavy chain (he) to light chain (lc) genes encoded on either one or two plasmids. However, there is no evidence to suggest that this gene ratio is optimal for stable or transient production of recombinant Mab. In this study we have determined the optimal ratio of hc:lc genes for production of a recombinant IgG(4) Mab, cB72.3, by Chinese hamster ovary (CHO) cells using both empirical and mathematical modeling approaches. Polyethyleneimine-mediated transient expression of cB72.3 at varying ratios of hc:lc genes encoded on separate plasmids yielded an optimal Mab titer at a hc:lc gene ratio of 3:2; a conclusion confirmed by separate mathematical modeling of the Mab folding and assembly process using transient expression data. On the basis of this information, we hypothesized that utilization of he genes at low hc:lc gene ratios is more efficient. To confirm this, cB72.3 Mab was transiently produced by CHO cells at constant he and varying lc gene dose. Under these conditions, Mab yield was increased with a concomitant increase in lc gene dose. To determine if the above findings also apply to stably transfected CHO cells producing recombinant Mab, we compared the intra- and extracellular ratios of HC and LC polypeptides for three GS-CHO cells lines transfected with a 1:1 ratio of hc:lc genes and selected for stable expression of the same recombinant Mab, cB72.3. Intra- and extracellular HC:LC polypeptide ratios ranged from 1:2 to 1:5, less than that observed on transient expression of the same Mab in parental CHO cells using the same vector. In conclusion, our data suggest that the optimal ratio of hc:lc genes used for transient and stable expression of Mab differ. In the case of the latter, we infer that optimal Mab production by stably transfected cells represents a compromise between HC abundance limiting productivity and the requirement for excess LC to render Mab folding and assembly more efficient.

A Drug-Based Intervention Study on the Importance of Buffaloes for Human Schistosoma Japonicum Infection around Poyang Lake, People’s Republic of China

Schistosomiasis japonica is a zoonosis of major public health importance in southern China. We undertook a drug intervention to test the hypothesis that buffalo are major reservoirs for human infection in the marshlands/lake areas, where one million people are infected. We compared human and buffalo infection rates and intensity in an intervention village (Jishan), where humans and buffalo were treated with praziquantel, and a control village (Hexi), where only humans were treated, in the Poyang Lake region. Over the four-year study, human incidence in Jishan decreased but increased in Hexi. Adjustment of incidence by age, sex, water exposure, year, and village further confirmed the decreased human infection in Jishan. Chemotherapy for buffaloes resulted in a decrease in buffalo infection rates in Jishan, which coincided with the reduction in human infection rates there in the last two years of the study. Mathematical modeling predicted that buffalo are responsible for 75% of human transmission in Jishan. Copyright © 2006 by The American Society of Tropical Medicine and Hygiene.

Optimal production planning for PCB assembly

It is indisputable that printed circuit boards (PCBs) play a vital role in our daily lives. With the ever-increasing applications of PCBs, one of the crucial ways to increase a PCB manufacturer’s competitiveness in terms of operation efficiency is to minimize the production time so that the products can be introduced to the market sooner. Optimal Production Planning for PCB Assembly is the first book to focus on the optimization of the PCB assembly lines’ efficiency. This is done by: • integrating the component sequencing and the feeder arrangement problems together for both the pick-and-place machine and the chip shooter machine; • constructing mathematical models and developing an efficient and effective heuristic solution approach for the integrated problems for both types of placement machines, the line assignment problem, and the component allocation problem; and • developing a prototype of the PCB assembly planning system. The techniques proposed in Optimal Production Planning for PCB Assembly will enable process planners in the electronics manufacturing industry to improve the assembly line’s efficiency in their companies. Graduate students in operations research can familiarise themselves with the techniques and the applications of mathematical modeling after reading this advanced introduction to optimal production planning for PCB assembly.

The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier

Three-tiered kinase modules, such as the Raf-MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase)-ERK (extracellular signal-regulated kinase) mitogen-activated protein kinase pathway, are widespread in biology, suggesting that this structure conveys evolutionarily advantageous properties. We show that the three-tiered kinase amplifier module combined with negative feedback recapitulates the design principles of a negative feedback amplifier (NFA), which is used in electronic circuits to confer robustness, output stabilization, and linearization of nonlinear signal amplification. We used mathematical modeling and experimental validation to demonstrate that the ERK pathway has properties of an NFA that (i) converts intrinsic switch-like activation kinetics into graded linear responses, (ii) conveys robustness to changes in rates of reactions within the NFA module, and (iii) stabilizes outputs in response to drug-induced perturbations of the amplifier. These properties determine biological behavior, including activation kinetics and the response to drugs.

Applied operational research with SAS

Using a wide range of operational research (OR) optimization examples, Applied Operational Research with SAS demonstrates how the OR procedures in SAS work. The book is one of the first to extensively cover the application of SAS procedures to OR problems, such as single criterion optimization, project management decisions, printed circuit board assembly, and multiple criteria decision making. The text begins with the algorithms and methods for linear programming, integer linear programming, and goal programming models. It then describes the principles of several OR procedures in SAS. Subsequent chapters explain how to use these procedures to solve various types of OR problems. Each of these chapters describes the concept of an OR problem, presents an example of the problem, and discusses the specific procedure and its macros for the optimal solution of the problem. The macros include data handling, model building, and report writing. While primarily designed for SAS users in OR and marketing analytics, the book can also be used by readers interested in mathematical modeling techniques. By formulating the OR problems as mathematical models, the authors show how SAS can solve a variety of optimization problems.

An Intelligent System for Investigations and Provision of Safety for Complex Constructions

Methodology of computer-aided investigation and provision of safety for complex constructions and a prototype of the intelligent applied system, which implements it, are considered. The methodology is determined by the model of the object under scrutiny, by the structure and functions of investigation of safety as well as by a set of research methods. The methods are based on the technologies of object-oriented databases, expert systems and on the mathematical modeling. The intelligent system’s prototype represents component software, which provides for support of decision making in the process of safety investigations and investigation of the cause of failure. Support of decision making is executed by analogy, by determined search for the precedents (cases) with respect to predicted (on the stage of design) and observed (on the stage of exploitation) parameters of the damage, destruction and malfunction of a complex hazardous construction.

Experimental Support of Argument-based Syntactic Computation

Linguistic theory, cognitive, information, and mathematical modeling are all useful while we attempt to achieve a better understanding of the Language Faculty (LF). This cross-disciplinary approach will eventually lead to the identification of the key principles applicable in the systems of Natural Language Processing. The present work concentrates on the syntax-semantics interface. We start from recursive definitions and application of optimization principles, and gradually develop a formal model of syntactic operations. The result – a Fibonacci- like syntactic tree – is in fact an argument-based variant of the natural language syntax. This representation (argument-centered model, ACM) is derived by a recursive calculus that generates a mode which connects arguments and expresses relations between them. The reiterative operation assigns primary role to entities as the key components of syntactic structure. We provide experimental evidence in support of the argument-based model. We also show that mental computation of syntax is influenced by the inter-conceptual relations between the images of entities in a semantic space.

A Method for Classification of Doubly Resolvable Designs and Its Application

This article presents the principal results of the Ph.D. thesis Investigation and classification of doubly resolvable designs by Stela Zhelezova (Institute of Mathematics and Informatics, BAS), successfully defended at the Specialized Academic Council for Informatics and Mathematical Modeling on 22 February 2010.

Method of Linear Programming as an Idea for High School Curriculum

2010 Mathematics Subject Classification: 97D40, 97M10, 97M40, 97N60, 97N80, 97R80

Developing Financial Expertise Through Mathematics and IT School Curricula

Report published in the Proceedings of the National Conference on "Education and Research in the Information Society", Plovdiv, May, 2014

HIV, cardiovascular diseases, and chronic arsenic exposure co-exist in a positive synergy

Recent epidemiological evidences indicate that arsenic exposure increases risk of atherosclerosis, cardio vascular diseases (CVD) such as hypertension, atherosclerosis, coronary artery disease (CAD) and microangiopathies in addition to the serious global health concern related to its carcinogenic effects. In experiments on animals, acute and chronic exposure to arsenic directly correlates with cardiac tachyarrhythmia, and atherogenesis in a concentration and duration dependent manner. Moreover, the other effects of long-term arsenic exposure include induction of non-insulin dependent diabetes by mechanisms yet to be understood. On the other hand, there are controversial issues, gaps in knowledge, and future research priorities in accelerated incidences of CVD and mortalities in patients with HIV who are under long-termanti-retroviral therapy (ART). Although, both HIV infection itself and various components of ART initiate significant pathological alterations in the myocardium and the vasculature, simultaneous environmental exposure to arsenic which is more convincingly being recognized as a facilitator of HIV viral cycling in the infected immune cells, may contribute an additional layer of adversity in these patients. A high degree of suspicion and early screening may allow appropriate interventional guidelines to improve the quality of lives of those affected. In this mini-review which have been fortified with our own preliminary data, we will discuss some of the key current understating of chronic arsenic exposure, and its possible impact on the accelerated HIV/ART induced CVD. The review will conclude with notes on recent developments in mathematical modeling in this field that probabilistically forecast incidence prevalence as functions of aging and life style parameters, most of which vary with time themselves; this interdisciplinary approach provides a complementary kernel to conventional biology.

Informatika, telekommunikáció és gazdasági stabilitás (Information technology, telecommunications and economic stability)

Fizikai példákon és matematikai modelleken bemutatjuk, hogy a rendszerek működésének hatékonyságnövekedése instabilitást eredményezhet. Megvizsgáljuk, hogy az informatika és a telekommunikáció fejlődése okozhat-e rendszerszintű instabilitást, illetve milyen gazdasági eszközök vannak a stabilitás fenntartására. / === / Using examples from physics and mathematical modeling, the paper shows that increasing efficiency in systems can lead to instability. The question thus arises whether the development of information and telecommunication technology can lead to instability in the economic system. The policy tools used to maintain stability are also discussed.

Theoretical Investigation of Intra- and Inter-cellular Spatiotemporal Calcium Patterns in Microcirculation

Microcirculatory vessels are lined by endothelial cells (ECs) which are surrounded by a single or multiple layer of smooth muscle cells (SMCs). Spontaneous and agonist induced spatiotemporal calcium (Ca2+) events are generated in ECs and SMCs, and regulated by complex bi-directional signaling between the two layers which ultimately determines the vessel tone. The contractile state of microcirculatory vessels is an important factor in the determination of vascular resistance, blood flow and blood pressure. This dissertation presents theoretical insights into some of the important and currently unresolved phenomena in microvascular tone regulation. Compartmental and continuum models of isolated EC and SMC, coupled EC-SMC and a multi-cellular vessel segment with deterministic and stochastic descriptions of the cellular components were developed, and the intra- and inter-cellular spatiotemporal Ca2+ mobilization was examined. Coupled EC-SMC model simulations captured the experimentally observed localized subcellular EC Ca2+ events arising from the opening of EC transient receptor vanilloid 4 (TRPV4) channels and inositol triphosphate receptors (IP3Rs). These localized EC Ca2+ events result in endothelium-derived hyperpolarization (EDH) and Nitric Oxide (NO) production which transmit to the adjacent SMCs to ultimately result in vasodilation. The model examined the effect of heterogeneous distribution of cellular components and channel gating kinetics in determination of the amplitude and spread of the Ca2+ events. The simulations suggested the necessity of co-localization of certain cellular components for modulation of EDH and NO responses. Isolated EC and SMC models captured intracellular Ca2+ wave like activity and predicted the necessity of non-uniform distribution of cellular components for the generation of Ca2+ waves. The simulations also suggested the role of membrane potential dynamics in regulating Ca2+ wave velocity. The multi-cellular vessel segment model examined the underlying mechanisms for the intercellular synchronization of spontaneous oscillatory Ca2+ waves in individual SMC. From local subcellular events to integrated macro-scale behavior at the vessel level, the developed multi-scale models captured basic features of vascular Ca2+ signaling and provide insights for their physiological relevance. The models provide a theoretical framework for assisting investigations on the regulation of vascular tone in health and disease.

Secagem de resíduo de goiaba em secador convectivo de bandejas: modelagem matemática e análise do processo

Actually, Brazil is one of the larger fruit producer worldwide, with most of its production being consumed in nature way or either as juice or pulp. It is important to highlig ht in the fruit productive chain there are a lot lose due mainly to climate reasons, as well as storage, transportation, season, market, etc. It is known that in the pulp and fruit processing industy a yield of 50% (in mass) is usually obtained, with the other part discarded as waste. However, since most this waste has a high nutrient content it can be used to generate added - value products. In this case, drying plays an important role as an alternative process in order to improve these wastes generated by the fruit industry. However, despite the advantage of using this technique in order to improve such wastes, issues as a higher power demand as well as the thermal efficiency limitation should be addressed. Therefore, the control of the main variables in t his drying process is quite important in order to obtain operational conditions to produce a final product with the target specification as well as with a lower power cost. M athematical models can be applied to this process as a tool in order to optimize t he best conditions. The main aim of this work was to evaluate the drying behaviour of a guava industrial pulp waste using a batch system with a convective - tray dryer both experimentally and using mathematical modeling. In the experimental study , the dryin g carried out using a group of trays as well as the power consume were assayed as response to the effects of operational conditions (temperature, drying air flow rate and solid mass). Obtained results allowed observing the most significant variables in the process. On the other hand, the phenomenological mathematical model was validated and allowed to follow the moisture profile as well as the temperature in the solid and gas phases in every tray. Simulation results showed the most favorable procedure to o btain the minimum processing time as well as the lower power demand.

Desempenho de uma lagoa de infiltração na absorção de cheias e na recarga de aquífero

A type of macro drainage solution widely used in urban areas with predomi-nance of closed catchments (basins without outlet) is the implementation of detention and infiltration reservoirs (DIR). This type of solution has the main function of storing surface runoff and to promote soil infiltration and, consequently, aquifer recharge. The practice is to avoid floods in the drainage basin low-lying areas. The catchment waterproofing reduces the distributed groundwater recharge in urban areas, as is the case of Natal city, RN. However, the advantage of DIR is to concentrate the runoff and to promote aquifer recharge to an amount that can surpass the distributed natu-ral recharge. In this paper, we proposed studying a small urban drainage catchment, named Experimental Mirassol Watershed (EMW) in Natal, RN, whose outlet is a DIR. The rainfall-runoff transformation processes, water accumulation in DIR and the pro-cess of infiltration and percolation in the soil profile until the free aquifer were mod-eled and, from rainfall event observations, water levels in DIR and free aquifer water level measurements, and also, parameter values determination, it is was enabled to calibrate and modeling these combined processes. The mathematical modeling was carried out from two numerical models. We used the rainfall-runoff model developed by RIGHETTO (2014), and besides, we developed a one-dimensional model to simu-late the soil infiltration, percolation, redistribution soil water and groundwater in a combined system to the reservoir water balance. Continuous simulation was run over a period of eighteen months in time intervals of one minute. The drainage basin was discretized in blocks units as well as street reaches and the soil profile in vertical cells of 2 cm deep to a total depth of 30 m. The generated hydrographs were transformed into inlet volumes to the DIR and then, it was carried out water balance in these time intervals, considering infiltration and percolation of water in the soil profile. As a re-sult, we get to evaluate the storage water process in DIR as well as the infiltration of water, redistribution into the soil and the groundwater aquifer recharge, in continuous temporal simulation. We found that the DIR has good performance to storage excess water drainage and to contribute to the local aquifer recharge process (Aquifer Dunas / Barreiras).