Zoledronic acid in combination with alfacalcidol has additive effects on trabecular microarchitecture and mechanical properties in osteopenic ovariectomized rats

We conducted the present study to investigate the therapeutic effects of the antiresorptive agent zoledronic acid (ZOL), alone and in combination with alfacalcidol (ALF), in a rat model of postmenopausal osteoporosis. Female Wistar rats were ovariectomized (OVX) or sham-operated at 3 months of age. Twelve weeks post surgery, rats were randomized into six groups: (1) sham + vehicle, (2) OVX + vehicle, (3) OVX + ZOL (100 mu g/kg, i.v. single dose), (4) OVX + ZOL (50 mu g/kg, i.v. single dose), (5) OVX + ALF (0.5 mu g/kg, oral gauge daily) and (6) OVX + ZOL (50 mu g/kg, i.v. single dose) + ALF (0.5 mu g/kg, oral gauge daily) for 12 weeks. After treatment, we evaluated the mechanical properties of the lumbar vertebra and femoral mid-shaft. Femurs were also tested for bone density, porosity and trabecular micro-architecture. Biochemical markers in serum and urine were also determined. With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid-shaft, the combination treatment of ZOL and ALF was more effective than each administered as a monotherapy. Moreover, combination therapy using ZOL and ALF preserved the trabecular micro-architecture and cortical bone porosity. Furthermore, the combination treatment of ZOL and ALF corrected the decrease in serum calcium and increase in serum alkaline phosphatase and the tartarate-resistant acid phosphatase level better than single-drug therapy using ZOL or ALF in OVX rats. In addition, the combination treatment of ZOL and ALF corrected the increase in urine calcium, phosphorous and creatinine levels better than single-drug therapy using ZOL or ALF in OVX rats. These data suggest that the combination treatment of ZOL and ALF has a therapeutic advantage over each monotherapy for the treatment of osteoporosis.

Multimodal therapy for complete regression of malignant melanoma using constrained nonlinear optimal dynamic inversion

Using a realistic nonlinear mathematical model for melanoma dynamics and the technique of optimal dynamic inversion (exact feedback linearization with static optimization), a multimodal automatic drug dosage strategy is proposed in this paper for complete regression of melanoma cancer in humans. The proposed strategy computes different drug dosages and gives a nonlinear state feedback solution for driving the number of cancer cells to zero. However, it is observed that when tumor is regressed to certain value, then there is no need of external drug dosages as immune system and other therapeutic states are able to regress tumor at a sufficiently fast rate which is more than exponential rate. As model has three different drug dosages, after applying dynamic inversion philosophy, drug dosages can be selected in optimized manner without crossing their toxicity limits. The combination of drug dosages is decided by appropriately selecting the control design parameter values based on physical constraints. The process is automated for all possible combinations of the chemotherapy and immunotherapy drug dosages with preferential emphasis of having maximum possible variety of drug inputs at any given point of time. Simulation study with a standard patient model shows that tumor cells are regressed from 2 x 107 to order of 105 cells because of external drug dosages in 36.93 days. After this no external drug dosages are required as immune system and other therapeutic states are able to regress tumor at greater than exponential rate and hence, tumor goes to zero (less than 0.01) in 48.77 days and healthy immune system of the patient is restored. Study with different chemotherapy drug resistance value is also carried out. (C) 2014 Elsevier Ltd. All rights reserved.

Investigations on Optimal Pulse-Width Modulation to Minimize Total Harmonic Distortion in the Line Current

PWM waveforms with positive voltage transition at the positive zero crossing of the fundamental voltage (type-A) are generally considered for PWM waveform with even number of switching angles per quarter whereas, waveforms with negative voltage transition at the positive zero crossing (type-B) are considered for odd number of switching angles per quarter. Optimal PWM, for minimization of total harmonic distortion of line to line (VWTHD), is generally solved with the aforementioned criteria. This paper establishes that a combination of both types of waveforms gives better performance than any individual type in terms of minimum VWTHD for complete range of modulation index (M). Optimal PWM for minimum VWTHD is solved for PWM waveforms with pulse numbers (P) of 5 and 7. Both type-A and type-B waveforms are found to be better in different ranges of M. The theoretical findings are confirmed through simulation and experimental results on a 3.7 kW squirrel cage induction motor in an open-loop V/f drive. Further, the optimal PWM is analysed from a space vector point of view.

Multicomponent Adducts of Pyridoxine: An Evaluation of the Formation of Eutectics and Molecular Salts

Cocrystallization of pyridoxine (vitamin B6) with several biologically important molecules was undertaken with the intent of successfully designing various hydrogen bonded adducts such as salts, cocrystals, and eutectics. Pyridoxine formed eutectics with isoniazid (an antitubercular drug) and nicotinic acid (vitamin B3) and molecular salts with para-aminobenzoic acid (a bioactive) and saccharin (an artificial sweetener), respectively, in accordance to our design strategy. A salt cocrystal, a precisely conjugate acid-base cocrystal, was obtained for the pyridoxine-para-nitrobenzoic acid combination. The role of supramolecular affinity of hydrogen bonding functional groups and Delta pK(a) differences leading to the formation of above diverse adducts was discussed. This study underpins the need for full-fledged supramolecular compatibility studies of multivitamin/drug combinations toward the development of optimal and/or synergistic combination formulations.

Physical constraints, fundamental limits, and optimal locus of operating points for an inverted pendulum based actuated dynamic walker

The inverted pendulum is a popular model for describing bipedal dynamic walking. The operating point of the walker can be specified by the combination of initial mid-stance velocity (v(0)) and step angle (phi(m)) chosen for a given walk. In this paper, using basic mechanics, a framework of physical constraints that limit the choice of operating points is proposed. The constraint lines thus obtained delimit the allowable region of operation of the walker in the v(0)-phi(m) plane. A given average forward velocity v(x,) (avg) can be achieved by several combinations of v(0) and phi(m). Only one of these combinations results in the minimum mechanical power consumption and can be considered the optimum operating point for the given v(x, avg). This paper proposes a method for obtaining this optimal operating point based on tangency of the power and velocity contours. Putting together all such operating points for various v(x, avg,) a family of optimum operating points, called the optimal locus, is obtained. For the energy loss and internal energy models chosen, the optimal locus obtained has a largely constant step angle with increasing speed but tapers off at non-dimensional speeds close to unity.

Limits and tradeoffs in the control of autocatalytic systems

Despite the complexity of biological networks, we find that certain common architectures govern network structures. These architectures impose fundamental constraints on system performance and create tradeoffs that the system must balance in the face of uncertainty in the environment. This means that while a system may be optimized for a specific function through evolution, the optimal achievable state must follow these constraints. One such constraining architecture is autocatalysis, as seen in many biological networks including glycolysis and ribosomal protein synthesis. Using a minimal model, we show that ATP autocatalysis in glycolysis imposes stability and performance constraints and that the experimentally well-studied glycolytic oscillations are in fact a consequence of a tradeoff between error minimization and stability. We also show that additional complexity in the network results in increased robustness. Ribosome synthesis is also autocatalytic where ribosomes must be used to make more ribosomal proteins. When ribosomes have higher protein content, the autocatalysis is increased. We show that this autocatalysis destabilizes the system, slows down response, and also constrains the system’s performance. On a larger scale, transcriptional regulation of whole organisms also follows architectural constraints and this can be seen in the differences between bacterial and yeast transcription networks. We show that the degree distributions of bacterial transcription network follow a power law distribution while the yeast network follows an exponential distribution. We then explored the evolutionary models that have previously been proposed and show that neither the preferential linking model nor the duplication-divergence model of network evolution generates the power-law, hierarchical structure found in bacteria. However, in real biological systems, the generation of new nodes occurs through both duplication and horizontal gene transfers, and we show that a biologically reasonable combination of the two mechanisms generates the desired network.

Optimal design of building structures using genetic algorithms

A general framework for multi-criteria optimal design is presented which is well-suited for automated design of structural systems. A systematic computer-aided optimal design decision process is developed which allows the designer to rapidly evaluate and improve a proposed design by taking into account the major factors of interest related to different aspects such as design, construction, and operation.

The proposed optimal design process requires the selection of the most promising choice of design parameters taken from a large design space, based on an evaluation using specified criteria. The design parameters specify a particular design, and so they relate to member sizes, structural configuration, etc. The evaluation of the design uses performance parameters which may include structural response parameters, risks due to uncertain loads and modeling errors, construction and operating costs, etc. Preference functions are used to implement the design criteria in a "soft" form. These preference functions give a measure of the degree of satisfaction of each design criterion. The overall evaluation measure for a design is built up from the individual measures for each criterion through a preference combination rule. The goal of the optimal design process is to obtain a design that has the highest overall evaluation measure - an optimization problem.

Genetic algorithms are stochastic optimization methods that are based on evolutionary theory. They provide the exploration power necessary to explore high-dimensional search spaces to seek these optimal solutions. Two special genetic algorithms, hGA and vGA, are presented here for continuous and discrete optimization problems, respectively.

The methodology is demonstrated with several examples involving the design of truss and frame systems. These examples are solved by using the proposed hGA and vGA.

Dose terapêutica de radiação ionizante induz um fenótipo migratório em células de carcinoma de colon humano (caco-2): vias de sinalização envolvidas

O câncer colo-retal é a terceira neoplasia mais frequente em todo o mundo e a recorrência local e neoplasia refratária são desafios no tratamento do câncer colo-retal após a cirurgia convencional. Com o intuito de controlar a recorrência e aumentar a média de sobrevida dos pacientes, uma estratégia multidisciplinar que combina a radioterapia (RT) e a quimioterapia com o processo cirúrgico tem sido protocolo clínico de escolha. Embora esta combinação seja capaz de otimizar o tratamento, nem todos os pacientes são beneficiados com o protocolo quimio-rádio combinado, uma vez que existem os insucessos terapêuticos relacionados com a incidência de neoplasias secundárias tardias em pacientes que foram submetidos à RT para tratamento de neoplasias anteriores. Além da doença refratária, outro agravante da RT são os efeitos colaterais produzidos pela radiação ionizante (IR), em especial àqueles do trato gastrointestinal. Estes efeitos estão relacionados com alterações da homeostase do epitélio intestinal, através da desorganização dos complexos juncionais. Porém, os mecanismos que medeiam estes efeitos ainda não estão elucidados. Este estudo avaliou as vias de sinalização que medeiam os efeitos da IR em células Caco-2. Foi observado que a IR causa uma desorganização da junção aderente via Src, EGFR e MAPK, sendo estas alterações acompanhadas por desorganização do citoesqueleto de actina em todo o volume celular. Src, EGFR e MAPK participam de maneira diferenciada na modulação destes efeitos. Observamos também que a radiação aumenta a motilidade dessas células via Src e MAPK e não induz alteração na proliferação celular até 48 horas após o tratamento. Este é o primeiro trabalho que correlaciona vias de sobrevivência celular como Src, EGFR e MAPK com alterações nas proteínas de junção aderente, alterações do citoesqueleto e migração celular. Estes eventos são relacionados aos efeitos colaterais primários e tardios induzidos pela IR, e podem favorecer à aquisição de um fenótipo maligno herdável durante o fracionamento de doses na RT, favorecendo a progressão tumoral do câncer colo-retal. Logo, além da correlação das vias de sinalização envolvidas nos eventos induzidos pela IR mostrados neste estudo, os resultados também corroboram para um melhor entendimento da atividade farmacológica dos inibidores químicos utilizados, uma vez que muitos deles encontram-se em fase de ensaios pré-clínicos e clínicos.

Risk-sensitive optimal feedback control accounts for sensorimotor behavior under uncertainty.

Many aspects of human motor behavior can be understood using optimality principles such as optimal feedback control. However, these proposed optimal control models are risk-neutral; that is, they are indifferent to the variability of the movement cost. Here, we propose the use of a risk-sensitive optimal controller that incorporates movement cost variance either as an added cost (risk-averse controller) or as an added value (risk-seeking controller) to model human motor behavior in the face of uncertainty. We use a sensorimotor task to test the hypothesis that subjects are risk-sensitive. Subjects controlled a virtual ball undergoing Brownian motion towards a target. Subjects were required to minimize an explicit cost, in points, that was a combination of the final positional error of the ball and the integrated control cost. By testing subjects on different levels of Brownian motion noise and relative weighting of the position and control cost, we could distinguish between risk-sensitive and risk-neutral control. We show that subjects change their movement strategy pessimistically in the face of increased uncertainty in accord with the predictions of a risk-averse optimal controller. Our results suggest that risk-sensitivity is a fundamental attribute that needs to be incorporated into optimal feedback control models.

Coupling ecology and economy: modeling optimal release scenarios for summer flounder (Paralichthys dentatus) stock enhancement

Increasing interest in the use of stock enhancement as a management tool necessitates a better understanding of the relative costs and benefits of alternative release strategies. We present a relatively simple model coupling ecology and economic costs to make inferences about optimal release scenarios for summer flounder (Paralichthys dentatus), a subject of stock enhancement interest in North Carolina. The model, parameterized from mark-recapture experiments, predicts optimal release scenarios from both survival and economic standpoints for varyious dates-of-release, sizes-at-release, and numbers of fish released. Although most stock enhancement efforts involve the release of relatively small fish, the model suggests that optimal results (maximum survival and minimum costs) will be obtained when relatively large fish (75–80 mm total length) are released early in the nursery season (April). We investigated the sensitivity of model predictions to violations of the assumption of density-independent mortality by including density-mortality relationships based on weak and strong type-2 and type-3 predator functional responses (resulting in depensatory mortality at elevated densities). Depending on postrelease density, density-mortality relationships included in the model considerably affect predicted postrelease survival and economic costs associated with enhancement efforts, but do not alter the release scenario (i.e. combination of release variables) that produces optimal results. Predicted (from model output) declines in flounder over time most closely match declines observed in replicate field sites when mortality in the model is density-independent or governed by a weak type-3 functional response. The model provides an example of a relatively easy-to-develop predictive tool with which to make inferences about the ecological and economic potential of stock enhancement of summer flounder and provides a template for model creation for additional species that are subjects of stock enhancement interest, but for which limited empirical data exist.

Risk-sensitive optimal feedback control accounts for sensorimotor behavior under uncertainty

Many aspects of human motor behavior can be understood using optimality principles such as optimal feedback control. However, these proposed optimal control models are risk-neutral; that is, they are indifferent to the variability of the movement cost. Here, we propose the use of a risk-sensitive optimal controller that incorporates movement cost variance either as an added cost (risk-averse controller) or as an added value (risk-seeking controller) to model human motor behavior in the face of uncertainty. We use a sensorimotor task to test the hypothesis that subjects are risk-sensitive. Subjects controlled a virtual ball undergoing Brownian motion towards a target. Subjects were required to minimize an explicit cost, in points, that was a combination of the final positional error of the ball and the integrated control cost. By testing subjects on different levels of Brownian motion noise and relative weighting of the position and control cost, we could distinguish between risk-sensitive and risk-neutral control. We show that subjects change their movement strategy pessimistically in the face of increased uncertainty in accord with the predictions of a risk-averse optimal controller. Our results suggest that risk-sensitivity is a fundamental attribute that needs to be incorporated into optimal feedback control models. © 2010 Nagengast et al.

Effect of gamma radiation in combination with freezing on the microbiological changes in frozen shrimp Penaeus monodon

In this study gamma radiation (3, 6 and 9 kGy) in combination with low temperature (-20°C) were applied to retain the quality and shelf-life of shrimp, Penaeus monodon for a longer period. The quality was assessed by monitoring microbiological changes (TBC, TMC, TYC, TCC and Salmonella count) in irradiated and non-irradiated (control) samples. Among microbiological indicators of spoilage, total bacterial count (TBC) values for irradiated shrimps were found to be 1875, 1625 and 1525 cfugˉ¹ of sample at 3, 6 and 9 kGy respectively after 90 days whereas for non-irradiated samples it was found 2475 cfugˉ¹ of sample. Total moulds count (TMC) value for non-irradiated samples after 90 days were found 425 cfugˉ¹ sample whereas that for irradiated shrimps at 3, 6 and 9 kGy were found to be 275, 250 and 200 cfugˉ¹ sample respectively. Total yeast count (TYC) value for non-irradiated samples after 90 days were found 4125 cfugˉ¹ sample whereas that for irradiated shrimps at 3, 6 and 9 kGy were found to be 2850, 2150 and 1725 cfugˉ¹ sample respectively. Total coliform count and Salmonella count showed that those were absent during 90 days storage period. From this study, it was clear that gamma radiation in combination with low temperature showed shelf-life extension (90 days) in each dose of radiation used but during the use of 9 kGy radiation, Penaeus monodon showed best quality.

Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys

With advancing age, monkeys develop deficits in spatial working memory resembling those induced by lesions of the prefrontal cortex (PFC). Aged monkeys also exhibit marked loss of dopamine from the PFC, a transmitter known to be important for proper PFC cognitive function. Previous results suggest that D1 agonist treatment can improve spatial working memory abilities in aged monkeys. However, this research was limited by the use of drugs with either partial agonist actions or significant D2 receptor actions. In our study, the selective dopamine D1 receptor full agonists A77636 and SKF81297 were examined in aged monkeys for effects on the working memory functions of the PFC. Both compounds produced a significant, dose-related effect on delayed response performance without evidence of side effects: low doses improved performance although higher doses impaired or had no effect on performance. Both the improvement and impairment in performance were reversed by pretreatment with the D1 receptor antagonist, SCH23390. These findings are consistent with previous results demonstrating that there is a narrow range of D1 receptor stimulation for optimal PFC cognitive function, and suggest that very low doses of D1 receptor agonists may have cognitive-enhancing actions in the elderly.

An optimal design process for an adequate product?

The 'optimal' or 'best' design process may be the shortest or cheapest process, or the one that leads to a particularly desirable product, or to a reliable and maintainable product, or to a manufacturable product, or some combination of all of these. It is likely to satisfy the aspirations of the organisation to invest an appropriate amount of resource in the development of a specific new market opportunity, set in the context of longer-term business goals. This paper describes the progress made in over ten years of research on process modelling undertaken at the Cambridge Engineering Design Centre to identify an 'optimal' design process with which to develop an 'adequate' product.

Optimal recall from bounded metaplastic synapses: predicting functional adaptations in hippocampal area CA3.

A venerable history of classical work on autoassociative memory has significantly shaped our understanding of several features of the hippocampus, and most prominently of its CA3 area, in relation to memory storage and retrieval. However, existing theories of hippocampal memory processing ignore a key biological constraint affecting memory storage in neural circuits: the bounded dynamical range of synapses. Recent treatments based on the notion of metaplasticity provide a powerful model for individual bounded synapses; however, their implications for the ability of the hippocampus to retrieve memories well and the dynamics of neurons associated with that retrieval are both unknown. Here, we develop a theoretical framework for memory storage and recall with bounded synapses. We formulate the recall of a previously stored pattern from a noisy recall cue and limited-capacity (and therefore lossy) synapses as a probabilistic inference problem, and derive neural dynamics that implement approximate inference algorithms to solve this problem efficiently. In particular, for binary synapses with metaplastic states, we demonstrate for the first time that memories can be efficiently read out with biologically plausible network dynamics that are completely constrained by the synaptic plasticity rule, and the statistics of the stored patterns and of the recall cue. Our theory organises into a coherent framework a wide range of existing data about the regulation of excitability, feedback inhibition, and network oscillations in area CA3, and makes novel and directly testable predictions that can guide future experiments.