Experimental design methodologies for the identification of Michaelis-Menten type kinetics

The main objective of this work was to investigate the application of experimental design techniques for the identification of Michaelis-Menten kinetic parameters. More specifically, this study attempts to elucidate the relative advantages/disadvantages of employing complex experimental design techniques in relation to equidistant sampling when applied to different reactor operation modes. All studies were supported by simulation data of a generic enzymatic process that obeys to the Michaelis-Menten kinetic equation. Different aspects were investigated, such as the influence of the reactor operation mode (batch, fed-batch with pulse wise feeding and fed-batch with continuous feeding) and the experimental design optimality criteria on the effectiveness of kinetic parameters identification. The following experimental design optimality criteria were investigated: 1) minimization of the sum of the diagonal of the Fisher information matrix (FIM) inverse (A-criterion), 2) maximization of the determinant of the FIM (D-criterion), 3) maximization of the smallest eigenvalue of the FIM (E-criterion) and 4) minimization of the quotient between the largest and the smallest eigenvalue (modified E-criterion). The comparison and assessment of the different methodologies was made on the basis of the Cramér-Rao lower bounds (CRLB) error in respect to the parameters vmax and Km of the Michaelis-Menten kinetic equation. In what concerns the reactor operation mode, it was concluded that fed-batch (pulses) is better than batch operation for parameter identification. When the former operation mode is adopted, the vmax CRLB error is lowered by 18.6 % while the Km CRLB error is lowered by 26.4 % when compared to the batch operation mode. Regarding the optimality criteria, the best method was the A-criterion, with an average vmax CRLB of 6.34 % and 5.27 %, for batch and fed-batch (pulses), respectively, while presenting a Km’s CRLB of 25.1 % and 18.1 %, for batch and fed-batch (pulses), respectively. As a general conclusion of the present study, it can be stated that experimental design is justified if the starting parameters CRLB errors are inferior to 19.5 % (vmax) and 45% (Km), for batch processes, and inferior to 42 % and to 50% for fed-batch (pulses) process. Otherwise equidistant sampling is a more rational decision. This conclusion clearly supports that, for fed-batch operation, the use of experimental design is likely to largely improve the identification of Michaelis-Menten kinetic parameters.

Analysis of temperature time-series: embedding dynamics into the MDS method

Global warming and the associated climate changes are being the subject of intensive research due to their major impact on social, economic and health aspects of the human life. Surface temperature time-series characterise Earth as a slow dynamics spatiotemporal system, evidencing long memory behaviour, typical of fractional order systems. Such phenomena are difficult to model and analyse, demanding for alternative approaches. This paper studies the complex correlations between global temperature time-series using the Multidimensional scaling (MDS) approach. MDS provides a graphical representation of the pattern of climatic similarities between regions around the globe. The similarities are quantified through two mathematical indices that correlate the monthly average temperatures observed in meteorological stations, over a given period of time. Furthermore, time dynamics is analysed by performing the MDS analysis over slices sampling the time series. MDS generates maps describing the stations’ locus in the perspective that, if they are perceived to be similar to each other, then they are placed on the map forming clusters. We show that MDS provides an intuitive and useful visual representation of the complex relationships that are present among temperature time-series, which are not perceived on traditional geographic maps. Moreover, MDS avoids sensitivity to the irregular distribution density of the meteorological stations.

Self-similarity principle: the reduced description of randomness

A new general fitting method based on the Self-Similar (SS) organization of random sequences is presented. The proposed analytical function helps to fit the response of many complex systems when their recorded data form a self-similar curve. The verified SS principle opens new possibilities for the fitting of economical, meteorological and other complex data when the mathematical model is absent but the reduced description in terms of some universal set of the fitting parameters is necessary. This fitting function is verified on economical (price of a commodity versus time) and weather (the Earth’s mean temperature surface data versus time) and for these nontrivial cases it becomes possible to receive a very good fit of initial data set. The general conditions of application of this fitting method describing the response of many complex systems and the forecast possibilities are discussed.

Towards a unified theory of health-disease: II. Holopathogenesis

This article presents a systematic framework for modeling several classes of illness-sickness-disease named as Holopathogenesis. Holopathogenesis is defined as processes of over-determination of diseases and related conditions taken as a whole, comprising selected facets of the complex object Health. First, a conceptual background of Holopathogenesis is presented as a series of significant interfaces (biomolecular-immunological, physiopathological-clinical, epidemiological-ecosocial). Second, propositions derived from Holopathogenesis are introduced in order to allow drawing the disease-illness-sickness complex as a hierarchical network of networks. Third, a formalization of intra- and inter-level correspondences, over-determination processes, effects and links of Holopathogenesis models is proposed. Finally, the Holopathogenesis frame is evaluated as a comprehensive theoretical pathology taken as a preliminary step towards a unified theory of health-disease.

Complex-order forced van der Pol oscillator

In this paper we consider a complex-order forced van der Pol oscillator. The complex derivative Dα1jβ, with α, β ∈ ℝ+, is a generalization of the concept of an integer derivative, where α = 1, β = 0. The Fourier transforms of the periodic solutions of the complex-order forced van der Pol oscillator are computed for various values of parameters such as frequency ω and amplitude b of the external forcing, the damping μ, and parameters α and β. Moreover, we consider two cases: (i) b = 1, μ = {1.0, 5.0, 10.0}, and ω = {0.5, 2.46, 5.0, 20.0}; (ii) ω = 20.0, μ = {1.0, 5.0, 10.0}, and b = {1.0, 5.0, 10.0}. We verified that most of the signal energy is concentrated in the fundamental harmonic ω0. We also observed that the fundamental frequency of the oscillations ω0 varies with α and μ. For the range of tested values, the numerical fitting led to logarithmic approximations for system (7) in the two cases (i) and (ii). In conclusion, we verify that by varying the parameter values α and β of the complex-order derivative in expression (7), we accomplished a very effective way of perturbing the dynamical behavior of the forced van der Pol oscillator, which is no longer limited to parameters b and ω.

Complex order van der Pol oscillator

In this paper a complex-order van der Pol oscillator is considered. The complex derivative Dα±ȷβ , with α,β∈R + is a generalization of the concept of integer derivative, where α=1, β=0. By applying the concept of complex derivative, we obtain a high-dimensional parameter space. Amplitude and period values of the periodic solutions of the two versions of the complex-order van der Pol oscillator are studied for variation of these parameters. Fourier transforms of the periodic solutions of the two oscillators are also analyzed.

Modeling of the lung impedance using a fractional order ladder network with constant phase elements

The self similar branching arrangement of the airways makes the respiratory system an ideal candidate for the application of fractional calculus theory. The fractal geometry is typically characterized by a recurrent structure. This study investigates the identification of a model for the respiratory tree by means of its electrical equivalent based on intrinsic morphology. Measurements were obtained from seven volunteers, in terms of their respiratory impedance by means of its complex representation for frequencies below 5 Hz. A parametric modeling is then applied to the complex valued data points. Since at low-frequency range the inertance is negligible, each airway branch is modeled by using gamma cell resistance and capacitance, the latter having a fractional-order constant phase element (CPE), which is identified from measurements. In addition, the complex impedance is also approximated by means of a model consisting of a lumped series resistance and a lumped fractional-order capacitance. The results reveal that both models characterize the data well, whereas the averaged CPE values are supraunitary and subunitary for the ladder network and the lumped model, respectively.

Cobalt complexes with pyrazole ligands as catalyst precursors for the peroxidative oxidation of cyclohexane: Z-ray absorption spectroscopy studies and biological applications

[CoCl(-Cl)(Hpz(Ph))(3)](2) (1) and [CoCl2(Hpz(Ph))(4)] (2) were obtained by reaction of CoCl2 with HC(pz(Ph))(3) and Hpz(Ph), respectively (Hpz(Ph)=3-phenylpyrazole). The compounds were isolated as air-stable solids and fully characterized by IR and far-IR spectroscopy, MS(ESI+/-), elemental analysis, cyclic voltammetry (CV), controlled potential electrolysis, and single-crystal X-ray diffraction. Electrochemical studies showed that 1 and 2 undergo single-electron irreversible (CoCoIII)-Co-II oxidations and (CoCoI)-Co-II reductions at potentials measured by CV, which also allowed, in the case of dinuclear complex 1, the detection of electronic communication between the Co centers through the chloride bridging ligands. The electrochemical behavior of models of 1 and 2 were also investigated by density functional theory (DFT) methods, which indicated that the vertical oxidation of 1 and 2 (that before structural relaxation) affects mostly the chloride and pyrazolyl ligands, whereas adiabatic oxidation (that after the geometry relaxation) and reduction are mostly metal centered. Compounds 1 and 2 and, for comparative purposes, other related scorpionate and pyrazole cobalt complexes, exhibit catalytic activity for the peroxidative oxidation of cyclohexane to cyclohexanol and cyclohexanone under mild conditions (room temperature, aqueous H2O2). Insitu X-ray absorption spectroscopy studies indicated that the species derived from complexes 1 and 2 during the oxidation of cyclohexane (i.e., Ox-1 and Ox-2, respectively) are analogous and contain a Co-III site. Complex 2 showed low invitro cytotoxicity toward the HCT116 colorectal carcinoma and MCF7 breast adenocarcinoma cell lines.

Insights into the mechanims underlyng the antiproliferative potential of a Co(II) coordination compound bearing 1,10-Phenanthroline-5,6-Dione: DNA and protein interaction studies

The very high antiproliferative activity of [Co(Cl)(H2O)(phendione)(2)][BF4] (phendione is 1,10-phenanthroline-5,6-dione) against three human tumor cell lines (half-maximal inhibitory concentration below 1 mu M) and its slight selectivity for the colorectal tumor cell line compared with healthy human fibroblasts led us to explore the mechanisms of action underlying this promising antitumor potential. As previously shown by our group, this complex induces cell cycle arrest in S phase and subsequent cell death by apoptosis and it also reduces the expression of proteins typically upregulated in tumors. In the present work, we demonstrate that [Co(Cl)(phendione)(2)(H2O)][BF4] (1) does not reduce the viability of nontumorigenic breast epithelial cells by more than 85 % at 1 mu M, (2) promotes the upregulation of proapoptotic Bax and cell-cycle-related p21, and (3) induces release of lactate dehydrogenase, which is partially reversed by ursodeoxycholic acid. DNA interaction studies were performed to uncover the genotoxicity of the complex and demonstrate that even though it displays K (b) (+/- A standard error of the mean) of (3.48 +/- A 0.03) x 10(5) M-1 and is able to produce double-strand breaks in a concentration-dependent manner, it does not exert any clastogenic effect ex vivo, ruling out DNA as a major cellular target for the complex. Steady-state and time-resolved fluorescence spectroscopy studies are indicative of a strong and specific interaction of the complex with human serum albumin, involving one binding site, at a distance of approximately 1.5 nm for the Trp214 indole side chain with log K (b) similar to 4.7, thus suggesting that this complex can be efficiently transported by albumin in the blood plasma.

New water-soluble Ruthenium(II) cytotoxic complex: biological activity and celular distribution

A novel water soluble organometallic compound, [RuCp(mTPPMSNa)(2,2'-bipy)][CF3SO3] (TM85, where Cp=eta(5)-cyclopentadienyl, mTPPMS = diphenylphosphane-benzene-3-sulfonate and 2,2'-bipy = 2,2'-bipyridine) is presented herein. Studies of interactions with relevant proteins were performed to understand the behavior and mode of action of this complex in the biological environment. Electrochemical and fluorescence studies showed that TM85 strongly binds to albumin. Studies carried out to study the formation of TM85 which adducts with ubiquitin and cytochrome c were performed by electrospray ionization mass spectrometry (ESI-MS). Antitumor activity was evaluated against a variety of human cancer cell lines, namely A2780, A2780cisR, MCF7, MDAMB231, HT29, PC3 and V79 non-tumorigenic cells and compared with the reference drug cisplatin. TM85 cytotoxic effect was reduced in the presence of endocytosis modulators at low temperatures, suggesting an energy-dependent mechanism consistent with endocytosis. Ultrastructural analysis by transmission electron microscopy (TEM) revealed that TM85 targets the endomembranar system disrupting the Golgi and also affects the mitochondria. Disruption of plasma membrane observed by flow cytometry could lead to cellular damage and cell death. On the whole, the biological activity evaluated herein combined with the water solubility property suggests that complex TM85 could be a promising anticancer agent. (C) 2013 Elsevier Inc. All rights reserved.

H → Zr in the complex two Higgs doublet model

The latest LHC data confirmed the existence of a Higgs-like particle and made interesting measurements on its decays into gamma gamma, ZZ*, WW*, tau(+)tau(-), and b (b) over bar. It is expected that a decay into Z gamma might be measured at the next LHC round, for which there already exists an upper bound. The Higgs-like particle could be a mixture of scalar with a relatively large component of pseudoscalar. We compute the decay of such a mixed state into Z gamma, and we study its properties in the context of the complex two Higgs doublet model, analysing the effect of the current measurements on the four versions of this model. We show that a measurement of the h -> Z gamma rate at a level consistent with the SM can be used to place interesting constraints on the pseudoscalar component. We also comment on the issue of a wrong sign Yukawa coupling for the bottom in Type II models.

Performance evaluation of hospitals that provide care in the public health system, Brazil

OBJECTIVE To analyze if size, administrative level, legal status, type of unit and educational activity influence the hospital network performance in providing services to the Brazilian Unified Health System.METHODS This cross-sectional study evaluated data from the Hospital Information System and the Cadastro Nacional de Estabelecimentos de Saúde (National Registry of Health Facilities), 2012, in Sao Paulo, Southeastern Brazil. We calculated performance indicators, such as: the ratio of hospital employees per bed; mean amount paid for admission; bed occupancy rate; average length of stay; bed turnover index and hospital mortality rate. Data were expressed as mean and standard deviation. The groups were compared using analysis of variance (ANOVA) and Bonferroni correction.RESULTS The hospital occupancy rate in small hospitals was lower than in medium, big and special-sized hospitals. Higher hospital occupancy rate and bed turnover index were observed in hospitals that include education in their activities. The hospital mortality rate was lower in specialized hospitals compared to general ones, despite their higher proportion of highly complex admissions. We found no differences between hospitals in the direct and indirect administration for most of the indicators analyzed.CONCLUSIONS The study indicated the importance of the scale effect on efficiency, and larger hospitals had a higher performance. Hospitals that include education in their activities had a higher operating performance, albeit with associated importance of using human resources and highly complex structures. Specialized hospitals had a significantly lower rate of mortality than general hospitals, indicating the positive effect of the volume of procedures and technology used on clinical outcomes. The analysis related to the administrative level and legal status did not show any significant performance differences between the categories of public hospitals.

From design-for-test to design-for-debug-and-test: analysis of requirements and limitations for 1149.1

The increasing complexity of VLSI circuits and the reduced accessibility of modern packaging and mounting technologies restrict the usefulness of conventional in-circuit debugging tools, such as in-circuit emulators for microprocessors and microcontrollers. However, this same trend enables the development of more complex products, which in turn require more powerful debugging tools. These conflicting demands could be met if the standard scan test infrastructures now common in most complex components were able to match the debugging requirements of design verification and prototype validation. This paper analyses the main debug requirements in the design of microprocessor-based applications and the feasibility of their implementation using the mandatory, optional and additional operating modes of the standard IEEE 1149.1 test infrastructure.

Multidimensional scaling visualization of earthquake phenomena

Earthquakes are associated with negative events, such as large number of casualties, destruction of buildings and infrastructures, or emergence of tsunamis. In this paper, we apply the Multidimensional Scaling (MDS) analysis to earthquake data. MDS is a set of techniques that produce spatial or geometric representations of complex objects, such that, objects perceived to be similar/distinct in some sense are placed nearby/distant on the MDS maps. The interpretation of the charts is based on the resulting clusters since MDS produces a different locus for each similarity measure. In this study, over three million seismic occurrences, covering the period from January 1, 1904 up to March 14, 2012 are analyzed. The events, characterized by their magnitude and spatiotemporal distributions, are divided into groups, either according to the Flinn–Engdahl seismic regions of Earth or using a rectangular grid based in latitude and longitude coordinates. Space-time and Space-frequency correlation indices are proposed to quantify the similarities among events. MDS has the advantage of avoiding sensitivity to the non-uniform spatial distribution of seismic data, resulting from poorly instrumented areas, and is well suited for accessing dynamics of complex systems. MDS maps are proven as an intuitive and useful visual representation of the complex relationships that are present among seismic events, which may not be perceived on traditional geographic maps. Therefore, MDS constitutes a valid alternative to classic visualization tools, for understanding the global behavior of earthquakes.

Large pseudoscalar Yukawa couplings in the complex 2HDM

We start by presenting the current status of a complex flavour conserving two-Higgs doublet model. We will focus on some very interesting scenarios where unexpectedly the light Higgs couplings to leptons and to b-quarks can have a large pseudoscalar component with a vanishing scalar component. Predictions for the allowed parameter space at end of the next run with a total collected luminosity of 300 fb(-1) and 3000 fb(-1) are also discussed. These scenarios are not excluded by present data and most probably will survive the next LHC run. However, a measurement of the mixing angle phi(tau), between the scalar and pseudoscalar component of the 125 GeV Higgs, in the decay h -> tau(+)tau(-) will be able to probe many of these scenarios, even with low luminosity. Similarly, a measurement of phi(t) in the vertex (t) over bar th could help to constrain the low tan beta region in the Type I model.