Biomedical subjects

Kwang-Hyun Cho

Publications and source records attributed to Kwang-Hyun Cho.

At least 19 recordsLinked to original sources

PubMed2007

Least-squares methods for identifying biochemical regulatory networks from noisy measurements.

BACKGROUND: We consider the problem of identifying the dynamic interactions in biochemical networks from noisy experimental data. Typically, approaches for solving this problem make use of an estimation algorithm such as the well-known linear Least-Squares (LS) estimation technique. We demonstrate that when time-series measurements are corrupted by white noise and/or drift noise, more accurate and reliable identification of network interactions can be achieved by employing an estimation algorithm known as Constrained Total Least Squares (CTLS). The Total Least Squares (TLS) technique is a generalised least squares method to solve an overdetermined set of equations whose coefficients are noisy. The CTLS is a natural extension of TLS to the case where the noise components of the coefficients are correlated, as is usually the case with time-series measurements of concentrations and expression profiles in gene networks. RESULTS: The superior performance of the CTLS method in identifying network interactions is demonstrated on three examples: a genetic network containing four genes, a network describing p53 activity and mdm2 messenger RNA interactions, and a recently proposed kinetic model for interleukin (IL)-6 and (IL)-12b messenger RNA expression as a function of ATF3 and NF-kappaB promoter binding. For the first example, the CTLS significantly reduces the errors in the estimation of the Jacobian for the gene network. For the second, the CTLS reduces the errors from the measurements that are corrupted by white noise and the effect of neglected kinetics. For the third, it allows the correct identification, from noisy data, of the negative regulation of (IL)-6 and (IL)-12b by ATF3. CONCLUSION: The significant improvements in performance demonstrated by the CTLS method under the wide range of conditions tested here, including different levels and types of measurement noise and different numbers of data points, suggests that its application will enable more accurate and reliable identification and modelling of biochemical networks.

Algorithms↗

PubMed2007

Coupled positive and negative feedback circuits form an essential building block of cellular signaling pathways.

Cellular circuits have positive and negative feedback loops that allow them to respond properly to noisy external stimuli. It is intriguing that such feedback loops exist in many cases in a particular form of coupled positive and negative feedback loops with different time delays. As a result of our mathematical simulations and investigations into various experimental evidences, we found that such coupled feedback circuits can rapidly turn on a reaction to a proper stimulus, robustly maintain its status, and immediately turn off the reaction when the stimulus disappears. In other words, coupled feedback loops enable cellular systems to produce perfect responses to noisy stimuli with respect to signal duration and amplitude. This suggests that coupled positive and negative feedback loops form essential signal transduction motifs in cellular signaling systems.

Animals↗

PubMed2006

The multi-step phosphorelay mechanism of unorthodox two-component systems in E. coli realizes ultrasensitivity to stimuli while maintaining robustness to noises.

E. coli has two-component systems composed of histidine kinase proteins and response regulator proteins. For a given extracellular stimulus, a histidine kinase senses the stimulus, autophosphorylates and then passes the phosphates to the cognate response regulators. The histidine kinase in an orthodox two-component system has only one histidine domain where the autophosphorylation occurs, but a histidine kinase in some unusual two-component systems (unorthodox two-component systems) has two histidine domains and one aspartate domain. So, the unorthodox two-component systems have more complex phosphorelay mechanisms than orthodox two-component systems. In general, the two-component systems are required to promptly respond to external stimuli for survival of E. coli. In this respect, the complex multi-step phosphorelay mechanism seems to be disadvantageous, but there are several unorthodox two-component systems in E. coli. In this paper, we investigate the reason why such unorthodox two-component systems are present in E. coli. For this purpose, we have developed simplified mathematical models of both orthodox and unorthodox two-component systems and analyzed their dynamical characteristics through extensive computer simulations. We have finally revealed that the unorthodox two-component systems realize ultrasensitive responses to external stimuli and also more robust responses to noises than the orthodox two-component systems.

Cell Survival↗

PubMed2006

Possible interethnic differences in quinidine-induced QT prolongation between healthy Caucasian and Korean subjects.

AIMS: The aim of this study was to evaluate the pharmacokinetics and pharmacodynamics of quinidine-induced QT prolongation in healthy Caucasian and Korean subjects to investigate interethnic differences in susceptibility to drug-induced arrhythmia. METHODS: A randomized, double-blind crossover study was conducted in 24 (12 male and 12 female) Korean and 13 (seven male and six female) Caucasian subjects. After a 20 min infusion of quinidine (4 mg kg(-1)) or saline, the serum concentration of quinidine and the QT interval corrected by Bazett's formula (QTc) were monitored. The dynamic data were analyzed by means of a population modelling approach using NONMEM. RESULTS: There were no statistical differences in the pharmacokinetic profiles of quinidine between ethnic groups. The QTc values in Caucasians were higher than those in Koreans at the same quinidine concentrations, especially at higher quinidine concentrations and in female subjects. According to an E(max) model [equation: see text], the population modelling approach revealed that E0 (ms) was related to gender (408 + [34*(1 - Sex)]; 1 for male and 0 for female), DeltaE(max) (ms) was related to ethnicity ((136*f(ETHN)) + C(female): f(ETHN) = 1 for Koreans and 1.26 for Caucasians; C(female) was 106 only for Caucasian females), and EC50 was estimated to be 3.13 microm. CONCLUSIONS: These results suggest that Korean subjects were less sensitive to quinidine-induced QT prolongation than Caucasian subjects, and that this trend was particularly true for females. Further population-based studies are merited to characterize more completely the ethnic differences in drug-induced QT prolongation between Asians and other ethnic groups.

Adult↗

PubMed2006

Switching feedback mechanisms realize the dual role of MCIP in the regulation of calcineurin activity.

Calcineurin (CaN) assists T-cell activation, growth and differentiation of skeletal and cardiac myocytes, memory, and apoptosis. It also activates transcription of the nuclear factor of activated T-cells (NFAT) family including hypertrophic target genes. It has been reported that the modulatory calcineurin-interacting protein (MCIP) inhibits the CaN activity and thereby reduces the hypertrophic response. However, it has been shown that MCIP facilitates or permits the hypertrophic response under some stress conditions such as isoproterenol infusion or pressure overload by transverse aortic constriction. As there is no direct experimental evidence that can explain these paradoxical phenomena, there has been a controversy concerning the functional role of MCIP in developing the hypertrophic response. It is therefore crucial to establish a hypothesis that can clearly explain these phenomena. Towards this end, we propose in this paper a hypothesis that is based on available experimental evidence as well as mathematical modeling and computer simulations. We hypothesize that there is a threshold in the nuclear NFAT concentration above which MCIP is switched on. Below this threshold, the inhibition of active CaN by MCIP is negligible, while the activated protein kinase increases the dissociation rate of the CaN/MCIP complex. This leads to an augmentation of active CaN. This mechanism realizes the positive effect (i.e., removing any negative feedback) of MCIP in the hypertrophic response. On the other hand, the over-expression of active CaN increases nuclear NFAT to values above the threshold, while CaN is inhibited through binding of MCIP (expressed by the nuclear NFAT). This mechanism realizes the introduction of a negative feedback mechanism. To unravel this switching feedback mechanism, we have developed a mathematical model for which computer simulations are in agreement with the existing experimental data. The simulations demonstrate how the apparently paradoxical behavior can emerge as a result of cellular conditions.

Animals↗

PubMed2006

Serotonin inhibits the induction of NMDA receptor-dependent long-term potentiation in the rat primary visual cortex.

An increase in serotonin [5-hydroxytryptamine (5-HT)] levels in the rat visual cortex is correlated with the developmental decrease in long-term potentiation (LTP), and 5-HT may play an important role in the closure of the critical period by regulating LTP. The effect of 5-HT on the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent and metabotropic glutamate receptor (mGluR)-dependent LTP in visual cortex slices from young rats was investigated. The field potential in layer II/III was recorded by stimulating the underlying layer IV. NMDAR-dependent LTP was induced in slices from 3-week-old rats by theta-burst stimulation (TBS) but not in slices from 5-week-old rats. However, LTP was induced in 5-HT-depleted slices from 5-week-old rats by incubation with para-chloroamphetamine (10 microM, 2 h), a 5-HT-depleting agent. The reinstated LTP in 5-HT-depleted slices was inhibited by the application of D-aminopentanoate, an NMDAR antagonist (50 microM) and 5-HT (10 and 30 microM). In contrast, the induction of mGluR-dependent LTP by weak TBS in disinhibited slices with picrotoxin (1 microM) in the bath was not affected by 5-HT application. The coapplication of 5-HT1A and 5-HT2 receptor agonists inhibited the induction of NMDAR-dependent LTP in 5-HT-depleted slices. 5-HT levels in the visual cortex increased with age. Based on these findings, we conclude that NMDAR-dependent LTP is specifically inhibited by coactivation of 5-HT1A and 5-HT2 receptors with the increase in 5-HT levels in the rat visual cortex at the end of the critical period.

Animals↗

PubMed2006

Wnt pathway mutations selected by optimal beta-catenin signaling for tumorigenesis.

Mutations in components of the Wnt/beta-catenin pathway are observed to be the earliest initiating event for most colorectal tumors. The majority of the mutations occur in the tumor suppressor adenomatous polyposis coli (APC), even though there are other genes that are capable of modulating the pathway activity. Moreover, the specific APC mutations associated in colon cancer indicate the possibility that the tumor selects for certain truncated forms of APC that partially retain its function, namely, inhibition of beta-catenin. We estimated the effects of various mutations in APC and other known mutations using a recent mathematical model of the Wnt pathway that was constructed to represent the conserved core molecular events. We provide evidence that APC mutations are selected not based on the maximal level of beta-catenin but rather based on distinct state of activity that appears to be optimal for the tissue-specific tumorigenesis. This optimal level is determined by balancing beta-catenin signaling and the induction of Axin2 that acts as a potent negative feedback. The predominant pattern of APC mutations may provide synergistic oncogenic effects that promote colorectal tumorigenesis: the optimal signaling for cell survival and renewal, disrupted cell adhesion, chromosomal instability, and altered asymmetric division of stem cells.

Adenomatous Polyposis Coli↗

PubMed2006

Inferring biomolecular regulatory networks from phase portraits of time-series expression profiles.

Reverse engineering of biomolecular regulatory networks such as gene regulatory networks, protein interaction networks, and metabolic networks has received an increasing attention as more high-throughput time-series measurements become available. In spite of various approaches developed from this motivation, it still remains as a challenging subject to develop a new reverse engineering scheme that can effectively uncover the functional interaction structure of a biomolecular network from given time-series expression profiles (TSEPs). We propose a new reverse engineering scheme that makes use of phase portraits constructed by projection of every two TSEPs into respective phase planes. We introduce two measures of a slope index (SI) and a winding index (WI) to quantify the interaction properties embedded in the phase portrait. Based on the SI and WI, we can reconstruct the functional interaction network in a very efficient and systematic way with better inference results compared to previous approaches. By using the SI, we can also estimate the time-lag accompanied with the interaction between molecular components of a network.

Animals↗

PubMed2006

Identification of biochemical networks by S-tree based genetic programming.

MOTIVATION: Most previous approaches to model biochemical networks have focused either on the characterization of a network structure with a number of components or on the estimation of kinetic parameters of a network with a relatively small number of components. For system-level understanding, however, we should examine both the interactions among the components and the dynamic behaviors of the components. A key obstacle to this simultaneous identification of the structure and parameters is the lack of data compared with the relatively large number of parameters to be estimated. Hence, there are many plausible networks for the given data, but most of them are not likely to exist in the real system. RESULTS: We propose a new representation named S-trees for both the structural and dynamical modeling of a biochemical network within a unified scheme. We further present S-tree based genetic programming to identify the structure of a biochemical network and to estimate the corresponding parameter values at the same time. While other evolutionary algorithms require additional techniques for sparse structure identification, our approach can automatically assemble the sparse primitives of a biochemical network in an efficient way. We evaluate our algorithm on the dynamic profiles of an artificial genetic network. In 20 trials for four settings, we obtain the true structure and their relative squared errors are <5% regardless of releasing constraints about structural sparseness. In addition, we confirm that the proposed algorithm is robust within +/-10% noise ratio. Furthermore, the proposed approach ensures a reasonable estimate of a real yeast fermentation pathway. The comparatively less important connections with non-zero parameters can be detected even though their orders are below 10(-2). To demonstrate the usefulness of the proposed algorithm for real experimental biological data, we provide an additional example on the transcriptional network of SOS response to DNA damage in Escherichia coli. We confirm that the proposed algorithm can successfully identify the true structure except only one relation.

Algorithms↗

PubMed2006

Spatial profile of back-propagating action potential-evoked Ca2+ transients in basal dendrites.

Calcium influx in basal dendrites evoked by back-propagating action potentials is important for understanding the input-specific modulation of synaptic transmission. Calcium transients evoked by back-propagating action potentials were measured for the basal dendrites of layer II/III pyramidal neurons in visual cortex slices. In contrast to apical dendrites, the peak calcium transients evoked by a single somatic action potential increased with distance from the soma. The peak calcium transients evoked by bursts of back-propagating action potentials (three or five pulses, 20 Hz) were greater than those evoked by a single back-propagating action potential. These different spatial profiles for calcium transients triggered by back-propagating action potentials between apical and basal dendrites suggest that the segregated inputs from brain areas might be modulated in different ways, according to their synaptic location.

Action Potentials↗

PubMed2006

The influence of the signal dynamics of activated form of IKK on NF-kappaB and anti-apoptotic gene expressions: a systems biology approach.

NF-kappaB activation plays a crucial role in anti-apoptotic responses in response to the apoptotic signaling during tumor necrosis factor (TNF)-alpha stimulation. TNF-alpha induces apoptosis sensitive to the hepatitis B virus (HBV) infected cells, despite sustained NF-kappaB activation. Our results indicate that the HBV infection induces sustained NF-kappaB activation, in a manner similar to the TNF-alpha stimulation. However, these effects are not merely combined. Computational simulations show that the level of form of the IKK complex activated by phosphorylation (IKK-p) affects the dynamic pattern of NF-kappaB activation during TNF-alpha stimulation in the following ways: (i) the initial level of IKK-p determines the incremental change in IKK-p at the same level of TNF-alpha stimulation, (ii) the incremental change in IKK-p determines the amplitudes of active NF-kappaB oscillation, and (iii) the steady state level of IKK-p after the incremental change determines the period of active NF-kappaB oscillation. Based on experiments, we observed that the initial level of IKK-p was upregulated and the active NF-kappaB oscillation showed smaller amplitudes for a shorter period in HepG2.2.15 cells (HBV-producing cells) during TNF-alpha stimulation, as was indicated by the computational simulations. Furthermore, we found that during TNF-alpha stimulation, NF-kappaB-regulated anti-apoptotic genes were upregulated in HepG2 cells but were downregulated in HepG2.2.15 cells. Based on the previously mentioned results, we can conclude that the IKK-p-level changes induced by HBV infection modulate the dynamic pattern of active NF-kappaB and thereby could affect NF-kappaB-regulated anti-apoptotic gene expressions. Finally, we postulate that the sensitive apoptotic response of HBV-infected cells to TNF-alpha stimulation is governed by the dynamic patterns of active NF-kappaB based on IKK-p level changes.

Apoptosis↗

PubMed2006

Bee venom injection significantly reduces nociceptive behavior in the mouse formalin test via capsaicin-insensitive afferents.

UNLABELLED: Peripheral bee venom (BV) administration produces 2 contrasting effects, nociception and antinociception. This study was designed to evaluate whether the initial nociceptive effect induced by BV injection into the Zusanli acupoint is involved in producing the more prolonged antinociceptive effect observed in the mouse formalin test, and whether capsaicin-sensitive primary afferents are involved in these effects. BV injection into the Zusanli point increased spinal Fos expression but not spontaneous nociceptive behavior. BV pretreatment 10 minutes before intraplantar formalin injection dose-dependently attenuated nociceptive behavior associated with the second phase of the formalin test. The destruction of capsaicin-sensitive primary afferents by resiniferatoxin (RTX) pretreatment selectively decreased BV-induced spinal Fos expression but did not affect BV-induced antinociception. Furthermore, BV injection increased Fos expression in tyrosine hydroxylase immunoreactive neurons in the locus caeruleus, and this expression was unaltered by RTX pretreatment. Finally, BV's antinociception was blocked by intrathecal injection of 10 microg idazoxan, and this effect was not modified by RTX pretreatment. These findings suggest that subcutaneous BV stimulation of the Zusanli point activates central catecholaminergic neurons via capsaicin-insensitive afferent fibers without induction of nociceptive behavior. This in turn leads to the activation of spinal alpha2-adrenoceptors, which ultimately reduces formalin-evoked nociceptive behaviors. PERSPECTIVE: This study demonstrates that BV acupuncture produces a significant antinociception without nociceptive behavior in rodents, which is mediated by capsaicin-insensitive afferents and involves activation of central adrenergic circuits. These results further suggest that BV stimulation into this acupuncture point might be a valuable alternative to traditional electrical or mechanical acupoint stimulation.

Acupuncture Analgesia↗

PubMed2006

Dynamics of biological systems: role of systems biology in medical research.

Cellular systems are networks of interacting components that change with time in response to external and internal events. Studying the dynamic behavior of these networks is the basis for an understanding of cellular functions and disease mechanisms. Quantitative time-series data leading to meaningful models can improve our knowledge of human physiology in health and disease, and aid the search for earlier diagnoses, better therapies and a healthier life. The advent of systems biology is about to take the leap into clinical research and medical applications. This review emphasizes the importance of a dynamic view and understanding of cell function. We discuss the potential for computer-aided mathematical modeling of biological systems in medical research with examples from some of the major therapeutic areas: cancer, cardiovascular, diabetic and neurodegenerative medicine.

Animals↗

PubMed2005

Distinct sets of genetic alterations in melanoma.

BACKGROUND: Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different susceptibility to ultraviolet light. METHODS: We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas. RESULTS: We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89 percent accuracy. Eighty-one percent of melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway. CONCLUSIONS: The genetic alterations identified in melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.

Adult↗

PubMed2005

A unified framework for unraveling the functional interaction structure of a biomolecular network based on stimulus-response experimental data.

We propose a unified framework for the identification of functional interaction structures of biomolecular networks in a way that leads to a new experimental design procedure. In developing our approach, we have built upon previous work. Thus we begin by pointing out some of the restrictions associated with existing structure identification methods and point out how these restrictions may be eased. In particular, existing methods use specific forms of experimental algebraic equations with which to identify the functional interaction structure of a biomolecular network. In our work, we employ an extended form of these experimental algebraic equations which, while retaining their merits, also overcome some of their disadvantages. Experimental data are required in order to estimate the coefficients of the experimental algebraic equation set associated with the structure identification task. However, experimentalists are rarely provided with guidance on which parameters to perturb, and to what extent, to perturb them. When a model of network dynamics is required then there is also the vexed question of sample rate and sample time selection to be resolved. Supplying some answers to these questions is the main motivation of this paper. The approach is based on stationary and/or temporal data obtained from parameter perturbations, and unifies the previous approaches of Kholodenko et al. (PNAS 99 (2002) 12841-12846) and Sontag et al. (Bioinformatics 20 (2004) 1877-1886). By way of demonstration, we apply our unified approach to a network model which cannot be properly identified by existing methods. Finally, we propose an experiment design methodology, which is not limited by the amount of parameter perturbations, and illustrate its use with an in numero example.

Computational Biology↗

PubMed2005

The dynamic systems approach to control and regulation of intracellular networks.

Systems theory and cell biology have enjoyed a long relationship that has received renewed interest in recent years in the context of systems biology. The term 'systems' in systems biology comes from systems theory or dynamic systems theory: systems biology is defined through the application of systems- and signal-oriented approaches for an understanding of inter- and intra-cellular dynamic processes. The aim of the present text is to review the systems and control perspective of dynamic systems. The biologist's conceptual framework for representing the variables of a biochemical reaction network, and for describing their relationships, are pathway maps. A principal goal of systems biology is to turn these static maps into dynamic models, which can provide insight into the temporal evolution of biochemical reaction networks. Towards this end, we review the case for differential equation models as a 'natural' representation of causal entailment in pathways. Block-diagrams, commonly used in the engineering sciences, are introduced and compared to pathway maps. The stimulus-response representation of a molecular system is a necessary condition for an understanding of dynamic interactions among the components that make up a pathway. Using simple examples, we show how biochemical reactions are modelled in the dynamic systems framework and visualized using block-diagrams.

Animals↗

PubMed2005

Erythrodiol-3-acetate, pentacyclic triterpenoid from Styrax japonica, expressions of matrix metalloproteinase-1,2 in cultured human skin fibroblasts.

Although many studies have been performed to elucidate the molecular consequences of ultraviolet irradiation, little is known about the effect of natural products. Ultraviolet irradiation is widely considered to be an environmental stress. Here we investigated the effect of erythrodiol-3-acetate on the expressions of MMP-1,2 in cultured human skin fibroblasts. Erythrodiol-3-acetate was isolated from the stems of Styrax japonica (Styracaceae). Erythrodiol-3-acetate reduced the expression of MMP-1 but not MMP-2, at the mRNA and protein levels in a dose-dependent manner by ultraviolet irradiation. Taken together, our results suggest that erythrodiol-3-acetate an important role in the reduction of MMP-1 induction by ultraviolet irradiation.

Acetates↗

PubMed2005

Cross-linking of 4-1BB activates TCR-signaling pathways in CD8+ T lymphocytes.

Cross-linking of 4-1BB, a member of the TNFR family, increased tyrosine phosphorylation of TCR-signaling molecules such as CD3epsilon, CD3zeta, Lck, the linker for activation of T cells, and SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76). In addition, incubation of activated CD8+ T cells with p815 cells expressing 4-1BBL led to redistribution of the lipid raft domains and Lck, protein kinase C-theta;, SLP-76, and phospholipase C-gamma1 (PLC-gamma1) on the T cell membranes to the areas of contact with the p815 cells and recruitment of 4-1BB, TNFR-associated factor 2, and phospho-tyrosine proteins to the raft domains. 4-1BB ligation also caused translocation of TNFR-associated factor 2, protein kinase C-theta;, PLC-gamma1, and SLP-76 to detergent-insoluble compartments in the CD8+ T cells, and cross-linking of 4-1BB increased intracellular Ca2+ levels apparently by activating PLC-gamma1. The redistribution of lipid rafts and Lck, as well as translocation of PLC-gamma1, and degradation of IkappaB-alpha in response to 4-1BB were inhibited by disrupting the formation of lipid rafts with methyl-beta-cyclodextrin. These findings demonstrate that 4-1BB is a T cell costimulatory receptor that activates TCR-signaling pathways in CD8+ T cells.

4-1BB Ligand↗