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Kwang-Hyun Cho

Publications and source records attributed to Kwang-Hyun Cho.

At least 37 records · Page 2Linked to original sources
PubMed2005

In silico identification of the key components and steps in IFN-gamma induced JAK-STAT signaling pathway.

Systems biology efforts are increasingly adopting quantitative, mechanistic modeling to study cellular signal transduction pathways and other networks. However, it is uncertain whether the particular set of kinetic parameter values of the model closely approximates the corresponding biological system. We propose that the parameters be assigned statistical distributions that reflect the degree of uncertainty for a comprehensive simulation analysis. From this analysis, we globally identify the key components and steps in signal transduction networks at a systems level. We investigated a recent mathematical model of interferon gamma induced Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway by applying multi-parametric sensitivity analysis that is based on simultaneous variation of the parameter values. We find that suppressor of cytokine signaling-1, nuclear phosphatases, cytoplasmic STAT1, and the corresponding reaction steps are sensitive perturbation points of this pathway.

Computational Biology↗
PubMed2005

A hybrid systems framework for cellular processes.

With the availability of technologies that allow us to obtain stimulus-response time series data for modeling and system identification, there is going to be an increasing need for conceptual frameworks in which to formulate and test hypotheses about intra- and inter-cellular dynamics, in general and not just dependent on a particular cell line, cell type, organism, or technology. While the semantics can be quite different, biologists and systems scientists use in many cases a similar language (notion of feedback, regulation, etc.). A more abstract system-theoretic framework for signals, systems, and control could provide the biologist with an interface between the domains. Apart from recent examples to identify functional elements and describing them in engineering terms, there have been various more abstract developments to describe dynamics at the cell level in the past. This includes Rosen's (M,R)-systems. This paper presents an abstract and general compact mathematical framework of intracellular dynamics, regulation and regime switching inspired by (M,R)-theory and based on hybrid automata.

Algorithms↗
PubMed2005

Identification of small scale biochemical networks based on general type system perturbations.

New technologies enable acquisition of large data-sets containing genomic, proteomic and metabolic information that describe the state of a cell. These data-sets call for systematic methods enabling relevant information about the inner workings of the cell to be extracted. One important issue at hand is the understanding of the functional interactions between genes, proteins and metabolites. We here present a method for identifying the dynamic interactions between biochemical components within the cell, in the vicinity of a steady-state. Key features of the proposed method are that it can deal with data obtained under perturbations of any system parameter, not only concentrations of specific components, and that the direct effect of the perturbations does not need to be known. This is important as concentration perturbations are often difficult to perform in biochemical systems and the specific effects of general type perturbations are usually highly uncertain, or unknown. The basis of the method is a linear least-squares estimation, using time-series measurements of concentrations and expression profiles, in which system states and parameter perturbations are estimated simultaneously. An important side-effect of also employing estimation of the parameter perturbations is that knowledge of the system's steady-state concentrations, or activities, is not required and that deviations from steady-state prior to the perturbation can be dealt with. Time derivatives are computed using a zero-order hold discretization, shown to yield significant improvements over the widely used Euler approximation. We also show how network interactions with dynamics that are too fast to be captured within the available sampling time can be determined and excluded from the network identification. Known and unknown moiety conservation relationships can be processed in the same manner. The method requires that the number of samples equals at least the number of network components and, hence, is at present restricted to relatively small-scale networks. We demonstrate herein the performance of the method on two small-scale in silico genetic networks.

Cell Physiological Phenomena↗
PubMed2005

Unravelling the functional interaction structure of a cellular network from temporal slope information of experimental data.

Due to the unavoidable nonbiological variations accompanying many experiments, it is imperative to consider a way of unravelling the functional interaction structure of a cellular network (e.g. signalling cascades or gene networks) by using the qualitative information of time-series experimental data instead of computation through the measured absolute values. In this spirit, we propose a very simple but effective method of identifying the functional interaction structure of a cellular network based on temporal ascending or descending slope information from given time-series measurements. From this method, we can gain insight into the acceptable measurement error ranges in order to estimate the correct functional interaction structure and we can also find guidance for a new experimental design to complement the insufficient information of a given experimental dataset. We developed experimental sign equations, making use of the temporal slope sign information from time-series experimental data, without a specific assumption on parameter perturbations for each network node. Based on these equations, we further describe the available specific information from each part of experimental data in detail and show the functional interaction structure obtained by integrating such information. In this procedure, we use only simple algebra on sign changes without complicated computations on the measured absolute values of the experimental data. The result is, however, verified through rigorous mathematical definitions and proofs. The present method provides us with information about the acceptable measurement error ranges for correct estimation of the functional interaction structure and it further leads to a new experimental design to complement the given experimental data by informing us about additional specific sampling points to be chosen for further required information.

Cell Physiological Phenomena↗
PubMed2004

Alteration of the TGF-beta/SMAD pathway in intrinsically and UV-induced skin aging.

In an effort to characterize transforming growth factor (TGF-beta) signaling and to determine its association with the aging and photoaging processes, we directly compared the expressions of TGF-beta/SMAD in intrinsically aged and photoaged human skin in vivo. By using an RNase protection assay and by immunohistochemistry, we found that the expression levels of TbetaRII mRNA and protein in the epidermis of the forearm (sun-exposed) of the elderly were significantly lower than that of the upper-inner arm (sun-protected) skin of the same individual. In the epidermis, the expressions of Smad7 mRNA in both the intrinsically aged and photoaged skin of the elderly were higher than in the sun-protected skin of the young, and this was elevated in the photoaged epidermis. Decreased pSmad2 immunoreactivity was observed in the epidermis of photoaged forearm skin versus matched intrinsically aged skin. This decrease was also found in the epidermis of upper-inner arm skin of the elderly versus the young. These results suggest that the UV-induced down-regulation of TbetaRII and the concerted over-expression of Smad7 may trigger the inhibition of the TGF-beta-induced phosphorylation of Smad2.

Adult↗
PubMed2004

The effects of epidermal keratinocytes and dermal fibroblasts on the formation of cutaneous basement membrane in three-dimensional culture systems.

The cutaneous basement membrane (BM) plays an important role in normal and pathological conditions. However, few studies have addressed the formation of the cutaneous BM using three-dimensional culture systems. In this study, to elucidate the effects of human epidermal keratinocytes and dermal fibroblasts on the formation of the cutaneous BM, keratinocytes were cultured on several dermal substrates in the presence or absence of fibroblasts at the air-liquid interface. After 2 weeks of culture, immunohistochemical stainings for the components of the BM and electron microscopic studies of the BM zone (BMZ) were performed. In cultures of keratinocytes alone on dead reticular dermis or collagen gel without fibroblasts, beta4 integrin chain, laminin, type IV and VII collagens were all expressed. However, ultrastructurally, BMZ was not formed. In cultures of keratinocytes on fibroblast-populated collagen matrix, laminin, and type IV and VII collagens were expressed more strongly than in the absence of fibroblasts. In addition, elements of the BMZ such as hemidesmosomes, lamina lucida, lamina densa and anchoring fibrils were formed, although it was still incomplete. In the culture of keratinocytes alone on de-epidermized dermis (DED) (surface up), beta4 integrin chain, laminin, and type IV and VII collagens were strongly expressed. Also, the BMZ appeared similar to that in normal skin. In cocultures of keratinocytes and fibroblasts on DED or cultures of keratinocytes on DED combined with fibroblast-populated collagen matrix, type IV collagen was expressed more strongly than in cultures of keratinocytes alone. Ultrastructurally, similar findings to those of cultures of keratinocytes alone on DED were seen. Interestingly, when keratinocytes and fibroblasts were cocultured on DED, some fibroblasts were seen in the upper dermis as a result of migration into the dermis through partial loss of the lamina densa. These results show that keratinocytes produce most of the components of the BM such as laminin, and type IV and VII collagens. In addition, fibroblasts stimulate the expression of the components of the BM and the formation of a BMZ, suggesting that fibroblasts may produce laminin, and type IV and VII collagens or influence the effects of keratinocytes on the formation of the BM through a keratinocyte-fibroblast interaction.

Basement Membrane↗
PubMed2004

Advanced significance analysis of microarray data based on weighted resampling: a comparative study and application to gene deletions in Mycobacterium bovis.

MOTIVATION: When analyzing microarray data, non-biological variation introduces uncertainty in the analysis and interpretation. In this paper we focus on the validation of significant differences in gene expression levels, or normalized channel intensity levels with respect to different experimental conditions and with replicated measurements. A myriad of methods have been proposed to study differences in gene expression levels and to assign significance values as a measure of confidence. In this paper we compare several methods, including SAM, regularized t-test, mixture modeling, Wilk's lambda score and variance stabilization. From this comparison we developed a weighted resampling approach and applied it to gene deletions in Mycobacterium bovis. RESULTS: We discuss the assumptions, model structure, computational complexity and applicability to microarray data. The results of our study justified the theoretical basis of the weighted resampling approach, which clearly outperforms the others.

Algorithms↗
PubMed2004

Optimal sampling time selection for parameter estimation in dynamic pathway modeling.

Systems Biology is an emerging research area, which considers mathematical representations of inter- and intra-cellular dynamics. Among the many research problems that have been addressed, dynamic modeling of signal transduction pathways has received increasing attention. The usual approach to represent intra-cellular dynamics are nonlinear, usually ordinary, differential equations. The purpose of the models is to test and generate hypothesis of specific pathways and it is therefore required to estimate model parameters from experimental data. The experiments to generate data are complex and expensive, as a consequence of which the time series available are usually rather short, with few if any replicates. Almost certainly, not all variables one would like to include in a model can be measured. Parameter estimation is therefore an important research problem in Systems Biology and the focus of this paper. In particular, we are interested in optimizing the sampling time selection in order to minimize the variance of the parameter estimation error. With few sampling time points feasible, their selection is of practical importance in experimental design. Finally, the theoretical results are supported with an application.

Computer Simulation↗
PubMed2004

Modeling and simulation of intracellular dynamics: choosing an appropriate framework.

Systems biology is a reemerging paradigm which, among other things, focuses on mathematical modeling and simulation of biochemical reaction networks in intracellular processes. For most simulation tools and publications, they are usually characterized by either preferring stochastic simulation or rate equation models. The use of stochastic simulation is occasionally accompanied with arguments against rate equations. Motivated by these arguments, we discuss in this paper the relationship between these two forms of representation. Toward this end, we provide a novel compact derivation for the stochastic rate constant that forms the basis of the popular Gillespie algorithm. Comparing the mathematical basis of the two popular conceptual frameworks of generalized mass action models and the chemical master equation, we argue that some of the arguments that have been put forward are ignoring subtle differences and similarities that are important for answering the question in which conceptual framework one should investigate intracellular dynamics.

Algorithms↗
PubMed2003

Investigations into the analysis and modeling of the TNF alpha-mediated NF-kappa B-signaling pathway.

In this study, we propose a system-theoretic approach to the analysis and quantitative modeling of the TNFalpha-mediated NF-kappaB-signaling pathway. Tumor necrosis factor alpha (TNFalpha) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation, in the control of cell proliferation, differentiation, and apoptosis. To date, there have been numerous approaches to model cellular dynamics. The most prominent uses ordinary differential equations (ODEs) to describe biochemical reactions. This approach can provide us with mathematically well-founded and tractable interpretations regarding pathways, especially those best described by enzyme reactions. This work first introduces a graphical method to intuitively represent the TNFalpha-mediated NF-kappaB-signaling pathway and then utilizes ODEs to quantitatively model the pathway. The simulation study shows qualitative validation of the proposed model compared with experimental results for this pathway. The proposed system-theoretic approach is expected to be further applicable to predict the signaling behavior of NF-kappaB in a quantitative manner for any variation of the ligand, TNFalpha.

Computer Simulation↗
PubMed2003

Two types of ion channel formation of tolaasin, a Pseudomonas peptide toxin.

Tolaasin is a peptide toxin produced by Pseudomonas tolaasii and causes brown blotch disease of the cultivated mushrooms. Two types of ion channels were identified by the incorporation of tolaasin into lipid bilayer. The slope conductance of type 1 channel measured in the buffer containing 100 mM KCl was 150 pS with a linear current vs. voltage relationship. The type 2 tolaasin channel had two subconductance states of 300 and 500 pS. Both channels were inhibited by Zn(2+). Ion channel formations of tolaasin were concentration-dependent and single channel currents were successfully obtained at 0.6 unit tolaasin, 15.9 nM. The type 1 channel was obtained more frequently than the type 2 channel and the ratio of their appearance was approximately 4:1, respectively.

Agaricales↗
PubMed2003

A serologically diagnosed human case of cutaneous larva migrans caused by Ancylostoma caninum.

A 15-year-old boy, who had recently arrived back from a trip to Cambodia for a missionary camp, presented with several serpiginous thread-like skin lesions that began as small papules on the left upper extremities 2 weeks before his visit to Hospital. The skin lesions were pruritic and erythematous, and had migrated to the chest and abdomen. The histopathological findings showed only lymphocytic and eosinophilic infiltrations in the dermis of the biopsied skin lesion. The patient's serum reacted strongly to the Ancylostoma caninum antigen by an ELISA method. Therefore, he was diagnosed with cutaneous larva migrans by A. caninum. After the oral administration of albendazole and ivermectin, the skin lesions resolved without recurrence. This is the first reported case of a cutaneous larva migrans caused by Ancylostoma canimum diagnosed serologically using ELISA in Korea.

Adolescent↗
PubMed2003

The statistical distribution of the intensity of pixels within spots of DNA microarrays: what is the appropriate single-value representative?

This paper opens a discussion about an important issue in the analysis of data from spotted DNA microarrays: how to summarise into a single value the distribution for the intensity values of the pixels within a spot. Although the most popular statistic used is the median, there is no clear study demonstrating why it is more appropriate than other measures of central tendency such as the mean or the mode. Here, we argue that the median intensity is not the most appropriate measure for many common cases and discuss a frequently encountered case of a 'doughnut'-shaped spot for which the mode is closest to the 'expected' spot intensity. For an 'ideal' spot with a clear boundary and uniformly hybridised, the intensity of its pixels should approximately be normally distributed. In practical situations, these two requirements are often not met due to the physical properties of pins and the particularities of the printing and hybridisation processes. As a consequence, the distribution of the intensity of the pixels is usually negatively skewed. This asymmetry results in a larger displacement for the mean and median than for the mode from the ideal situation mentioned above.

Algorithms↗
PubMed2003

Microarray data clustering based on temporal variation: FCV with TSD preclustering.

The aim of this paper is to present a new clustering algorithm for short time-series gene expression data that is able to characterise temporal relations in the clustering environment (ie data-space), which is not achieved by other conventional clustering algorithms such as k -means or hierarchical clustering. The algorithm called fuzzy c -varieties clustering with transitional state discrimination preclustering (FCV-TSD) is a two-step approach which identifies groups of points ordered in a line configuration in particular locations and orientations of the data-space that correspond to similar expressions in the time domain. We present the validation of the algorithm with both artificial and real experimental datasets, where k -means and random clustering are used for comparison. The performance was evaluated with a measure for internal cluster correlation and the geometrical properties of the clusters, showing that the FCV-TSD algorithm had better performance than the k -means algorithm on both datasets.

Algorithms↗
PubMed2002

Vitamin D receptor genotypes are not associated with clinical response to calcipotriol in Korean psoriasis patients.

Conflicting results have been reported on the association between BsmI restriction fragment length polymorphism (RFLP) at the vitamin D receptor gene (VDR) locus and the clinical response of psoriasis patients to calcitriol or calcipotriol therapy. We evaluated RFLPs of the VDR gene by analyzing the restriction pattern of polymerase chain reaction products in 55 Korean psoriasis patients receiving topical calcipotriol therapy, and evaluated the clinical response. Of the 55 patients, 43 completed the 8-week treatment protocol, and the response was evaluated as excellent in 9 patients, good in 20, and poor in 14. Thus, in our 43 patients BsmI and ApaI polymorphism in the VDR gene did not correlate with response to calcipotriol. The marked predominance of the b allele in the Korean population precludes the possibility that BsmI polymorphism is associated with clinical response to calcipotriol. The pattern of prevalence of the VDR genotypes in the Korean population is very different from that in Western populations. There were no differences in VDR genotype between controls and psoriasis patients at the BsmI site, but there were significant difference in terms of ApaI RFLP as previously reported. In conclusion, polymorphism analysis of the VDR gene with BsmI and ApaI restriction enzymes in psoriasis patients was not helpful in predicting clinical response to calcipotriol.

Adolescent↗
PubMed2002

Fibroblasts and ascorbate regulate epidermalization in reconstructed human epidermis.

Skin equivalent model provides a new investigating system to study the role of extracellular matrix and dermal factors such as collagen, basement membrane components and fibroblasts (Fb) which contribute to cell-cell and cell-matrix interactions. Although basement membrane factors is known to play an important role in epidermal differentiation and epidermal-matrix adhesion, comparative effects of these extracellular matrix and dermal factors on the reconstruction of epidermis are little known. In this study, we investigated effects of type I collagen (Coll I), type IV collagen plus laminin (LAM) coated Coll I (Coll IV+LAM), and human Fb enriched Coll I (Coll I+Fb) on epidermal reconstruction. When human keratinocytes were cultured on three different gels containing Coll I, Coll IV+LAM and Coll I+Fb, basal keratinocytes were cuboidal and perpendicular to the dermo-epidermal junction only in the gel containing Coll I+Fb. Proliferation marker expression was prominent and differentiation marker expression was similar with those of normal skin in the gel containing Coll I+Fb than in the other gel models. Since ascorbate is suspected to exert an effect as a modulator of proliferation and differentiation in keratinocytes, we tested the effects of ascorbate on human epidermis reconstruction. When 25 microg/ml ascorbate was added, disordered arrangement of epidermis was disappeared and differentiation marker expression was similar with its expression in normal skin. These data indicate that human Fb and a modulator of proliferation and differentiation such as ascorbate are essential for epidermalization in reconstructed epidermis.

Ascorbic Acid↗
PubMed2002

A case of multiple disseminated eruptive Spitz nevi.

Spitz nevus is usually a solitary lesion. However, multiple Spitz nevi do arise and can be divided into two variants, agminated (grouped) or disseminated. We report an interesting case of multiple disseminated eruptive Spitz nevi with an unusual feature. The appearance of most of the nevi resembled that of melanocytic nevi, and clinically it was impossible to distinguish these multiple disseminated eruptive Spitz nevi from eruptive melanocytic one.

Adult↗