• Title/Summary/Keyword: Combinatorial Regulation

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Inferring Transcriptional Interactions and Regulator Activities from Experimental Data

  • Wang, Rui-Sheng;Zhang, Xiang-Sun;Chen, Luonan
    • Molecules and Cells
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    • v.24 no.3
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    • pp.307-315
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    • 2007
  • Gene regulation is a fundamental process in biological systems, where transcription factors (TFs) play crucial roles. Inferring transcriptional interactions between TFs and their target genes has utmost importance for understanding the complex regulatory mechanisms in cellular systems. On one hand, with the rapid progress of various high-throughput experiment techniques, more and more biological data become available, which makes it possible to quantitatively study gene regulation in a systematic manner. On the other hand, transcription regulation is a complex biological process mediated by many events such as post-translational modifications, degradation, and competitive binding of multiple TFs. In this review, with a particular emphasis on computational methods, we report the recent advances of the research topics related to transcriptional regulatory networks, including how to infer transcriptional interactions, reveal combinatorial regulation mechanisms, and reconstruct TF activity profiles.

Dual Roles of Autophagy and Their Potential Drugs for Improving Cancer Therapeutics

  • Shin, Dong Wook
    • Biomolecules & Therapeutics
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    • v.28 no.6
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    • pp.503-511
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    • 2020
  • Autophagy is a major catabolic process that maintains cell metabolism by degrading damaged organelles and other dysfunctional proteins via the lysosome. Abnormal regulation of this process has been known to be involved in the progression of pathophysiological diseases, such as cancer and neurodegenerative disorders. Although the mechanisms for the regulation of autophagic pathways are relatively well known, the precise regulation of this pathway in the treatment of cancer remains largely unknown. It is still complicated whether the regulation of autophagy is beneficial in improving cancer. Many studies have demonstrated that autophagy plays a dual role in cancer by suppressing the growth of tumors or the progression of cancer development, which seems to be dependent on unknown characteristics of various cancer types. This review summarizes the key targets involved in autophagy and malignant transformation. In addition, the opposing tumor-suppressive and oncogenic roles of autophagy in cancer, as well as potential clinical therapeutics utilizing either regulators of autophagy or combinatorial therapeutics with anti-cancer drugs have been discussed.

Quantitative Frameworks for Multivalent Macromolecular Interactions in Biological Linear Lattice Systems

  • Choi, Jaejun;Kim, Ryeonghyeon;Koh, Junseock
    • Molecules and Cells
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    • v.45 no.7
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    • pp.444-453
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    • 2022
  • Multivalent macromolecular interactions underlie dynamic regulation of diverse biological processes in ever-changing cellular states. These interactions often involve binding of multiple proteins to a linear lattice including intrinsically disordered proteins and the chromosomal DNA with many repeating recognition motifs. Quantitative understanding of such multivalent interactions on a linear lattice is crucial for exploring their unique regulatory potentials in the cellular processes. In this review, the distinctive molecular features of the linear lattice system are first discussed with a particular focus on the overlapping nature of potential protein binding sites within a lattice. Then, we introduce two general quantitative frameworks, combinatorial and conditional probability models, dealing with the overlap problem and relating the binding parameters to the experimentally measurable properties of the linear lattice-protein interactions. To this end, we present two specific examples where the quantitative models have been applied and further extended to provide biological insights into specific cellular processes. In the first case, the conditional probability model was extended to highlight the significant impact of nonspecific binding of transcription factors to the chromosomal DNA on gene-specific transcriptional activities. The second case presents the recently developed combinatorial models to unravel the complex organization of target protein binding sites within an intrinsically disordered region (IDR) of a nucleoporin. In particular, these models have suggested a unique function of IDRs as a molecular switch coupling distinct cellular processes. The quantitative models reviewed here are envisioned to further advance for dissection and functional studies of more complex systems including phase-separated biomolecular condensates.

The Regulatory Effects of Radiation and Histone Deacetylase Inhibitor on Liver Cancer Cell Cycle

  • Lee, Sang Ho;Han, Chang Hee;Kang, Su Man;Park, Cheol Woo
    • International Journal of Contents
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    • v.8 no.4
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    • pp.74-77
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    • 2012
  • Radiation has been an effective tool for treating cancer for a long time. Radiation therapy induces DNA damage within cancer cells and destroys their ability to reproduce. Radiation therapy is often combined with other treatments, like surgery and chemotherapy. Here, we describe the effects of radiation and histone deacetylase inhibitor, Trichostain A, on cell cycle regulation in hepatoma cells. The combinatorial treatment of radiation and Trichostain A induced cell cycle arrest and thereby increasing the hepatoma cell death. Furthermore, the regulatory effects of radiation and Trichostatin A on cell cycle applied in cell type specifically. These results suggest that the treatment of radiation and Trichostatin A may play a central role in hepatoma cell death and might be a good remedy to improve the efficiency of radiation therapy.

Calibrating Thresholds to Improve the Detection Accuracy of Putative Transcription Factor Binding Sites

  • Kim, Young-Jin;Ryu, Gil-Mi;Park, Chan;Kim, Kyu-Won;Oh, Berm-Seok;Kim, Young-Youl;Gu, Man-Bok
    • Genomics & Informatics
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    • v.5 no.4
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    • pp.143-151
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    • 2007
  • To understand the mechanism of transcriptional regulation, it is essential to detect promoters and regulatory elements. Various kinds of methods have been introduced to improve the prediction accuracy of regulatory elements. Since there are few experimentally validated regulatory elements, previous studies have used criteria based solely on the level of scores over background sequences. However, selecting the detection criteria for different prediction methods is not feasible. Here, we studied the calibration of thresholds to improve regulatory element prediction. We predicted a regulatory element using MATCH, which is a powerful tool for transcription factor binding site (TFBS) detection. To increase the prediction accuracy, we used a regulatory potential (RP) score measuring the similarity of patterns in alignments to those in known regulatory regions. Next, we calibrated the thresholds to find relevant scores, increasing the true positives while decreasing possible false positives. By applying various thresholds, we compared predicted regulatory elements with validated regulatory elements from the Open Regulatory Annotation (ORegAnno) database. The predicted regulators by the selected threshold were validated through enrichment analysis of muscle-specific gene sets from the Tissue-Specific Transcripts and Genes (T-STAG) database. We found 14 known muscle-specific regulators with a less than a 5% false discovery rate (FDR) in a single TFBS analysis, as well as known transcription factor combinations in our combinatorial TFBS analysis.

Estimation of Moving Information for Tracking of Moving Objects

  • Park, Jong-An;Kang, Sung-Kwan;Jeong, Sang-Hwa
    • Journal of Mechanical Science and Technology
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    • v.15 no.3
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    • pp.300-308
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    • 2001
  • Tracking of moving objects within video streams is a complex and time-consuming process. Large number of moving objects increases the time for computation of tracking the moving objects. Because of large computations, there are real-time processing problems in tracking of moving objects. Also, the change of environment causes errors in estimation of tracking information. In this paper, we present a new method for tracking of moving objects using optical flow motion analysis. Optical flow represents an important family of visual information processing techniques in computer vision. Segmenting an optical flow field into coherent motion groups and estimating each underlying motion are very challenging tasks when the optical flow field is projected from a scene of several moving objects independently. The problem is further complicated if the optical flow data are noisy and partially incorrect. Optical flow estimation based on regulation method is an iterative method, which is very sensitive to the noisy data. So we used the Combinatorial Hough Transform (CHT) and Voting Accumulation for finding the optimal constraint lines. To decrease the operation time, we used logical operations. Optical flow vectors of moving objects are extracted, and the moving information of objects is computed from the extracted optical flow vectors. The simulation results on the noisy test images show that the proposed method finds better flow vectors and more correctly estimates the moving information of objects in the real time video streams.

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The CD28-B7 Family in Anti-Tumor Immunity: Emerging Concepts in Cancer Immunotherapy

  • Leung, Joanne;Suh, Woong-Kyung
    • IMMUNE NETWORK
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    • v.14 no.6
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    • pp.265-276
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    • 2014
  • The interactions between B7 molecules and CD28-family receptors are crucial in the regulation of adaptive cellular immunity. In cancer, the aberrant expression of co-inhibitory B7 molecules has been attributed to reduced anti-tumor immunity and cancer immune evasion, prompting the development of cancer therapeutics that can restore T cell function. Murine tumor models have provided significant support for the targeting of multiple immune checkpoints involving CTLA-4, PD-1, ICOS, B7-H3 and B7-H4 during tumor growth, and clinical studies investigating the therapeutic effects of CTLA-4 and PD-1 blockade have shown exceptionally promising results in patients with advanced melanoma and other cancers. The expression pattern of co-inhibitory B7 ligands in the tumor microenvironment has also been largely correlated with poor patient prognosis, and recent evidence suggests that the presence of several B7 molecules may predict the responsiveness of immunotherapies that rely on pre-existing tumor-associated immune responses. While monotherapies blocking T cell co-inhibition have beneficial effects in reducing tumor burden, combinatorial immunotherapy targeting multiple immune checkpoints involved in various stages of the anti-tumor response has led to the most substantial impact on tumor reduction. In this review, we will examine the contributions of B7- and CD28-family members in the context of cancer development, and discuss the implications of current human findings in cancer immunotherapy.

Protein Tyrosine Phosphatase Profiling Analysis of HIB-1B Cells during Brown Adipogenesis

  • Choi, Hye-Ryung;Kim, Won Kon;Kim, Eun Young;Jung, Hyeyun;Kim, Jeong-Hoon;Han, Baek-Soo;You, Kwan-Hee;Lee, Sang Chul;Bae, Kwang-Hee
    • Journal of Microbiology and Biotechnology
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    • v.22 no.7
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    • pp.1029-1033
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    • 2012
  • A number of evidence have been accumulated that the regulation of reversible tyrosine phosphorylation, which can be regulated by the combinatorial activity of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), plays crucial roles in various biological processes including differentiation. There are a total of 107 PTP genes in the human genome, collectively referred to as the "PTPome." In this study, we performed PTP profiling analysis of the HIB-1B cell line, a brown preadipocyte cell line, during brown adipogenesis. Through RT-PCR and real-time PCR, several PTPs showing differential expression pattern during brown adipogenesis were identified. In the case of PTP-RE, it was shown to decrease significantly until 4 days after brown adipogenic differentiation, followed by a dramatic increase at 6 days. The overexpression of PTP-RE led to decreased brown adipogenic differentiation via reducing the tyrosine phosphorylation of the insulin receptor, indicating that PTP-RE functions as a negative regulator at the early stage of brown adipogenesis.

Synergistic Increase of BDNF Release from Rat Primary Cortical Neuron by Combination of Several Medicinal Plant-Derived Compounds

  • Jeon, Se-Jin;Bak, Hae-Rang;Seo, Jung-Eun;Kwon, Kyung-Ja;Kang, Young-Sun;Kim, Hee-Jin;Cheong, Jae-Hoon;Ryu, Jong-Hoon;Ko, Kwang-Ho;Shin, Chan-Young
    • Biomolecules & Therapeutics
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    • v.18 no.1
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    • pp.39-47
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    • 2010
  • Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor involved in neuronal differentiation, plasticity, survival and regeneration. BDNF draws massive attention mainly due to the potential as a therapeutic target in neurological diseases such as depression and Alzheimer's disease. In a primary screening for the natural compounds enhancing BDNF release from cultured rat primary cortical neuron, we found that compounds such as baicalein, tanshinone IIa, cinnamic acid, epiberberine, genistein and wogonin among many others increased BDNF release. All the compounds at $0.1{\mu}M$ of concentration barely showed stimulatory effect on BDNF induction, however, their combination (mixture 1; baicalein, tanshinone IIa and cinnamic acid, mixture 2; epiberberine, genistein and wogonin) showed synergistic increase in BDNF release as well as mRNA and protein expression. The level of BDNF expression was comparable to the maximum BDNF stimulation attainable by a positive control oroxylin A ($20{\mu}M$) without cell toxicity as determined by MTT analysis. Both mixtures synergistically increased the phosphorylation of extracellular signal-regulated kinase (ERK) as well as cAMP response element binding protein (CREB), an immediate and essential regulator of BDNF expression. Similar to these results, mixture of these compounds synergistically inhibited the up-regulation of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide treatments in rat primary astrocytes. These results suggest that the combinatorial treatment of natural compounds in lower concentration might be a useful strategy to obtain sufficient BDNF stimulation in neurological disease condition such as depression, while minimizing potential side effects and toxicity of higher concentration of a single compound.

Comparison of Association Rule Learning and Subgroup Discovery for Mining Traffic Accident Data (교통사고 데이터의 마이닝을 위한 연관규칙 학습기법과 서브그룹 발견기법의 비교)

  • Kim, Jeongmin;Ryu, Kwang Ryel
    • Journal of Intelligence and Information Systems
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    • v.21 no.4
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    • pp.1-16
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    • 2015
  • Traffic accident is one of the major cause of death worldwide for the last several decades. According to the statistics of world health organization, approximately 1.24 million deaths occurred on the world's roads in 2010. In order to reduce future traffic accident, multipronged approaches have been adopted including traffic regulations, injury-reducing technologies, driving training program and so on. Records on traffic accidents are generated and maintained for this purpose. To make these records meaningful and effective, it is necessary to analyze relationship between traffic accident and related factors including vehicle design, road design, weather, driver behavior etc. Insight derived from these analysis can be used for accident prevention approaches. Traffic accident data mining is an activity to find useful knowledges about such relationship that is not well-known and user may interested in it. Many studies about mining accident data have been reported over the past two decades. Most of studies mainly focused on predict risk of accident using accident related factors. Supervised learning methods like decision tree, logistic regression, k-nearest neighbor, neural network are used for these prediction. However, derived prediction model from these algorithms are too complex to understand for human itself because the main purpose of these algorithms are prediction, not explanation of the data. Some of studies use unsupervised clustering algorithm to dividing the data into several groups, but derived group itself is still not easy to understand for human, so it is necessary to do some additional analytic works. Rule based learning methods are adequate when we want to derive comprehensive form of knowledge about the target domain. It derives a set of if-then rules that represent relationship between the target feature with other features. Rules are fairly easy for human to understand its meaning therefore it can help provide insight and comprehensible results for human. Association rule learning methods and subgroup discovery methods are representing rule based learning methods for descriptive task. These two algorithms have been used in a wide range of area from transaction analysis, accident data analysis, detection of statistically significant patient risk groups, discovering key person in social communities and so on. We use both the association rule learning method and the subgroup discovery method to discover useful patterns from a traffic accident dataset consisting of many features including profile of driver, location of accident, types of accident, information of vehicle, violation of regulation and so on. The association rule learning method, which is one of the unsupervised learning methods, searches for frequent item sets from the data and translates them into rules. In contrast, the subgroup discovery method is a kind of supervised learning method that discovers rules of user specified concepts satisfying certain degree of generality and unusualness. Depending on what aspect of the data we are focusing our attention to, we may combine different multiple relevant features of interest to make a synthetic target feature, and give it to the rule learning algorithms. After a set of rules is derived, some postprocessing steps are taken to make the ruleset more compact and easier to understand by removing some uninteresting or redundant rules. We conducted a set of experiments of mining our traffic accident data in both unsupervised mode and supervised mode for comparison of these rule based learning algorithms. Experiments with the traffic accident data reveals that the association rule learning, in its pure unsupervised mode, can discover some hidden relationship among the features. Under supervised learning setting with combinatorial target feature, however, the subgroup discovery method finds good rules much more easily than the association rule learning method that requires a lot of efforts to tune the parameters.