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Search Results: 1 - 10 of 88738 matches for " Chung-Jung Liu "
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A Unified View of “How Allostery Works”
Chung-Jung Tsai ,Ruth Nussinov
PLOS Computational Biology , 2014, DOI: doi/10.1371/journal.pcbi.1003394
Abstract: The question of how allostery works was posed almost 50 years ago. Since then it has been the focus of much effort. This is for two reasons: first, the intellectual curiosity of basic science and the desire to understand fundamental phenomena, and second, its vast practical importance. Allostery is at play in all processes in the living cell, and increasingly in drug discovery. Many models have been successfully formulated, and are able to describe allostery even in the absence of a detailed structural mechanism. However, conceptual schemes designed to qualitatively explain allosteric mechanisms usually lack a quantitative mathematical model, and are unable to link its thermodynamic and structural foundations. This hampers insight into oncogenic mutations in cancer progression and biased agonists' actions. Here, we describe how allostery works from three different standpoints: thermodynamics, free energy landscape of population shift, and structure; all with exactly the same allosteric descriptors. This results in a unified view which not only clarifies the elusive allosteric mechanism but also provides structural grasp of agonist-mediated signaling pathways, and guides allosteric drug discovery. Of note, the unified view reasons that allosteric coupling (or communication) does not determine the allosteric efficacy; however, a communication channel is what makes potential binding sites allosteric.
Tandem Domains with Tuned Interactions Are a Powerful Biological Design Principle
Ruth Nussinov?,Chung-Jung Tsai
PLOS Biology , 2015, DOI: 10.1371/journal.pbio.1002306
Abstract: Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein’s shape, or conformation. In a cell, there are many copies of the same protein, all experiencing these perturbations in a dynamic fashion and fluctuating through different conformations and activity states. According to the “conformational selection and population shift” theory, ligand binding selects a particular conformation. This perturbs the ensemble and induces a population shift. In a new PLOS Biology paper, Melacini and colleagues describe a novel model of protein regulation, the “Double-Conformational Selection Model”, which demonstrates how two tandem ligand-binding domains interact to regulate protein function. Here we explain how tandem domains with tuned interactions—but not single domains—can provide a blueprint for sensitive activation sensors within a narrow window of ligand concentration, thereby promoting signaling control.
Applying the Bispectral Analysis on Widespread Diffuse Cross-Frequency Interactive Effects
Chia-Ju Liu,Cheng-Hsieh Yu,Chin-Fei Huang,Ray-Ying Huang,Chung-Jung Wang,Yi-Shan Liu,Tsung-Ching Chen,Ming-Chung Ho
Journal of Medical Engineering , 2013, DOI: 10.1155/2013/412802
Abstract: The aim of this paper is applying the bispectral analysis on widespread diffuse cross-frequency interactive effects. The event-related potentials (ERPs) research method was used in this study and it could collect the widespread diffuse cross-frequency from mild cognitive impairment (MCI) patients’ brain wave. In this study, the brain wave data were collected from 12 MCI subjects, 12 healthy elderly, and 12 healthy young. The findings showed that the decreased interhemispheric coherence of 8.8?Hz for MCI compared with healthy elderly in the central-parietal cortex to respective surrounding sites and each MCI subject showed significantly widespread diffuse pattern of cross-frequency interactions in comparison with the healthy controls in the left central-parietal and right frontal. This study provides some explanation and suggestions for these findings. 1. Introduction Looking for a reliable and sensitive method to identify more accurately mild Alzheimer’s disease (AD) patients is one of the challenges of the current research. Now, the research method about event-related potentials (ERPs) provides a noninvasive electrophysiological measure as the earliest markers of mild AD. The past studies demonstrated that the P300 amplitude was relatively smaller and P300 latency was longer for AD compared to healthy controls [1–4]. Hence, the P300 which is a component of ERPs data was supposed to be used as an indicator to detect mild AD. The previous study mentioned that the auditory oddball paradigm is related to “focused attention,” “target recognition,” “motor response,” “signal detection,” “working memory,” “executive functions,” and “decision making” [5]. The auditory oddball task is an easy task for mild AD patients to respond [4]. Despite the group differences in the auditory oddball task condition, P300 amplitude and latency are not yet sensitive enough to discriminate between mild AD and normal aging [4]. The event-related oscillatory activity in various frequency bands may reflect different aspects of physiological information processing. Also, the oscillatory changes are basic phenomena during cognitive performance [6]. The construct of dementia has been proposed to designate an early, but abnormal, state of cognitive impairment [7]. Mild AD is supposed to represent a substantial proportion of patients with Alzheimer disease [8]. But it lacks the sensitive indicator to diagnose the mild AD. The hemispheric cooperation model [9, 10] is the study conception underlying the compensation view of bilateral activation in healthy elderly. The previous studies
Clonal Dissemination of Genetically Diverse Fluoroquinolone-Resistant Extended-Spectrum Beta-Lactamase (ESBL)-Producing Escherichia coli ST131 in a Veterans Hospital in Southern Taiwan  [PDF]
Wen-Chung Chang, Chung-Jung Wu, Chuan-Shee Liu, Yilin Tsai, Jen-Jain Lee, Yuting Hsiao, Shu-Ling Chou, Chih-Hao Sun, Chishih Chu
Advances in Microbiology (AiM) , 2016, DOI: 10.4236/aim.2016.69059
Abstract: Uropathogenic Escherichia coli is the common pathogen to cause urinary tract infections (UTIs) and have become multidrug-resistant (MDR) extended-spectrum β-lactamase (ESBL) producers. The differences in the antimicrobial susceptibility, 5 bla genes, 12 virulence genes of 87 clinical ESBL-producing E. coli isolates and genomic variations and sequence types of 18 recurrent and repeated isolates from 9 patients were investigated. The 87 MDR-ESBL isolates collected mainly from indwelling urinary catheters (IUCs) and UTIs were highly resistant to fluoroquinolones, with over 50% of the isolates being resistant to cefepime and piperacillin/tazobactam and a few being resistant to carbapenem. These isolates carried at least two of the five bla genes examined, with the highest prevalence (87.4%) found for blaCTX-M (blaCTX-M3-like and blaCTX-M14-like), followed by blaCMY-2 (80.5%) and blaSHV (56.3%). The predominant virulence genes were the fimbriae gene fimH and the toxin genes cnf1 and hlyA in blood isolates and the capsule gene kpsMTII in UTI and blood isolates. Over 80% of the isolates carried yersiniabactin and aerobactin of siderophores. In 18 isolates, the fluoroquinolone-resistant ST131 isolate of pulsotypes I and II with blaCTX-M-15 was clonally disseminated in the hospital. The genomic plasticity of these ST131 occurred mainly through the conjugative plasmids with differences in replicon types A/C, I1, FIA, FIB and Y, size and number. In conclusion, MDR ESBL-producing E. coli isolates differed in virulence genes of UPEC and antibiotic resistance associated with the sources. Plasmid acquisition and chromosomal variations increase the spread of fluoroquinolone-resistant UPEC ST131 worldwide.
The Optimal First-Line Therapy of Helicobacter pylori Infection in Year 2012
Chao-Hung Kuo,Fu-Chen Kuo,Huang-Ming Hu,Chung-Jung Liu,Sophie S. W. Wang,Yen-Hsu Chen,Ming-Chia Hsieh,Ming-Feng Hou,Deng-Chyang Wu
Gastroenterology Research and Practice , 2012, DOI: 10.1155/2012/168361
Abstract: This paper reviews the literature about first-line therapies for H. pylori infection in recent years. First-line therapies are facing a challenge because of increasing treatment failure due to elevated antibiotics resistance. Several new treatment strategies that recently emerged to overcome antibiotic resistance have been surveyed. Alternative first-line therapies include bismuth-containing quadruple therapy, sequential therapy, concomitant therapy, and hybrid therapy. Levofloxacin-based therapy shows impressive efficacy but might be employed as rescue treatment due to rapidly raising resistance. Rifabutin-based therapy is also regarded as a rescue therapy. Several factors including antibiotics resistance, patient compliance, and CYP 2C19 genotypes could influence the outcome. Clinicians should use antibiotics according to local reports. It is recommended that triple therapy should not be used in areas with high clarithromycin resistance or dual clarithromycin and metronidazole resistance. 1. Introduction Eradicating Helicobacter pylori (H. pylori) is the most important aspect of managing H. pylori-related gastrointestinal diseases. In the past decade, the Maastricht III Consensus Report has recommended that proton pump inhibitor- (PPI-) clarithromycin-amoxicillin or metronidazole treatment is the first choice for H. pylori infection [1]. Although some studies have revealed that the eradication rates of standard triple therapies are around 80% (by per-protocol (PP) analysis) [2, 3], most studies have demonstrated the success rate of recommended triple therapies is falling [4–7]. According to recent studies, such eradication rates have plummeted to even 25%–60% [8–10]. The many causes of fall in efficacy are varied including antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and the cytochrome P450 2C19 (CYP2C19) polymorphism [10]. Compliance is an important factor where patients with good compliance (taking more than 60% of prescribed agents) have a higher treatment success compared to patients with poor compliance (96 versus 69%) [11]. The factors that negatively affect successful eradication are an increase in body mass index and smoking [12, 13]. Besides, other factors including the patient’s history of antibiotic use, the cost, and availability of the drugs would also influence the choice of regimen. In order to overcome the challenge of decreasing eradication rates, many novel first-line therapies have been developed. According to guidelines of the Maastricht III, the minimal acceptable eradication level recommended
JNK suppression is essential for 17β-Estradiol inhibits prostaglandin E2-Induced uPA and MMP-9 expressions and cell migration in human LoVo colon cancer cells
Hsi-Hsien Hsu, Wei-Syun Hu, Yueh-Min Lin, Wei-Wen Kuo, Li-Mien Chen, Wei-Kung Chen, Jin-Ming Hwang, Fuu-Jen Tsai, Chung-Jung Liu, Chih-Yang Huang
Journal of Biomedical Science , 2011, DOI: 10.1186/1423-0127-18-61
Abstract: We analyzed the protein expression of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), matrix metallopeptidases (MMPs), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinases (TIMPs), and the cellular motility in PGE2-stimulated human LoVo cells. 17β-Estradiol and the inhibitors including LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), QNZ (NFκB inhibitor) and ICI 182 780 were further used to explore the inhibitory effects of 17β-estradiol on PGE2-induced LoVo cell motility. Student's t-test was used to analyze the difference between the two groups.Upregulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA) and matrix metallopeptidases (MMPs) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. After administration of inhibitors including LY294002, U0126, SB203580, SP600125 or QNZ, we found that PGE2 treatment up-regulated uPA and MMP-9 expression via JNK1/2 signaling pathway, thus promoting cellular motility in human LoVo cancer cells. However, PGE2 treatment showed no effects on regulating expression of tPA, MMP-2, plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1, -2, -3 and -4 (TIMP-1, -2, -3 and -4). We further observed that 17β-estradiol treatment inhibited PGE2-induced uPA, MMP-9 and cellular motility by suppressing activation of JNK1/2 in human LoVo cancer cells.Collectively, these results suggest that 17β-estradiol treatment significantly inhibits PGE2-induced motility of human LoVo colon cancer cells.Colorectal carcinoma (CRC) is one of the most prevalent cancers world-wide [1], and is the secondary leading cause of cancer-related mortality in the developed countries [2]. Colon cancer accounts for more than 130,000 new cases per year [3] and causes more than 56,000 deaths per year in United States [4] des
Designing a Nanotube Using Naturally Occurring Protein Building Blocks
Chung-Jung Tsai,Jie Zheng,Ruth Nussinov
PLOS Computational Biology , 2006, DOI: 10.1371/journal.pcbi.0020042
Abstract: Here our goal is to carry out nanotube design using naturally occurring protein building blocks. Inspection of the protein structural database reveals the richness of the conformations of proteins, their parts, and their chemistry. Given target functional protein nanotube geometry, our strategy involves scanning a library of candidate building blocks, combinatorially assembling them into the shape and testing its stability. Since self-assembly takes place on time scales not affordable for computations, here we propose a strategy for the very first step in protein nanotube design: we map the candidate building blocks onto a planar sheet and wrap the sheet around a cylinder with the target dimensions. We provide examples of three nanotubes, two peptide and one protein, in atomistic model detail for which there are experimental data. The nanotube models can be used to verify a nanostructure observed by low-resolution experiments, and to study the mechanism of tube formation.
Effects on blood glucose, insulin, lipid and proatherosclerotic parameters in stable type 2 diabetic subjects during an oral fat challenge
Chung-Jung Wu, Zer-Ran Yu
Lipids in Health and Disease , 2004, DOI: 10.1186/1476-511x-3-17
Abstract: Blood glucose, insulin, lipid, leptin, TNF-α and PAI-1 were compared in 14 type 2 diabetic patients and 10 normal subjects after an oral fat challenge upto 2 hours (fasting, 15 min, 30 min, 45 min, 60 min, 90 min and 120 min).Postprandial glucose, total cholesterol, leptin, PAI-1 levels did not differ significantly from levels at fasting. Serum triglyceride increased significantly from baseline only in diabetic patients (P = 0.042). Serum insulin increased postprandially in both groups (P = 0.028 in diabetic group and P = 0.055 in normal group), with displaying a prolonged insulin response in diabetic subjects. TNF-α decreased postprandially in both groups without significant difference, although diabetic patients have higher baseline levels (P = 0.024 compared to normal subjects).Oral fat load does not have an acute effect on blood glucose, total cholesterol, leptin and PAI-1 levels in both type 2 diabetic and normal subjects. TNF-α value showed decreased trend in both diabetic and normal subjects. The tendency of a delayed postprandial insulin response and elevated serum triglyceride level in diabetic subjects might be related to insulin resistance at the level of adipose tissue. Additional research is needed to assess the impact of the use of fat contents on the macronutrient composition of the diet, and potentially healthy and nutritional benefits for patients with diabetes.The incidence of diabetes mellitus has been increasing rapidly in the past 2 decades and this is accompanied by the notably high prevalence of associated disorders, such as hypertension, atherogenic lipid profile and metabolic syndrome, which lead to significantly high cardiovascular morbidity and mortality in diabetic patients. For reducing the risk of developing cardiovascular disease in type 2 diabetic patients, there have been longstanding recommendations to reduce saturated fat intake to <10% of energy intake and to limit total fat intake to <30% of total daily calories. The study was to
Pathway drug cocktail: targeting Ras signaling based on structural pathways
Ruth Nussinov,Chung-Jung Tsai,Carla Mattos
Quantitative Biology , 2013, DOI: 10.1016/j.molmed.2013.07.009
Abstract: Tumors bearing Ras mutations are notoriously difficult to treat. Drug combinations targeting the Ras protein or its pathway have also not met with success. Pathway drug cocktails, which are combinations aiming at parallel pathways, appear more promising; however, to be usefully exploited, a repertoire of classified pathway combinations is desirable. This challenge would be facilitated by the availability of the structural network of signaling pathways. When integrated with functional and systems-level clinical data they can be powerful in advancing novel therapeutic platforms. Based on structural knowledge, drug cocktails may tear into multiple cellular processes that drive tumorigenesis, and help in deciphering the interrelationship between Ras mutations and the rewired Ras network. The pathway drug cocktail paradigm can be applied to other signaling protein targets.
Allo-network drugs: harnessing allostery in cellular networks
Ruth Nussinov,Chung-Jung Tsai,Peter Csermely
Quantitative Biology , 2011, DOI: 10.1016/j.tips.2011.08.004
Abstract: Allosteric drugs are increasingly used because they produce fewer side effects. Allosteric signal propagation does not stop at the 'end' of a protein, but may be dynamically transmitted across the cell. Here, we propose that the concept of allosteric drugs can be broadened to allo-network drugs, whose effects can propagate either within a protein, or across several proteins, to enhance or inhibit specific interactions along a pathway. We posit that current allosteric drugs are a special case of allo-network drugs, and suggest that allo-network drugs can achieve specific, limited changes at the systems level, and in this way can achieve fewer side effects and lower toxicity. Finally, we propose steps and methods to identify allo-network drug targets and sites outlining a new paradigm in systems-based drug design.
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