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1.  Comparative genomics of grass EST libraries reveals previously uncharacterized splicing events in crop plants 
BMC Plant Biology  2015;15:39.
Background
Crop plants such as rice, maize and sorghum play economically-important roles as main sources of food, fuel, and animal feed. However, current genome annotations of crop plants still suffer false-positive predictions; a more comprehensive registry of alternative splicing (AS) events is also in demand. Comparative genomics of crop plants is largely unexplored.
Results
We performed a large-scale comparative analysis (ExonFinder) of the expressed sequence tag (EST) library from nine grass plants against three crop genomes (rice, maize, and sorghum) and identified 2,879 previously-unannotated exons (i.e., novel exons) in the three crops. We validated 81% of the tested exons by RT-PCR-sequencing, supporting the effectiveness of our in silico strategy. Evolutionary analysis reveals that the novel exons, comparing with their flanking annotated ones, are generally under weaker selection pressure at the protein level, but under stronger pressure at the RNA level, suggesting that most of the novel exons also represent novel alternatively spliced variants (ASVs). However, we also observed the consistency of evolutionary rates between certain novel exons and their flanking exons, which provided further evidence of their co-occurrence in the transcripts, suggesting that previously-annotated isoforms might be subject to erroneous predictions. Our validation showed that 54% of the tested genes expressed the newly-identified isoforms that contained the novel exons, rather than the previously-annotated isoforms that excluded them. The consistent results were steadily observed across cultivated (Oryza sativa and O. glaberrima) and wild (O. rufipogon and O. nivara) rice species, asserting the necessity of our curation of the crop genome annotations. Our comparative analyses also inferred the common ancestral transcriptome of grass plants and gain- and loss-of-ASV events.
Conclusions
We have reannotated the rice, maize, and sorghum genomes, and showed that evolutionary rates might serve as an indicator for determining whether the identified exons were alternatively spliced. This study not only presents an effective in silico strategy for the improvement of plant annotations, but also provides further insights into the role of AS events in the evolution and domestication of crop plants. ExonFinder and the novel exons/ASVs identified are publicly accessible at http://exonfinder.sourceforge.net/.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0431-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-015-0431-7
PMCID: PMC4323234  PMID: 25652661
Crop plants; Alternative splicing; Plant transcriptome evolution; Evolutionary rate; Comparative genomics; Bioinformatics
2.  Transcription of the Lysine-2,3-Aminomutase Gene in the kam Locus of Bacillus thuringiensis subsp. kurstaki HD73 Is Controlled by Both σ54 and σK Factors 
Journal of Bacteriology  2014;196(16):2934-2943.
Lysine 2,3-aminomutase (KAM; EC 5.4.3.2) catalyzes the interconversion of l-lysine and l-β-lysine. The transcription and regulation of the kam locus, including lysine-2,3-aminomutase-encoding genes, in Bacillus thuringiensis were analyzed in this study. Reverse transcription-PCR (RT-PCR) analysis revealed that this locus forms two operons: yodT (yodT-yodS-yodR-yodQ-yodP-kamR) and kamA (kamA-yokU-yozE). The transcriptional start sites (TSSs) of the kamA gene were determined using 5′ rapid amplification of cDNA ends (RACE). A typical −12/−24 σ54 binding site was identified in the promoter PkamA, which is located upstream of the kamA gene TSS. A β-galactosidase assay showed that PkamA, which directs the transcription of the kamA operon, is controlled by the σ54 factor and is activated through the σ54-dependent transcriptional regulator KamR. The kamA operon is also controlled by σK and regulated by the GerE protein in the late stage of sporulation. kamR and kamA mutants were prepared by homologous recombination to examine the role of the kam locus. The results showed that the sporulation rate in B. thuringiensis HD(ΔkamR) was slightly decreased compared to that in HD73, whereas that in HD(ΔkamA) was similar to that in HD73. This means that other genes regulated by KamR are important for sporulation.
doi:10.1128/JB.01675-14
PMCID: PMC4135644  PMID: 24914178
4.  OSTEOPONTIN IS AN INITIAL MEDIATOR OF INFLAMMATION AND LIVER INJURY DURING OBSTRUCTIVE CHOLESTASIS AFTER BILE DUCT LIGATION IN MICE 
Toxicology letters  2013;224(2):10.1016/j.toxlet.2013.10.030.
Osteopontin (OPN) is a chemotactic factor which can be cleaved to the pro-inflammatory form by matrix metalloproteinases (MMPs). To test the hypothesis that OPN can modulate inflammatory liver injury during cholestasis, wild-type (WT) C57BL/6 and OPN knockout (OPN-KO) mice underwent bile duct ligation (BDL). OPN-KO mice showed significant reduction in liver injury (plasma ALT and necrosis) and neutrophil recruitment compared with WT animals at 24h but not 72h after BDL. In WT mice, a 4-fold increase in hepatic MMP-3 mRNA and elevated MMP activities and cleaved OPN levels were observed in bile. WT mice subjected to BDL in the presence of the MMP inhibitor BB-94 showed reduced liver injury, less neutrophil extravasation and diminished levels of cleaved OPN in bile. Thus, during obstructive cholestasis, OPN released from biliary epithelial cells could be cleaved by MMPs in bile. When the biliary system leaks, cleaved OPN enters the parenchyma and attracts neutrophils. In the absence of OPN, other chemoattractants, e.g. chemokines, mediate a delayed inflammatory response and injury. Taken together, our data suggest that OPN is the pro-inflammatory mediator that initiates the early neutrophil-mediated injury phase during obstructive cholestasis in mice.
doi:10.1016/j.toxlet.2013.10.030
PMCID: PMC3875222  PMID: 24188933
Inflammatory Liver Injury; Cholestasis; Bile duct ligation; Osteopontin; Neutrophils
5.  Validation of the Korean version of the European Community Respiratory Health Survey screening questionnaire for use in epidemiologic studies for adult asthma 
Asia Pacific Allergy  2015;5(1):25-31.
Background
Standardized questionnaire is one of key instruments for general population surveys.
Objective
The present study aimed to develop and validate the Korean version of the European Community Respiratory Health Survey (ECRHS) screening questionnaire for adult asthma surveys.
Methods
The ECRHS screening questionnaire was translated into Korean language according to the international criteria. Study participants were prospectively recruited from six referral hospitals and one health check-up center. Comprehensibility of the translation was tested in a pilot study of 10 patients. The reliability was evaluated by internal consistency and test-retest repeatability. Validity was assess with regard to physician-diagnosed asthma.
Results
A total of 100 adult asthma patients and 134 volunteers were recruited. Reliability was examined for 10 items in 100 asthmatics; Cronbach α coefficients were 0.84, and test-retest repeatability was good (Cohen κ coefficient, 0.71-1.00). Validity was assessed for 8 items in 234 participants; in particular, 'recent wheeze' showed a high sensitivity (0.89) for physician-diagnosed asthma. 'Recent asthma attack' and 'current asthma medication' showed high specificity (0.96-0.98).
Conclusion
The present study demonstrated that the Korean version of the ECRHS screening questionnaire was comprehensible, reliable and valid. We suggest the questionnaire to be utilized in further epidemiological studies for asthma in Korean adult populations.
doi:10.5415/apallergy.2015.5.1.25
PMCID: PMC4313752  PMID: 25653917
Asthma; Epidemiology; Questionnaires
6.  Plant-Plant-Microbe Mechanisms Involved in Soil-Borne Disease Suppression on a Maize and Pepper Intercropping System 
PLoS ONE  2014;9(12):e115052.
Background
Intercropping systems could increase crop diversity and avoid vulnerability to biotic stresses. Most studies have shown that intercropping can provide relief to crops against wind-dispersed pathogens. However, there was limited data on how the practice of intercropping help crops against soil-borne Phytophthora disease.
Principal Findings
Compared to pepper monoculture, a large scale intercropping study of maize grown between pepper rows reduced disease levels of the soil-borne pepper Phytophthora blight. These reduced disease levels of Phytophthora in the intercropping system were correlated with the ability of maize plants to form a “root wall” that restricted the movement of Phytophthora capsici across rows. Experimentally, it was found that maize roots attracted the zoospores of P. capsici and then inhibited their growth. When maize plants were grown in close proximity to each other, the roots produced and secreted larger quantities of 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA) and 6-methoxy-2-benzoxazolinone (MBOA). Furthermore, MBOA, benzothiazole (BZO), and 2-(methylthio)-benzothiazole (MBZO) were identified in root exudates of maize and showed antimicrobial activity against P. capsici.
Conclusions
Maize could form a “root wall” to restrict the spread of P. capsici across rows in maize and pepper intercropping systems. Antimicrobe compounds secreted by maize root were one of the factors that resulted in the inhibition of P. capsici. These results provide new insights into plant-plant-microbe mechanisms involved in intercropping systems.
doi:10.1371/journal.pone.0115052
PMCID: PMC4281244  PMID: 25551554
7.  Activation of gab cluster transcription in Bacillus thuringiensis by γ-aminobutyric acid or succinic semialdehyde is mediated by the Sigma 54-dependent transcriptional activator GabR 
BMC Microbiology  2014;14(1):2317.
Background
Bacillus thuringiensis GabR is a Sigma 54-dependent transcriptional activator containing three typical domains, an N-terminal regulatory domain Per-ARNT-Sim (PAS), a central AAA+ (ATPases associated with different cellular activities) domain and a C-terminal helix-turn-helix (HTH) DNA binding domain. GabR positively regulates the expression of the gabT gene of the gab gene cluster, which is responsible for the γ-aminobutyric acid (GABA) shunt.
Results
Purified GabR was shown to specifically bind to a repeat region that mapped 58 bp upstream of the gabT start codon. The specific signal factors GABA and succinic semialdehyde (SSA) activated gabT expression, whereas GABA- and SSA-inducible gabT transcription was abolished in sigL and gabR mutants. GABA and SSA did not induce the expression of either SigL or GabR. Deletion of the PAS domain of GabR resulted in increased gabT transcriptional activity, both in the presence and absence of GABA.
Conclusions
This study identified the GabR-binding site on the gabT promoter; however, GabR does not bind to its own promoter. gabT transcription is induced by GABA and SSA, and inducible expression is dependent on SigL and activated by GabR. The PAS domain in GabR is repressing its enhancer transcriptional activity on the gabT promoter. Repression is released upon GABA addition, whereupon transcription is induced.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-014-0306-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-014-0306-3
PMCID: PMC4279683  PMID: 25527261
GabR; Sigma 54; GABA; SSA; PAS domain
8.  CFS-1686 Causes Cell Cycle Arrest at Intra-S Phase by Interference of Interaction of Topoisomerase 1 with DNA 
PLoS ONE  2014;9(12):e113832.
CFS-1686 (chemical name (E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2-yl)vinyl)quinolin-4-ylamino)benzamide) inhibits cell proliferation and triggers late apoptosis in prostate cancer cell lines. Comparing the effect of CFS-1686 on cell cycle progression with the topoisomerase 1 inhibitor camptothecin revealed that CFS-1686 and camptothecin reduced DNA synthesis in S-phase, resulting in cell cycle arrest at the intra-S phase and G1-S boundary, respectively. The DNA damage in CFS-1686 and camptothecin treated cells was evaluated by the level of ATM phosphorylation, γH2AX, and γH2AX foci, showing that camptothecin was more effective than CFS-1686. However, despite its lower DNA damage capacity, CFS-1686 demonstrated 4-fold higher inhibition of topoisomerase 1 than camptothecin in a DNA relaxation assay. Unlike camptothecin, CFS-1686 demonstrated no activity on topoisomerase 1 in a DNA cleavage assay, but nevertheless it reduced the camptothecin-induced DNA cleavage of topoisomerase 1 in a dose-dependent manner. Our results indicate that CFS-1686 might bind to topoisomerase 1 to inhibit this enzyme from interacting with DNA relaxation activity, unlike campothecin's induction of a topoisomerase 1-DNA cleavage complex. Finally, we used a computer docking strategy to localize the potential binding site of CFS-1686 to topoisomerase 1, further indicating that CFS-1686 might inhibit the binding of Top1 to DNA.
doi:10.1371/journal.pone.0113832
PMCID: PMC4252032  PMID: 25460368
9.  Effective Anti-aging Strategies in an Era of Super-aging 
Journal of Menopausal Medicine  2014;20(3):85-89.
The societies of the world in the 21st century have faced challenges arising from an aging population as the fertility rate has dropped dramatically and medical advances have extended the average human life span. The elderly aged 65 years or older make up at least 20% of the population in Korea, making the country a super-aging society as defined by the United Nations. The number of elderly women is higher than that of elderly men and women live longer than men. Based on the analysis of recent trends in previous studies, this study aimed to suggest practical strategies to utilize isoflavones, substances chemically similar to the female hormone estrogen, and to search for effective anti-aging strategies using this substance for women to be prepared to reach the elderly stage in good health.
doi:10.6118/jmm.2014.20.3.85
PMCID: PMC4286659  PMID: 25580418
Anti-aging; Estrogen; Female; Hormone replacement therapy; Isoflavone; Quality of life
10.  Tumour Calcification and Calciphylaxis in End-Stage Renal Disease 
Case Reports in Medicine  2014;2014:108071.
Although soft tissue and vascular calcifications are common in CKD and progress as an independent risk factor of all-cause mortality, tumour calcification and calciphylaxis are uncommon in patients with end-stage renal disease (ESRD). Here, we discuss a rare case of a patient with tumour calcification complicated with calciphylaxis developed septic shock from infection. Our patient is a 57-year-old man in his late stage of renal disease who presented with a huge mass at the right hip and necrotic cutaneous ulcers on the lower legs followed by local and systemic infection and death due to septic shock.
doi:10.1155/2014/108071
PMCID: PMC4251359  PMID: 25477966
11.  Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G2/M phases of the cell cycle 
Cell Cycle  2013;12(22):3512-3525.
Cyclin-dependent kinase 4 (CDK4) is known to be a 33 kD protein that drives G1 phase progression of the cell cycle by binding to a CCND protein to phosphorylate RB proteins. Using different CDK4 antibodies in western blot, we detected 2 groups of proteins around 40 and 33 kD, respectively, in human and mouse cells; each group often appeared as a duplet or triplet of bands. Some CDK4 shRNAs could decrease the 33 kD wild-type (wt) CDK4 but increase some 40 kD proteins, whereas some other shRNAs had the opposite effects. Liquid chromatography–mass spectrometry/mass spectrometry analysis confirmed the existence of CDK4 isoforms smaller than 33 kD but failed to identify CDK4 at 40 kD. We cloned one CDK4 mRNA variant that lacks exon 2 and encodes a 26 kD protein without the first 74 amino acids of the wt CDK4, thus lacking the ATP binding sequence and the PISTVRE domain required for binding to CCND. Co-IP assay confirmed that this ΔE2 protein lost CCND1- and RB1-binding ability. Moreover, we found, surprisingly, that the wt CDK4 and the ΔE2 could inhibit G1–S progression, accelerate S–G2/M progression, and enhance or delay apoptosis in a cell line-specific manner in a situation where the cells were treated with a CDK4 inhibitor or the cells were serum-starved and then replenished. Hence, CDK4 seems to be expressed as multiple proteins that react differently to different CDK4 antibodies, respond differently to different shRNAs, and, in some situations, have previously unrecognized functions at the S–G2/M phases of the cell cycle via mechanisms independent of binding to CCND and RB.
doi:10.4161/cc.26510
PMCID: PMC3906337  PMID: 24091631
CDK4; alternative splicing; CCND1; RB1; cell cycle
12.  Non-Alcoholic Fatty Liver Disease in Children: Focus on Nutritional Interventions 
Nutrients  2014;6(11):4691-4705.
With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of NAFLD. Recently, there has been a growing body of evidence to implicate altered gut microbiota in the development of NAFLD through the gut-liver axis. The first line of prevention and treatment of NAFLD in children should be intensive lifestyle interventions such as changes in diet and physical activity. Recent advances have been focused on limitation of dietary fructose and supplementation of antioxidants, omega-3 fatty acids, and prebiotics/probiotics. Convincing evidences from both animal models and human studies have shown that reduction of dietary fructose and supplement of vitamin E, omega-3 fatty acids, and prebiotics/probiotics improve NAFLD.
doi:10.3390/nu6114691
PMCID: PMC4245557  PMID: 25353664
non-alcoholic fatty liver disease (NAFLD); nutrition; children
13.  The role of integrin-β/FAK in cyclic mechanical stimulation in MG-63 cells 
Objective: This study aims to explore the function of Integrin-β/FAK in the mechanical signal transduction and the connection with downstream ERK signal pathways. Methods: Human osteosarcoma MG63 cell lines were used in this study. The effects of mechanical strain on the Integrin-β1 expression, FAK and ERK signal pathway in Human osteosarcoma MG63 cells were detected using RT-PCR and Western-blotting methods. The localization of FAK in Human osteosarcoma MG63 cells were determined using immunofluorescent method. The interaction between Integrin-β1 and FAK were detected by using co-immunoprecipitation method. Results: The expression of Integrin-β1 shows a notable bimodel distribution, mechanical strain stimulation can promote Integrin-β1 expression and the phosphorylation of FAK and ERK, mechanical strain activated FAK and ERK mediated by Integrin-β1. Conclusion: Integrin-β1 may play an important role in osteoblast proliferation differentiation process, it might feel external strain stimulation through ECM composition and makes FAK phosphated through the interaction with FAK, thus causing a series of activation of signal molecules. Finally it reduces MAPK (ERK) activation and cellular responses to finish mechanical signal transduction.
PMCID: PMC4270589  PMID: 25550780
Integrin-β; human osteosarcoma MG63 cells; mechanical stimulation; focal adhesion kinase (FAK); ERK signal pathway
14.  Surgical Decompression of Painful Diabetic Peripheral Neuropathy: The Role of Pain Distribution 
PLoS ONE  2014;9(10):e109827.
Objective
To investigate the effect of surgical decompression on painful diabetic peripheral neuropathy (DPN) patients and discuss the role which pain distribution and characterization play in the management of painful DPN as well as the underlying mechanism involved.
Methods
A total of 306 patients with painful diabetic lower-extremity neuropathy were treated with Dellon surgical nerve decompression in our department. Clinical evaluation including Visual analogue scale (VAS), Brief Pain Inventory Short Form for diabetic peripheral neuropathy (BPI-DPN) questionnaire, two-point discrimination (2-PD), nerve conduction velocity (NCV) and high-resolution ultrasonography (cross-sectional area, CSA) were performed in all cases preoperatively, and at 6 month intervals for 2 years post-decompression. The patients who underwent surgery were retrospectively assigned into two subgroups (focal and diffuse pain) according to the distribution of the diabetic neuropathic pain. The control group included 92 painful DPN patients without surgery.
Results
The levels of VAS, scores in BPI-DPN, 2-PD, NCV results and CSA were all improved in surgical group when compared to the control group (P<0.05). More improvement of VAS, scores in BPI-DPN and CSA was observed in focal pain group than that in diffuse group (P<0.05).
Conclusions
Efficacy of decompression of multiple lower-extremity peripheral nerves in patients with painful diabetic neuropathy was confirmed in this study. While both focal and diffuse group could benefit from surgical decompression, pain relief and morphological restoration could be better achieved in focal group.
doi:10.1371/journal.pone.0109827
PMCID: PMC4188608  PMID: 25290338
15.  Dihydroartemisinin inhibits vascular endothelial growth factor-induced endothelial cell migration by a p38 mitogen-activated protein kinase-independent pathway 
Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has been demonstrated to possess a strong antiangiogenic activity. However, the molecular mechanisms underlying this effect remain unclear. Endothelial cell (EC) migration is an essential component of angiogenesis, and the p38 mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in the regulation of migration induced by vascular endothelial growth factor (VEGF). The aim of the present study was to investigate the effects of DHA on EC migration and the p38 MAPK signaling pathway. Human umbilical vein ECs (HUVECs) were treated with DHA and VEGF-induced migration was analyzed. The activation of p38 MAPK was detected by western blot analysis, and the migration assays were performed with a p38-specific inhibitor, SB203850. It was revealed that 20 μM DHA significantly reduced EC migration in the transwell migration assay, wound healing assay and electrical cell-substrate impedance sensing real-time analysis. However, DHA did not affect p38 MAPK phosphorylation or expression. In the absence or presence of SB203850, DHA induced a similar proportional reduction of EC migration in the three migration assays. Therefore, the present study demonstrated that DHA inhibits VEGF-induced EC migration via a p38 MAPK-independent pathway.
doi:10.3892/etm.2014.1997
PMCID: PMC4217775  PMID: 25371719
dihydroartemisinin; migration; p38 mitogen-activated protein kinase; endothelial cell; angiogenesis
16.  Rs7206790 and rs11644943 in FTO Gene Are Associated with Risk of Obesity in Chinese School-Age Population 
PLoS ONE  2014;9(9):e108050.
To evaluate the associations between candidate FTO single nucleotide polymorphisms (SNPs) and obesity, a case-control study was conducted among Chinese school-age children, which included 500 obese cases and 500 matched controls (age, gender and location). We selected 24 candidate FTO tag-SNPs via bio-informatics analysis and performed genotyping using SNPScan technology. Results indicated that rs7206790 and rs11644943 were significantly associated with obesity among school-age children in both additive and recessive models (P<0.05) after adjusting confounders. Comparing rs7206790 CC and CG genotype of carriers, those carrying the GG genotype had an increased risk of obesity (adjusted odds ratio [OR], 3.76; 95% Confidence interval [CI], 1.24–11.43). Carriers of the AA allele of rs11644943 had a lower risk of obesity (adjusted OR, 0.16; 95% CI, 0.04–0.72) compared with those of the T allele (TT and TA). These two SNPs (rs7206790 and rs11644943) were not Linkage Disequilibrium (LD) with previous reported obesity-associated SNPs. Under the recessive model adjusted for age and gender and location, rs7206790 GG allele carriers had significantly increased BMIs (P = 0.012), weight (P = 0.012), waist circumferences (WC) (P = 0.045) and hip circumferences (HC) (P = 0.033). Conversely, rs11644943 AA allele carriers had significantly decreased BMIs (P = 0.006), WC (P = 0.037) and Waist-to-height ratios (WHtR) (P = 0.012). A dose-response relationship was found between the number of risk alleles in rs7206790, rs11644943 and rs9939609 and the risk of obesity. The Genetic Risk Score (GRS) of the reference group was 3; in comparison, those of 2, 4, and ≥5 had ORs for obesity of 0.24 (95%CI, 0.05–1.13), 1.49 (95%CI, 1.10–2.01), and 5.20 (95%CI, 1.75–15.44), respectively. This study confirmed the role of FTO variation on genetic susceptibility to obesity. We reported two new obesity-related FTO SNPs (rs7206790 and rs11644943) among Chinese school-age children.
doi:10.1371/journal.pone.0108050
PMCID: PMC4176023  PMID: 25251416
17.  Efficient Gene Knockout in Goats Using CRISPR/Cas9 System 
PLoS ONE  2014;9(9):e106718.
The CRISPR/Cas9 system has been adapted as an efficient genome editing tool in laboratory animals such as mice, rats, zebrafish and pigs. Here, we report that CRISPR/Cas9 mediated approach can efficiently induce monoallelic and biallelic gene knockout in goat primary fibroblasts. Four genes were disrupted simultaneously in goat fibroblasts by CRISPR/Cas9-mediated genome editing. The single-gene knockout fibroblasts were successfully used for somatic cell nuclear transfer (SCNT) and resulted in live-born goats harboring biallelic mutations. The CRISPR/Cas9 system represents a highly effective and facile platform for targeted editing of large animal genomes, which can be broadly applied to both biomedical and agricultural applications.
doi:10.1371/journal.pone.0106718
PMCID: PMC4154755  PMID: 25188313
18.  Capsaicin cough sensitivity is related to the older female predominant feature in chronic cough patients 
Purpose
The present study aimed to examine the age and gender distributions among chronic cough patients referred to a tertiary cough clinic in Korea, and to investigate clinical factors related to the demographic findings.
Methods
Study participants were unselectively recruited from adult chronic cough patients who attended the cough clinic for the first time during one year. To validate their representativeness, their age and gender distributions were compared to the entire chronic cough population, or with those presenting with other chronic disease. Data from the baseline investigations were analyzed to identify clinical factors related to the demographic findings.
Results
A total of 272 chronic cough patients were included. They had a middle-aged female predominant feature (mean age: 52.8±15.7 years and female 69.1%). Their age and gender distributions were almost identical to the entire chronic cough population, but were distinct from patients with hypertension. Among clinical factors, the older female predominance was associated with enhanced capsaicin cough sensitivity, and also with the presence of 'cough by cold air' symptom. Allotussia and laryngeal paresthesia were highly common in chronic cough patients, affecting 94.8% and 86.8% of them, respectively.
Conclusions
The present study demonstrated older female predominance among adult chronic cough patients attending a referral cough clinic in Korea. The demographic features were significantly associated with the capsaicin cough responses and also potentially with allotussia (particularly cold air as the trigger). These findings suggest a role of cough reflex sensitization in the pathophysiology of chronic cough in adults.
doi:10.4168/aair.2014.6.5.401
PMCID: PMC4161680  PMID: 25228996
Cough; respiratory hypersensitivity
19.  ATF3 functions as a novel tumor suppressor with prognostic significance in esophageal squamous cell carcinoma 
Oncotarget  2014;5(18):8569-8582.
ATF3 was a transcription factor involved in the progression of certain cancers. Here, we sought to explore the expression and biological function of ATF3 in esophageal squamous cell carcinomas (ESCC). The prognostic significance of ATF3 expression was evaluated in 150 ESCC samples and 21 normal squamous cell epithelium tissues. Results showed that ATF3 was down-regulated in ESCC lesions compared with paired non-cancerous tissues and low tumorous ATF3 expression significantly correlated with shorter overall survival (OS) and disease-free survival (DFS). Cox regression analysis confirmed that ATF3 expression was an independent prognostic factor. Experimentally, forced expression of ATF3 led to decreased growth and invasion properties of ESCC cells in vitro and in vivo, whereas knockdown of ATF3 did the opposite. Furthermore, ATF3 upregulated the expression of MDM2 by increasing the nuclear translocation of P53 and formed an ATF3/MDM2/MMP-2 complex that facilitated MMP-2 degradation, which subsequently led to inhibition of cell invasion. Finally, we showed that Cisplatin could restrain the invasion of ESCC cells by inducing the expression of ATF3 via P53 signaling. Combined, our findings highlight a suppressed role for ATF3 in ESCC and targeting ATF3 might be a potential therapeutic strategy.
PMCID: PMC4226705  PMID: 25149542
ATF3; independent prognostic factor; cell invasion and metastasis; MMP-2; esophageal squamous cell carcinoma
20.  A Novel marRAB Operon Contributes to the Rifampicin Resistance in Mycobacterium smegmatis 
PLoS ONE  2014;9(8):e106016.
The multiple-antibiotic resistance regulator (MarR) plays an important role in modulating bacterial antibiotic resistance. However, the regulatory model of the marRAB operon in mycobacteria remains to be characterized. Here we report that a MarR, encoded by Ms6508, and its marRAB operon specifically contribute to rifampicin (RIF) resistance in Mycobacterium smegmatis. We show that the MarR recognizes a conserved 21-bp palindromic motif and negatively regulates the expression of two ABC transporters in the operon, encoded by Ms6509–6510. Unlike other known drug efflux pumps, overexpression of these two ABC transporters unexpectedly increased RIF sensitivity and deletion of these two genes increased mycobacterial resistance to the antibiotic. No change can be detected for the sensitivity of recombinant mycobacterial strains to three other anti-TB drugs. Furthermore, HPLC experiments suggested that Ms6509–Ms6510 could pump RIF into the mycobacterial cells. These findings indicated that the mycobacterial MarR functions as a repressor and constitutively inhibits the expression of the marRAB operon, which specifically contributes to RIF resistance in M. smegmatis. Therefore, our data suggest a new regulatory mechanism of RIF resistance and also provide the new insight into the regulatory model of a marRAB operon in mycobacteria.
doi:10.1371/journal.pone.0106016
PMCID: PMC4143341  PMID: 25153492
21.  The Effects of Genetic Variation in FTO rs9939609 on Obesity and Dietary Preferences in Chinese Han Children and Adolescents 
PLoS ONE  2014;9(8):e104574.
The association of the rs9939609 single nucleotide polymorphism in FTO gene with obesity has been extensively investigated in studies of populations of European, African, and Asian ancestry. However, inconsistent results have been reported in Asian populations, and the relationship of FTO variation and dietary behaviors has only rarely been examined in Chinese children and adolescents. The aim of this study was to assess the association of rs9939609 with obesity and dietary preferences in childhood in a Chinese population. Epidemiological data including dietary preferences were collected in interviews using survey questionnaires, and rs9939609 genotype was determined by real-time PCR. The associations of rs9939609 genotypes with obesity and dietary preferences were analyzed by multivariate logistic regression using both additive and dominant models. The results showed that subjects with a TA or AA genotype had an increased risk of obesity compared with the TT participants; the odds ratios (ORs) were 1.47 (95% CI: 1.25–1.71, P = 1.73×10−6), and 3.32 (95% CI: 2.01–5.47, P = 2.68×10−6), respectively. After adjusting for age and gender, body mass index, waist circumference, hip circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol were higher, and high-density lipoprotein cholesterol was lower in TA and AA participants than in those with the TT genotype. After additionally controlling for body mass index, the association remained significant only for systolic blood pressure (P = 0.005). Compared with TT participants, those with the AA genotype were more likely to prefer a meat-based diet (OR = 2.81, 95% CI: 1.52–5.21). The combined OR for obesity in participants with TA/AA genotypes and preference for a meat-based diet was 4.04 (95% CI: 2.8–5.81) compared with the TT participants who preferred a plant-based diet. These findings indicate the genetic variation of rs9939609 is associated with obesity and dietary preferences in Chinese children and adolescents.
doi:10.1371/journal.pone.0104574
PMCID: PMC4128666  PMID: 25110886
22.  Transcriptome analysis reveals the effect of oral contraceptive use on cervical cancer 
Molecular Medicine Reports  2014;10(4):1703-1708.
Differentially-expressed genes (DEGs) correlated to oral contraceptives (OCs) were identified by comparing the transcriptomes of cervical cancer patients who have taken OCs and those who have not. Their biological functions and relevance to clinical manifestations were investigated further in order to gain an understanding of the pathogenesis of cervical cancer and provide potential therapeutic targets. Level 3 RNA-sequencing (seq) data for cervical squamous-cell carcinoma and endocervical adenocarcinoma and the clinical information were downloaded from The Cancer Genome Atlas. The present study analyzed the RNA-seq data and information on OC use of 35 patients [OC users (n=18) and those who have never used OCs (n=17)]. Student’s t-test was used in order to identify DEGs and the false discovery rate (FDR) was estimated by a Beta-Uniform Mixture model, which was adopted in multiple testing corrections. A functional enrichment analysis was performed with the Database for Annotation, Visualization and Integrated Discovery tool and BioCarta. A total of 80 DEGs were identified in OC users while FDR=0.3 was set as the cut-off value. The metabolic process and human telomerase RNA gene transcription were significantly upregulated in DEGs. Furthermore, secreted LY6/PLAUR domain containing 1 was identified to be correlated to the pathological response, while the synapse defective 1 Rho GTPase homolog 2 was found to be significantly associated with the histological grade and overall survival time. In conclusion, present study shed light on the effect of OC use on the oncogenesis of the cervix and may indicate novel approaches for a targeted therapy of cervical cancer.
doi:10.3892/mmr.2014.2466
PMCID: PMC4148377  PMID: 25109897
cervical cancer; oral contraceptive; RNA-seq data; differentially expressed genes; biomarker
23.  Pharmaceutical stabilization of mast cells attenuates experimental atherogenesis in low-density lipoprotein receptor-deficient mice 
Atherosclerosis  2013;229(2):304-309.
Mast cells (MCs) contribute to atherogenesis by releasing pro-inflammatory mediators to activate vascular cells and other inflammatory cells. This study examined whether MC activation or stabilization affects diet-induced atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr−/−) mice. When Ldlr−/− mice consumed an atherogenic diet for 3 or 6 months, MC activation with compound 48/80 (C48/80) increased aortic arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels, whereas MC stabilization with cromolyn reduced these parameters. There were significant differences in arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels between C48/80-treated and cromolyn-treated mice. To examine a therapeutic application of cromolyn in atherosclerosis, we fed Ldlr−/− mice an atherogenic diet for 3 months followed by giving mice cromolyn for additional 3 months. Cromolyn did not affect aortic arch intima area, but significantly reduced lipid deposition in the thoracic-abdominal aortas. In aortic arches, however, cromolyn treatment significantly reduced lesion contents of Mac-3+ macrophages, CD4+ T cells, activated MCs, and lesion cell proliferation. While plasma total cholesterol and LDL levels increased and high-density lipoprotein (HDL) levels decreased from 3 months to 6 months of an atherogenic diet, cromolyn treatment decreased significantly plasma total cholesterol, LDL, and triglyceride levels and increased HDL levels above those of 3-month time point. These observations demonstrate that MC stabilization reduces lesion inflammation, ameliorates plasma lipid profiles, and may serve as a potential therapy for this cardiovascular disease.
doi:10.1016/j.atherosclerosis.2013.05.025
PMCID: PMC3724238  PMID: 23880180
mast cell; atherosclerosis; cromolyn; C48/80; LDL receptor-deficient mice
24.  Hepatoprotective effects of Limonium tetragonum, edible medicinal halophyte growing near seashores 
Pharmacognosy Magazine  2014;10(Suppl 3):S563-S568.
Background:
During the process of hepatic fibrosis, the activation of hepatic stellate cells (HSCs) is responsible for the increased formation and reduced degradation of extracellular matrix in the liver. By employing the hepatic stellate cell line, HSC-T6, it was found that the methanol extract of Limonium tetragonum, a halophyte living in salt marsh near south and western seashores of Korea significantly inhibited the proliferation of HSC-T6 cells.
Objective:
In the present study, we attempted to investigate the antifibrotic effects of the mathanolic extract of L. tetragonum (MELT) in the activated HSC-T6 cells.
Materials and Methods:
The proliferation of HSC-T6 was stimulated by culturing environment or platelet-derived growth factor (PDGF-BB) insult, and then the inhibitory activities of MELT were measured.
Results:
It was found that MELT suppressed the proliferation of the activated HSC-T6 in concentration- and time-dependent manners. The increased collagen deposition in the activated HSC-T6 cells was also decreased by the treatment of MELT. The maximal dose of MELT, however, had little effect on primary cultured rat hepatocytes. Wlammatory cytokine, tumor necrosis factor alpha (TNF-α) produced by lipopolysaccharide-stimulated RAW264.7 macrophages was inhibited by MELT.
Conclusion:
Collectively, the above results demonstrated that MELT suppressed HSCs proliferation but not in hepatocytes, implying that L. tetragonum may be useful candidates for developing therapeutic agents for the prevention and treatment of hepatic fibrosis.
doi:10.4103/0973-1296.139783
PMCID: PMC4189273  PMID: 25298675
Antifibrotic; HSC-T6; halophyte; Limonium tetragonum; RAW264.7
25.  Validation of the Headache Impact Test (HIT-6) in patients with chronic migraine 
Background
The Headache Impact Test (HIT)-6 was developed and has been validated in patients with various types of headache. The objective of this study was to report the psychometric properties of the HIT-6 among patients with chronic migraine.
Methods
Data came from two international, multicenter, randomized, double-blind, placebo-controlled clinical trials of chronic migraine patients (N = 1,384) undergoing prophylaxis therapy. Confirmatory factor analysis and differential item functioning (DIF) analysis were used to test the latent structure and cross-cultural comparability of the HIT-6. Reliability, construct validity, and responsiveness were assessed. Two sets of criterion groups were used: (1) 28-day headache frequency: <10, 10–14, and ≥15 days; (2) sample quartiles of the total cumulative hours of headache: <140, 140 to <280, 280 to <420, and ≥420 hours. Two sets of responsiveness categories were defined as reduction of <30%, 30% to <50%, or ≥50% in (1) number of headache days and (2) cumulative hours of headache.
Results
Measurement invariance tests supported the stability of the HIT-6 latent structure across studies. DIF analysis supported cross-cultural comparability. Good reliability was observed across studies (Cronbach’s α: 0.75–0.92; intraclass correlation coefficient: 0.76–0.80). HIT-6 scores correlated strongly (−0.86 to −0.59) with scores of the Migraine-Specific Quality-of-Life Questionnaire. Analysis of variance indicated that HIT-6 scores discriminated across both types of criterion groups (P<0.001), across studies and time points. HIT-6 change scores were significantly higher in magnitude in groups experiencing greater improvement (P<0.001).
Conclusion
All measurement properties were consistently verified across the two studies, supporting the validity of the HIT-6 among chronic migraine patients.
Trial registration
NCT00156910 and NCT00168428 on www.ClinicalTrials.gov.
doi:10.1186/s12955-014-0117-0
PMCID: PMC4243819  PMID: 25080874
Headache Impact Test (HIT-6); Psychometrics; Validity; Chronic migraine; Health-related quality of life; PREEMPT

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