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1.  Clinical Characteristics and Antimicrobial Susceptibility Pattern of Hospitalized Patients with Community Acquired Urinary Tract Infections at a Regional Hospital in Taiwan 
Healthcare infection  2013;19(1):20-25.
Community-acquired urinary tract infection (UTI) is the most common bacterial infection encountered at hospitals. Effective empirical antibiotic therapy relies on updated epidemiological data.
We described the epidemiology of patients with urosepsis presenting to a community hospital in Taiwan in order to assess the appropriateness of empirical therapy.
Retrospective cohort study of hospitalized adult patients with UTI from January 1 to December 31 in 2010. The clinical and microbiological characteristics were analyzed using descriptive statistics. Logistic regression analysis was performed to determine predictors of antibiotic resistance.
A total of 420 consecutive patients with 599 isolates were identified. Most patients were >=65 years old and women (75.4%), and 114 patients (27.1%) had bacteremia. Escherichia coli (69%) was the most common organism. Cefazolin was effective against E. coli, K. pneumoniae, and P. mirabilis in greater than 80% of the cases. In male patients, urinary catheter and renal stone were independent predictors for cefazolin resistance; while diabetes mellitus and malignancy were predictors among female patients.
Patients admitted with UTI should be screened to identify risk factors for bacteremia and antimicrobial resistance. The treatment guideline in Taiwan needs to be revised in the current era of increasing antimicrobial resistance.
PMCID: PMC4288472  PMID: 25580164
Epidemiology; Antimicrobial resistance; Guidelines; Urinary tract infection; Community Hospitals
2.  Clinical Manifestations and Risk Factors of Amebic Liver Abscess in Southeast Taiwan Compared with Other Regions of Taiwan 
Amebic liver abscess (ALA) had previously been endemic in Taiwan, particularly in the southern region, although its occurrence in the southeastern area was unknown. Thus, we conducted a retrospective study for southeastern Taiwan. We identified 14 patients who were diagnosed with ALA between July of 1995 and July of 2008. These patients were predominantly male and older in age. Most patients lived in rural areas (85.7%). Alcoholism (78.6%) and diabetes (35.7%) were risk factors for ALA. No human immunodeficiency virus (HIV) infections were detected. The most common clinical symptoms were fever (100%) and abdominal pain (100%). Short mean durations of symptoms, high bilirubin levels, and low albumin levels were also noted. Most patients (92.86%) had a single lesion, particularly in the right liver lobe (71.4%). Six patients also had secondary Klebsiella pneumoniae bacterial infections. Clinicians should be aware of the different risk factors in different regions when diagnosing amebic liver abscess in Taiwan.
PMCID: PMC3854904  PMID: 24166042
3.  Interactions of endoplasmic reticulum and mitochondria Ca2+ stores with capacitative calcium entry 
Metabolic brain disease  2014;29(4):1083-1093.
Thiamine dependent enzymes are diminished in Alzheimer’s disease (AD). Thiamine deficiency in vitro and in rodents is a useful model of this reduction. Thiamine interacts with cellular calcium stores. To directly test the relevance of the thiamine dependent changes to dynamic processes in AD, the interactions must be studied in cells from patients with AD. These studies employed fibroblasts. Mitochondrial dysfunction including reductions in thiamine dependent enzymes and abnormalities in calcium homeostasis and oxidative processes occur in fibroblasts from Alzheimer’s Disease (AD) patients. Bombesin-releasable calcium stores (BRCS) from the endoplasmic reticulum (ER) are exaggerated in fibroblasts from patients with AD bearing a presenilin-1 (PS-1) mutation and in control fibroblasts treated with oxidants. ER calcium regulates calcium entry into the cell through capacitative calcium entry (CCE), which is reduced in fibroblasts and neurons from mice bearing PS-1 mutations. Under physiological conditions, mitochondria and ER play important and interactive roles in the regulation of Ca2+ homeostasis. Thus, the interactions of mitochondria and oxidants with CCE were tested. Inhibition of ER Ca2+-ATPase by cyclopiazonic acid (CPA) stimulates CCE. CPA-induced CCE was diminished by inhibition of mitochondrial Ca2+ export (−60%) or import (−40%). Different aspects of mitochondrial Ca2+ coupled to CPA-induced-CCE were sensitive to select oxidants. The effects were very different when CCE was examined in the presence of InsP3, a physiological regulator of ER calcium release, and subsequent CCE. CCE under these conditions was only mildly reduced (20–25%) by inhibition of mitochondrial Ca2+ export, and inhibition of mitochondrial Ca2+ uptake exaggerated CCE (+53%). However, t-BHP reversed both abnormalities. The results suggest that in the presence of InsP3, mitochondria buffer the local Ca2+ released from ER following rapid activation of InsP3R and serve as a negative feedback to the CCE. The results suggest that mitochondrial Ca2+ modifies the depletion and refilling mechanism of ER Ca2+ stores.
PMCID: PMC4206688  PMID: 24748364
Calcium; Alzheimer’s disease; mitochondria; endoplasmic reticulum; oxidants; capacitative calcium entry; IP3; fibroblasts
4.  Derivation and Validation of Diagnostic Thresholds for Central Blood Pressure Measurements Based on Long-Term Cardiovascular Risks 
Journal of the American College of Cardiology  2013;62(19):10.1016/j.jacc.2013.06.029.
This study sought to derive and validate outcome-driven thresholds of central blood pressure (CBP) for diagnosing hypertension.
Current guidelines for managing patients with hypertension mainly rely on blood pressure (BP) measured at brachial arteries (cuff BP). However, BP measured at the central aorta (central BP [CBP]) may be a better prognostic factor for predicting future cardiovascular events than cuff BP.
In a derivation cohort (1,272 individuals and a median follow-up of 15 years), we determined diagnostic thresholds for CBP by using current guideline-endorsed cutoffs for cuff BP with a bootstrapping (resampling by drawing randomly with replacement) and an approximation method. To evaluate the discriminatory power in predicting cardiovascular outcomes, the derived thresholds were tested in a validation cohort (2,501 individuals with median follow-up of 10 years).
The 2 analyses yielded similar diagnostic thresholds for CBP. After rounding, systolic/diastolic threshold was 110/80 mm Hg for optimal BP and 130/90 mm Hg for hypertension. Compared with optimal BP, the risk of cardiovascular mortality increased significantly in subjects with hypertension (hazard ratio: 3.08, 95% confidence interval: 1.05 to 9.05). Of the multivariate Cox proportional hazards model, incorporation of a dichotomous variable by defining hypertension as CBP ≥130/90 mm Hg was associated with the largest contribution to the predictive power.
CBP of 130/90 mm Hg was determined to be the cutoff limit for normality and was characterized by a greater discriminatory power for long-term events in our validation cohort. This report represents an important step toward the application of the CBP concept in clinical practice.
PMCID: PMC3884552  PMID: 23850921
central blood pressure; diagnostic thresholds; high blood pressure; hypertension
5.  Discovery and Analysis of MicroRNAs in Leymus chinensis under Saline-Alkali and Drought Stress Using High-Throughput Sequencing 
PLoS ONE  2014;9(11):e105417.
Leymus chinensis (Trin.) Tzvel. is a perennial rhizome grass of the Poaceae (also called Gramineae) family, which adapts well to drought, saline and alkaline conditions. However, little is known about the stress tolerance of L. chinensis at the molecular level. microRNAs (miRNAs) are known to play critical roles in nutrient homeostasis, developmental processes, pathogen responses, and abiotic stress in plants. In this study, we used Solexa sequencing technology to generate high-quality small RNA data from three L. chinensis groups: a control group, a saline-alkaline stress group (100 mM NaCl and 200 mM NaHCO3), and a drought stress group (20% polyethylene glycol 2000). From these data we identified 132 known miRNAs and 16 novel miRNAs candidates. For these miRNAs we also identified target genes that encode a broad range of proteins that may be correlated with abiotic stress regulation. This is the first study to demonstrate differentially expressed miRNAs in L. chinensis under saline-alkali and drought stress. These findings may help explain the saline-alkaline and drought stress responses in L. chinensis.
PMCID: PMC4219666  PMID: 25369004
6.  Non-linear micromechanics of soft tissues 
Microstructure-based constitutive models have been adopted in recent studies of non-linear mechanical properties of biological soft tissues. These models provide more accurate predictions of the overall mechanical responses of tissues than phenomenological approaches. Based on standard approximations in non-linear mechanics, we classified the microstructural models into three categories: (1) uniform-field models with solid-like matrix, (2) uniform-field models with fluid-like matrix, and (3) second-order estimate models. The first two categories assume affine deformation field where the deformation of microstructure is the same as that of the tissue, regardless of material heterogeneities; i.e., they represent the upper bounds of the exact effective strain energy and stress of soft tissues. In addition, the first type is not purely structurally motivated and hence cannot accurately predict the microscopic mechanical behaviors of soft tissues. The third category considers realistic geometrical features, material properties of microstructure and interactions among them and allows for flexible deformation in each constituent. The uniform-field model with fluid-like matrix and the second-order estimate model are microstructure-based, and can be applied to different tissues based on micro-structural features.
PMCID: PMC4012686  PMID: 24817769
Collagenous tissue; Collagen; Elastin; Microstructure; Constitutive relation; Non-affine deformation
7.  CXCL17 Expression Predicts Poor Prognosis and Correlates with Adverse Immune Infiltration in Hepatocellular Carcinoma 
PLoS ONE  2014;9(10):e110064.
CXC ligand 17 (CXCL17) is a novel CXC chemokine whose clinical significance remains largely unknown. In the present study, we characterized the prognostic value of CXCL17 in patients with hepatocellular carcinoma (HCC) and evaluated the association of CXCL17 with immune infiltration. We examined CXCL17 expression in 227 HCC tissue specimens by immunohistochemical staining, and correlated CXCL17 expression patterns with clinicopathological features, prognosis, and immune infiltrate density (CD4 T cells, CD8 T cells, B cells, natural killer cells, neutrophils, macrophages). Kaplan-Meier survival analysis showed that both increased intratumoral CXCL17 (P = 0.015 for overall survival [OS], P = 0.003 for recurrence-free survival [RFS]) and peritumoral CXCL17 (P = 0.002 for OS, P<0.001 for RFS) were associated with shorter OS and RFS. Patients in the CXCL17low group had significantly lower 5-year recurrence rate compared with patients in the CXCL17high group (peritumoral: 53.1% vs. 77.7%, P<0.001, intratumoral: 58.6% vs. 73.0%, P = 0.001, respectively). Multivariate Cox proportional hazards analysis identified peritumoral CXCL17 as an independent prognostic factor for both OS (hazard ratio [HR] = 2.066, 95% confidence interval [CI] = 1.296–3.292, P = 0.002) and RFS (HR = 1.844, 95% CI = 1.218–2.793, P = 0.004). Moreover, CXCL17 expression was associated with more CD68 and less CD4 cell infiltration (both P<0.05). The combination of CXCL17 density and immune infiltration could be used to further classify patients into subsets with different prognosis for RFS. Our results provide the first evidence that tumor-infiltrating CXCL17+ cell density is an independent prognostic factor that predicts both OS and RFS in HCC. CXCL17 production correlated with adverse immune infiltration and might be an important target for anti-HCC therapies.
PMCID: PMC4193880  PMID: 25303284
8.  Microstructural Constitutive Model of Active Coronary Media 
Biomaterials  2013;34(31):7575-7583.
Although vascular smooth muscle cells (VSMCs) are pivotal in physiology and pathology, there is a lack of detailed morphological data on these cells. The objective of this study was to determine dimensions (width and length) and orientation of swine coronary VSMCs and to develop a microstructural constitutive model of active media. The dimensions, spatial aspect ratio and orientation angle of VSMCs measured at zero-stress state were found to follow continuous normal (or bimodal normal) distributions. The VSMCs aligned off circumferential direction of blood vessels with symmetrical polar angles 18.7°±10.9°, and the local VSMC deformation was affine with tissue-level deformation. A microstructure-based active constitutive model was developed to predict the biaxial vasoactivity of coronary media, based on experimental measurements of geometrical and deformation features of VSMCs. The results revealed that the axial active response of blood vessels is associated with multi-axial contraction as well as oblique VSMC arrangement. The present morphological data base is essential for developing accurate structural models and is seminal for understanding the biomechanics of muscular vessels.
PMCID: PMC4012690  PMID: 23859656
Biaxial vasoactivity; Vascular smooth muscle cell; Deformation; Morphology; Coronary artery
9.  A Mur Regulator Protein in the Extremophilic Bacterium Deinococcus radiodurans 
PLoS ONE  2014;9(9):e106341.
Ferric uptake regulator (Fur) is a transcriptional regulator that controls the expression of genes involved in the uptake of iron and manganese, as well as vital nutrients, and is essential for intracellular redox cycling. We identified a unique Fur homolog (DR0865) from Deinococcus radiodurans, which is known for its extreme resistance to radiation and oxidants. A dr0865 mutant (Mt-0865) showed a higher sensitivity to manganese stress, hydrogen peroxide, gamma irradiation and ultraviolet (UV) irradiation than the wild-type R1 strain. Cellular manganese (Mn) ion (Mn2+) analysis showed that Mn2+, copper (Cu2+), and ferric (Fe3+) ions accumulated significantly in the mutant, which suggests that the dr0865 gene is not only involved in the regulation of Mn2+ homeostasis, but also affects the uptake of other ions. In addition, transcriptome profiles under MnCl2 stress showed that the expression of many genes involved in Mn metabolism was significantly different in the wild-type R1 and DR0865 mutant (Mt-0865). Furthermore, we found that the dr0865 gene serves as a positive regulator of the manganese efflux pump gene mntE (dr1236), and as a negative regulator of Mn ABC transporter genes, such as dr2283, dr2284 and dr2523. Therefore, it plays an important role in maintaining the homoeostasis of intracellular Mn (II), and also other Mn2+, zinc (Zn2+) and Cu2+ ions. Based on its role in manganese homeostasis, DR0865 likely belongs to the Mur sub-family of Fur homolog.
PMCID: PMC4171365  PMID: 25243898
10.  Stuttering candidate genes DRD2 but not SLC6A3 is associated with developmental dyslexia in Chinese population 
Dyslexia is a polygenic developmental disorder characterized by difficulties in reading and spelling despite normal intelligence, educational backgrounds and perception. Increasing evidences indicated that dyslexia may share similar genetic mechanisms with other speech and language disorders. We proposed that stuttering candidate genes, DRD2 and SLC6A3, might be associated with dyslexia.
Methods and results
The study was conducted in an unrelated Chinese cohort with 502 dyslexic cases and 522 healthy controls. In total, 23 Tag SNPs covering the two genes were selected for genotyping through Tagger program. Association analysis was performed on each SNP alone and in haplotypes. One SNP markers in DRD2 showed significant association with developmental dyslexia.
These findings indicate that polymorphism of DRD2 gene may be a risk factor of developmental dyslexia in the Chinese population.
PMCID: PMC4236612  PMID: 25178928
Dyslexia; Dopamine D2 receptor (DRD2); Solute carrier family 6, member 3 (SLC6A3); Linkage study
11.  Identification of evolutionarily conserved amino acid residues in homeodomain of KNOX proteins for intercellular trafficking 
Plant Signaling & Behavior  2014;9:e28355.
Maize KNOTTED (KN1) homeodomain (HD) protein is a well-known mobile transcription factor crucial for stem cell maintenance. Recent studies have revealed that the trihelical HD of KNOTTED1-like homeobox (KNOX) proteins is necessary and sufficient for selective cell-to-cell trafficking. Also, the efficient trafficking ability for HD is likely to be acquired during the evolution of early nonvascular land plants. Here, using the point-mutated HD of KN1 and SHOOT MERISTEMLESS (STM) in the trichome rescue system, together with molecular structure modeling, we have found the evolutionarily conserved amino acid residues, such as arginine in helix α1 and leucine in helix α3, which are essential for intercellular trafficking. Our studies provided important clues for the 3-dimensional protein structure required for cell-to-cell movement of non-cell-autonomous transcription factors.
PMCID: PMC4091555  PMID: 24603432
homeodomain; intercellular protein trafficking; non-cell-autonomous; plasmodesmata; transcription factor
12.  TolC Promotes ExPEC Biofilm Formation and Curli Production in Response to Medium Osmolarity 
BioMed Research International  2014;2014:574274.
While a high osmolarity medium activates Cpx signaling and causes CpxR to repress csgD expression, and efflux protein TolC protein plays an important role in biofilm formation in Escherichia coli, whether TolC also responds to an osmolarity change to regulate biofilm formation in extraintestinal pathogenic E. coli (ExPEC) remains unknown. In this study, we constructed ΔtolC mutant and complement ExPEC strains to investigate the role of TolC in the retention of biofilm formation and curli production capability under different osmotic conditions. The ΔtolC mutant showed significantly decreased biofilm formation and lost the ability to produce curli fimbriae compared to its parent ExPEC strain PPECC42 when cultured in M9 medium or 1/2 M9 medium of increased osmolarity with NaCl or sucrose at 28°C. However, biofilm formation and curli production levels were restored to wild-type levels in the ΔtolC mutant in 1/2 M9 medium. We propose for the first time that TolC protein is able to form biofilm even under high osmotic stress. Our findings reveal an interplay between the role of TolC in ExPEC biofilm formation and the osmolarity of the surrounding environment, thus providing guidance for the development of a treatment for ExPEC biofilm formation.
PMCID: PMC4163439  PMID: 25243151
13.  Azvudine, A Novel Nucleoside Reverse Transcriptase Inhibitor Showed Good Drug Combination Features and Better Inhibition on Drug-Resistant Strains than Lamivudine In Vitro 
PLoS ONE  2014;9(8):e105617.
Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC50s ranging from 0.03 to 6.92 nM) and HIV-2 (EC50s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI-M184V at nanomolar range.
PMCID: PMC4140803  PMID: 25144636
14.  Refeeding syndrome in Southeastern Taiwan: Our experience with 11 cases 
World Journal of Gastroenterology : WJG  2014;20(30):10525-10530.
AIM: To present our experience with refeeding syndrome in southeastern Taiwan.
METHODS: We conducted a retrospective study during a 2-year period at the Mackay Memorial Hospital, Taitung Branch. We enrolled patients with very little or no nutrition intake for more than 10 d, a high risk group of refeeding syndrome, including those suffering from alcohol abuse, cancerous cachexia, chronic malnutrition, and prolonged starvation.
RESULTS: A total of 11 patients (7 males, 4 females) with nasogastric feeding were included as having refeeding syndrome. Most of them had the symptoms of diarrhea, lethargy, and leg edema. The initial nutritional supplement was found to be relatively high in calories (1355.1 ± 296.2 kcal/d), high in protein (47.3 ± 10.4 gm/d), low in vitamin B1 (2.0 ± 0.5 mg/d), low in potassium (1260.4 ± 297.7 mg/d), and low in phosphorus (660.1 ± 151.8 mg/d). Furthermore, hypophosphatemia (2.4 ± 0.9 mg/dL) was noted during follow-up. Based on the suggestions of a dietician and a gastroenterologist, the clinical disorders of diarrhea, malaise and leg edema were significantly improved. The level of phosphate was also increased (3.3 ± 0.6 mg/dL).
CONCLUSION: Refeeding syndrome is an overlooked and risky disorder that has some potentially fatal complications. Nasogastric feeding in nursing homes is an important risk factor for patients and deserves greater attention based on the initial results of this study.
PMCID: PMC4130862  PMID: 25132771
Refeeding syndrome; Nutrition status; Cachexia; Hypophosphatemia; Risk assessment
15.  Hepatocellular Carcinoma Presenting with Obstructive Jaundice during Pregnancy 
Case Reports in Surgery  2014;2014:502061.
Introduction. Both hepatocellular carcinoma (HCC) presenting during pregnancy and HCC presenting with obstructive jaundice due to a tumor cast in the biliary tract are very rare. The management of these patients remains challenging. Presentation of Case. A 23-year-old lady presented with obstructive jaundice at 38 weeks of gestation. Investigations showed HCC with a biliary tumor thrombus. She received percutaneous transhepatic biliary drainage (PTBD) and caesarean section. Right hepatectomy, extrahepatic bile duct resection, and left hepaticojejunostomy were carried out when the jaundice improved. The postoperative course was uneventful. She was discharged home on postoperative day 10. Histopathology showed HCC with a tumor thrombus in the bile duct. The surgical margins were clear. One year after surgery, the mother was disease-free and the baby was well. Conclusion. With proper management, curative treatment is possible in a pregnant patient who presented with obstructive jaundice due to a biliary tumor thrombus from HCC.
PMCID: PMC4139017  PMID: 25161794
16.  Early Contribution of Arterial Wave Reflection to Left Ventricular Relaxation Abnormalities in a Community-dwelling Population of Normotensive and Untreated Hypertensive Men and Women 
Journal of human hypertension  2013;28(2):85-91.
We examined the contribution of arterial wave reflection to early abnormalities in left ventricular relaxation, whether this association was modified by gender or hypertension, and the role of reflected wave timing and amplitude. We studied a cohort of normotensive and untreated essential hypertensive Taiwanese participants (675 men, 601 women, mean age 52 years). Doppler flow and applanation tonometry were performed to assess carotid-femoral pulse wave velocity (PWV) and augmentation index (AI). Diastolic parameters including transmitral E/A, E-deceleration time, and left atrial diameter were measured by echocardiography. In multivariate models predicting E/A, women were more likely to have lower E/A than men (β −0.08, p<.001). AI was significantly associated with lower E/A in both men (β −0.09, p=0.005) and women (β −0.12, p<.001) independent of PWV. Inclusion of AI in the overall model reduced the gender difference in E/A by 61% and rendered it non-significant. There was a significant interaction between AI and hypertension (p=0.02). The inverse association between AI and E/A was significant only in normotensive men and women, and only for the amplitude but not timing of the reflected wave. In conclusion, the contribution of wave reflection to left ventricular diastolic dysfunction was independent of arterial stiffness, more pronounced in normotensive individuals, and explained a significant portion of the gender difference in diastolic function.
PMCID: PMC3871982  PMID: 24048294
wave reflection; arterial stiffness; augmentation index; pulse wave velocity; diastolic function; hypertension
17.  Integrated Analysis Identifies Interaction Patterns between Small Molecules and Pathways 
BioMed Research International  2014;2014:931825.
Previous studies have indicated that the downstream proteins in a key pathway can be potential drug targets and that the pathway can play an important role in the action of drugs. So pathways could be considered as targets of small molecules. A link map between small molecules and pathways was constructed using gene expression profile, pathways, and gene expression of cancer cell line intervened by small molecules and then we analysed the topological characteristics of the link map. Three link patterns were identified based on different drug discovery implications for breast, liver, and lung cancer. Furthermore, molecules that significantly targeted the same pathways tended to treat the same diseases. These results can provide a valuable reference for identifying drug candidates and targets in molecularly targeted therapy.
PMCID: PMC4121214  PMID: 25114931
18.  MiR-195 affects cell migration and cell proliferation by down-regulating DIEXF in Hirschsprung’s Disease 
BMC Gastroenterology  2014;14:123.
Hirschsprung’s disease (HSCR) is the most common congenital gut motility disorder. We aimed to investigate the roles of miR-195 in the pathogenesis of HSCR.
In this study, we measured the expression levels of miRNA, mRNA, and protein in colon tissues from 78 patients with HSCR and 66 controls without HSCR. Transwell, Cell Counting Kit-8 (CCK-8) and flow cytometry assay were employed to detect the function role of miR-195 in vitro.
Our results showed that expression levels of miR-195 from patients with HSCR were significantly higher than control group; along with aberrant lower expression levels of digestive-organ expansion factor (DIEXF) were tested. Increased level of miR-195 could suppress the level of DIEXF in cell, which induced the impairment of cell migration and proliferation.
Aberrant expression of miR-195 may involved in the pathogenesis of HSCR by down-regulated the level of DIEXF.
PMCID: PMC4099404  PMID: 25007945
microRNA; Congenital diseases; Migration; Gastroenterology; HSCR
19.  A Prognostic Model of Triple-Negative Breast Cancer Based on miR-27b-3p and Node Status 
PLoS ONE  2014;9(6):e100664.
Triple-negative breast cancer (TNBC) is an aggressive but heterogeneous subtype of breast cancer. This study aimed to identify and validate a prognostic signature for TNBC patients to improve prognostic capability and to guide individualized treatment.
We retrospectively analyzed the prognostic performance of clinicopathological characteristics and miRNAs in a training set of 58 patients with invasive ductal TNBC diagnosed between 2002 and 2012. A prediction model was developed based on independent clinicopathological and miRNA covariates. The prognostic value of the model was further validated in a separate set of 41 TNBC patients diagnosed between 2007 and 2008.
Only lymph node status was marginally significantly associated with poor prognosis of TNBC (P = 0.054), whereas other clinicopathological factors, including age, tumor size, histological grade, lymphovascular invasion, P53 status, Ki-67 index, and type of surgery, were not. The expression levels of miR-27b-3p, miR-107, and miR-103a-3p were significantly elevated in the metastatic group compared with the disease-free group (P value: 0.008, 0.005, and 0.050, respectively). The Cox proportional hazards regression analysis revealed that lymph node status and miR-27b-3p were independent predictors of poor prognosis (P value: 0.012 and 0.027, respectively). A logistic regression model was developed based on these two independent covariates, and the prognostic value of the model was subsequently confirmed in a separate validation set. The two different risk groups, which were stratified according to the model, showed significant differences in the rates of distant metastasis and breast cancer-related death not only in the training set (P value: 0.001 and 0.040, respectively) but also in the validation set (P value: 0.013 and 0.012, respectively).
This model based on miRNA and node status covariates may be used to stratify TNBC patients into different prognostic subgroups for potentially individualized therapy.
PMCID: PMC4063964  PMID: 24945253
20.  RPA coordinates DNA end resection and prevents formation of DNA hairpins 
Molecular cell  2013;50(4):10.1016/j.molcel.2013.04.032.
Replication Protein A (RPA) is an essential eukaryotic single-stranded DNA binding protein with a central role in DNA metabolism. RPA directly participates in DNA double-strand break repair by stimulating 5’-3’ end resection by the Sgs1/BLM helicase and Dna2 endonuclease in vitro. Here we investigated the role of RPA in end resection in vivo, using a heat-inducible degron system that allows rapid conditional depletion of RPA in Saccharomyces cerevisiae. We found that RPA depletion eliminated both the Sgs1-Dna2 and Exo1-dependent extensive resection pathways, and synergized with mre11Δ to prevent end resection. The short single-stranded DNA tails formed in the absence of RPA were unstable due to 3’ strand loss and the formation of fold-back hairpin structures that required resection initiation and Pol32-dependent DNA synthesis. Thus, RPA is required to generate ssDNA, and also to protect ssDNA from degradation and inappropriate annealing that could lead to genome rearrangements.
PMCID: PMC3855855  PMID: 23706822
21.  Comparative Proteomic Analyses Provide New Insights into Low Phosphorus Stress Responses in Maize Leaves 
PLoS ONE  2014;9(5):e98215.
Phosphorus deficiency limits plant growth and development. To better understand the mechanisms behind how maize responds to phosphate stress, we compared the proteome analysis results of two groups of maize leaves that were treated separately with 1,000 µM (control, +P) and 5 µM of KH2PO4 (intervention group, −P) for 25 days. In total, 1,342 protein spots were detected on 2-DE maps and 15.43% had changed (P<0.05; ≥1.5-fold) significantly in quantity between the +P and −P groups. These proteins are involved in several major metabolic pathways, including photosynthesis, carbohydrate metabolism, energy metabolism, secondary metabolism, signal transduction, protein synthesis, cell rescue and cell defense and virulence. The results showed that the reduction in photosynthesis under low phosphorus treatment was due to the down-regulation of the proteins involved in CO2 enrichment, the Calvin cycle and the electron transport system. Electron transport and photosynthesis restrictions resulted in a large accumulation of peroxides. Maize has developed many different reactive oxygen species (ROS) scavenging mechanisms to cope with low phosphorus stress, including up-regulating its antioxidant content and antioxidase activity. After being subjected to phosphorus stress over a long period, maize may increase its internal phosphorus utilization efficiency by altering photorespiration, starch synthesis and lipid composition. These results provide important information about how maize responds to low phosphorus stress.
PMCID: PMC4032345  PMID: 24858307
22.  Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes 
Diabetes Care  2013;36(4):894-900.
Hypoglycemia is associated with serious health outcomes for patients treated for diabetes. However, the outcome of outpatients with type 2 diabetes who have experienced hypoglycemia episodes is largely unknown.
The study population, derived from the National Health Insurance Research Database released by the Taiwan National Health Research Institutes during 1998–2009, comprised 77,611 patients with newly diagnosed type 2 diabetes. We designed a prospective study consisting of randomly selected hypoglycemic type 2 diabetic patients and matched type 2 diabetic patients without hypoglycemia. We investigated the relationships of hypoglycemia with total mortality and cardiovascular events, including stroke, coronary heart disease, cardiovascular diseases, and all-cause hospitalization.
There were 1,844 hypoglycemic events (500 inpatients and 1,344 outpatients) among the 77,611 patients. Both mild (outpatient) and severe (inpatient) hypoglycemia cases had a higher percentage of comorbidities, including hypertension, renal diseases, cancer, stroke, and heart disease. In multivariate Cox regression models, including diabetes treatment adjustment, diabetic patients with hypoglycemia had a significantly higher risk of cardiovascular events during clinical treatment periods. After constructing a model adjusted with propensity scores, mild and severe hypoglycemia still demonstrated higher hazard ratios (HRs) for cardiovascular diseases (HR 2.09 [95% CI 1.63–2.67]), all-cause hospitalization (2.51 [2.00–3.16]), and total mortality (2.48 [1.41–4.38]).
Symptomatic hypoglycemia, whether clinically mild or severe, is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality. More attention may be needed for diabetic patients with hypoglycemic episodes.
PMCID: PMC3609481  PMID: 23223349
23.  FRET-Based System for Probing Protein-Protein Interactions between σR and RsrA from Streptomyces Coelicolor in Response to the Redox Environment 
PLoS ONE  2014;9(3):e92330.
Protein-protein interactions between sigma factor σR and its corresponding zinc-binding anti-sigma (ZAS) protein RsrA trigger the thioredoxin system for maintaining cellular redox homeostasis in S. coelicolor. RsrA bound to zinc associates with σR, inhibiting its transcriptional activity in a reducing environment. During disulfide stress it forms intramolecular disulfide bonds, leading to zinc release and dissociation from σR, which initiates transcription to produce reductase and thioredoxin. We designed a fluorescence resonance energy transfer (FRET) based system for monitoring protein-protein interactions between σR and RsrA to further understand how this redox switch regulates the thioredoxin system in S. coelicolor in response to its redox environment, especially various reactive oxygen species (ROS) derived from different metabolic pathways, and clarify the different response mechanisms between Zn-RsrA and apo-RsrA. By the use of the FRET approach described here, we showed that zinc protected thiols in RsrA and causes the σR-RsrA complex to form a more compact structure. This system was also utilized to detect changes in redox status induced by ROS and diamide in real time in E. coli cells.
PMCID: PMC3961337  PMID: 24651617
24.  The Effects of Needling Fenglong (ST40) and Neiguan (PC6) on IL-17 of ApoE-Gene-Knockout Mice's Liver 
The aim of the present paper was to observe the effects of needling ST40 and PC6 on IL-17 of ApoE−/− mice with fatty liver. Forty male ApoE−/− mice were randomized into Needling-Acupoint Group, Simvastatin Intragastric Administration Group, Needling Nonacupoint Group, and Model Group. Each was fed with high fat diet for 8 weeks since 16 weeks of age; after 8 weeks of intervention, mice were sacrificed and tested for various examinations. Result showed that the body weight, TC, and serum IL-17 in Needling-Acupoint Group decreased. Compared with Model Group, the immunohistochemical expressions of IL-17 in liver tissue were significantly decreased among the other three groups. In conclusion, acupuncture was able to lower the expression of IL-17 level both in serum and liver tissue in ApoE−/− mice, which is helpful to reduce the inflammation and defers the progress from fatty liver to cirrhosis.
PMCID: PMC3979069  PMID: 24778705
25.  Overcoming the chromatin barrier to end resection 
Cell Research  2012;23(3):317-319.
Repair of double-strand breaks by homologous recombination requires Repair of double-strand breaks by homologous recombination requires 5′-3′ resection of the DNA ends to create 3′ single-stranded DNA tails. While much progress has been made in identifying the proteins that directly participate in end resection, how this process occurs in the context of chromatin is not well understood. Two papers in Nature report that Fun30, a poorly characterized member of the Swi2/Snf2 family of chromatin remodelers, plays a role in end processing by facilitating the Exo1 and Sgs1-Dna2 resection pathways.
PMCID: PMC3587700  PMID: 23147792

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