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1.  Universal Stem-Loop Primer Method for Screening and Quantification of MicroRNA 
PLoS ONE  2014;9(12):e115293.
RT-qPCR is the accepted technique for the quantification of microRNA (miR) expression: however, stem-loop RT-PCR, the most frequently used method for quantification of miRs, is time- and reagent-consuming as well as inconvenient for scanning. We established a new method called ‘universal stem-loop primer’ (USLP) with 8 random nucleotides instead of a specific sequence at the 3′ end of the traditional stem-loop primer (TSLP), for screening miR profile and to semi-quantify expression of miRs. Peripheral blood samples were cultured with phytohaemagglutinin (PHA), and then 87 candidate miRs were scanned in cultured T cells. By USLP, our study revealed that the expression of miR-150-5p (miR-150) decreased nearly 10-fold, and miR-155-5p (miR-155) increased more than 7-fold after treated with PHA. The results of the dissociation curve and gel electrophoresis showed that the PCR production of the USLP and TSLP were specificity. The USLP method has high precision because of its low ICV (ICV<2.5%). The sensitivity of the USLP is up to 103 copies/µl miR. As compared with the TSLP, USLP saved 75% the cost of primers and 60% of the test time. The USLP method is a simple, rapid, precise, sensitive, and cost-effective approach that is suitable for screening miR profiles.
doi:10.1371/journal.pone.0115293
PMCID: PMC4280144  PMID: 25548906
2.  Simultaneous determination by UPLC-MS/MS of seven bioactive compounds in rat plasma after oral administration of Ginkgo biloba tablets: application to a pharmacokinetic study*  
A rapid, reliable, and sensitive method was developed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with an electrospray ionization (ESI) source for determination of seven bioactive compounds in rat plasma after oral administration of Ginkgo biloba tablets (GBTs). The method simultaneously detects bilobalide (BB), ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC), quercetin (QCT), kaempferol (KMF), and isorhamnetin (ISR) for pharmacokinetic study. The analytes and internal standard (IS) were extracted from rat plasma by acetidin. An MS/MS detection was conducted using multiple reaction monitoring (MRM) and operating in the negative ionization mode. The calibration curve ranges were 5–500, 5–500, 2.5–250, 1–100, 1–100, 1–100, and 1–100 ng/ml for BB, GA, GB, GC, QCT, KMF, and ISR, respectively. The mean recovery of the analytes ranged from 68.11% to 84.42%. The intra- and inter-day precisions were in the range of 2.33%–9.86% and the accuracies were between 87.67% and 108.37%. The method was used successfully in a pharmacokinetic study of GBTs. The pharmacokinetic parameters of seven compounds were analyzed using a non-compartment model. Plasma concentrations of the seven compounds were determined up to 48 h after administration, and their pharmacokinetic parameters were in agreement with previous studies.
doi:10.1631/jzus.B1400035
PMCID: PMC4228506  PMID: 25367786
Ginkgo biloba tablet; Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS); Pharmacokinetics
3.  Essential oil from Zanthoxylum bungeanum Maxim. and its main components used as transdermal penetration enhancers: a comparative study*  
Our previous studies had confirmed that the essential oil from Zanthoxylum bungeanum Maxim. (Z. bungeanum oil) could effectively enhance the percutaneous permeation of drug molecules as a natural transdermal penetration enhancer. The aim of the present study is to investigate and compare the skin penetration enhancement effect of Z. bungeanum oil and its main components on traditional Chinese medicine (TCM) active components. Toxicities of Z. bungeanum oil and three selected terpene compounds (terpinen-4-ol, 1,8-cineole, and limonene) in epidermal keratinocytes (HaCaT) and dermal fibroblast (CCC-ESF-1) cell lines were measured using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Five model drugs in TCM external preparations, namely osthole (OT), tetramethylpyrazine (TMP), ferulic acid (FA), puerarin (PR), and geniposide (GP), which were selected based on their lipophilicity denoted by logK o/w, were tested using in vitro permeation studies in which vertical Franz diffusion cells and rat abdominal skin were employed. The secondary structure changes of skin stratum corneum (SC) and drug thermodynamic activities were investigated to understand their mechanisms of action using Fourier transform infrared (FTIR) spectroscopy and saturation solubility studies, respectively. It was found that Z. bungeanum oil showed lower toxicities in both HaCaT cells and CCC-ESF-1 cells compared with three terpene compounds used alone. The enhancement permeation capacities by all tested agents were in the following increasing order: terpinen-4-ol≈1,8-cineole
doi:10.1631/jzus.B1400158
PMCID: PMC4228507  PMID: 25367787
Zanthoxylum bungeanum Maxim.; Essential oil; Limonene; Fourier transform infrared (FTIR) spectroscopy; Penetration enhancer; HaCaT
Ethnicity & disease  2013;23(3):310-315.
Objectives
This research examines the differences in estimated odds of developing diabetes mellitus for white, black, and Mexican-Americans age 51 and over for a period of 11 years.
Design, Setting, and Participants
Longitudinal data came from 14,783 respondents of the Health and Retirement Study (1995–2006) who report being diabetes-free at the first time period. Discrete-time survival models were used to analyze ethnic variations in the probability of developing diabetes.
Main Outcome Measure
Estimated odds of developing diabetes mellitus.
Results
The odds of newly diagnosed diabetes increased between 1995 and 2006, with 11% cumulative incidence for all study participants. The probability of incident diabetes among black Americans was 0.01 during the period of 1995/96–1998, which increased to 0.03 during 1998–2000 and remained at 0.03 throughout subsequent periods, with cumulative incidence over the 11 years at 12%. In contrast, for Mexican-Americans the probability more than doubled from 0.02 in 1995/96–1998 to 0.05 in 2004–2006, with cumulative incidence at 19%. White Americans had 11% cumulative incidence during the 11 year period.
Conclusions
Relative to white Americans, Mexican-Americans had significantly elevated odds of developing diabetes throughout the 11-year period of observation even after controlling for differences in demographic, socioeconomic, and time-varying health characteristics.
PMCID: PMC4106363  PMID: 23914416
Ethnic differences; diabetes mellitus incidence; discrete-time survival analysis
Ethnicity & disease  2012;22(2):175-180.
Objectives
This research examines the differences in estimated risk of developing hypertension in whites, blacks, and Mexican-Americans age 50 and over for a period of 11 years.
Design, Setting, and Participants
Data came from 9,259 respondents who reported being hypertension-free at the baseline in the Health and Retirement Study with up to five time intervals (1998-2006). Discrete-time survival models were used to analyze ethnic variations in the probability of developing hypertension.
Main Outcome Measure
Estimated odds of developing hypertension.
Results
The risk of newly diagnosed hypertension increased between 1995 and 2006 for HRS participants over age 50 years. After adjusting for demographic and health status, the probability of incident hypertension among black Americans was 0.10 during the period of 1995/96-1998, which increased steadily to 0.17 in 2004-2006, and cumulative incidence over the 11-year period at 51%. In contrast, among white Americans the risk was 0.07 during 1995/96-1998 and 0.13 in 2004-2006, with cumulative incidence at 43%. For Mexican-Americans, the probability also increased from 0.08 during 1995/96-1998 to 0.14 during 2004-2006, and cumulative incidence at 42%.
Conclusions
Relative to white and Mexican-Americans, black Americans had an elevated risk of incident hypertension throughout the 11-year period of observation. These variations persisted even when differences in health behaviors, socioeconomic status, demographic, and time-varying health characteristics are accounted for.
PMCID: PMC4084710  PMID: 22764639
Ethnic differences; hypertension incidence; discrete-time survival analysis
PLoS ONE  2014;9(7):e100416.
Background
Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model.
Methodology/Principal Findings
In order to address the difficulty of chemical modification of low abundant constituents in herb medicines, a novel one-pot combinatorial modification was used to diversify a partially purified tanshinone mixture from Salvia miltiorrhiza. This led to the isolation of ten new imidazole-tanshinones (Compounds 1–10) and one oxazole-tanshinone (Compound 11), the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. The angiogenesis activities of the new tanshinone derivatives were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested new derivatives, compound 10 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 µM. Moreover, the mechanism underlying the pro-angiogenesis effect of 10 probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signalling pathways by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors.
Conclusions/Significance
Taken together, our study demonstrated the more distinctive pro-angiogenic properties of 10 than other tanshinones and revealed 10 has potential for development as a pro-angiogenic agent for diseases associated with insufficient angiogenesis. Our results highlighted the great potential of adopting a newly modified one-pot approach to enhance the chemical diversity and biological activities of constituents from natural products regardless of their abundances.
doi:10.1371/journal.pone.0100416
PMCID: PMC4081027  PMID: 24992590
Introduction and hypothesis
This study describes pelvic organ support after childbirth.
Methods
This ancillary analysis of the Childbirth and Pelvic Symptoms Imaging Study compares pelvic organ prolapse quantification 6–12 months after childbirth among three cohorts of primiparous women: vaginal delivery with sphincter tear (n=106), vaginal delivery without sphincter tear (n=108), and cesarean without labor (n=39).
Results
Of participants, 31.2% had stage II support. Prolapse to or beyond the hymen was present in 14% after vaginal delivery with sphincter tear (95% confidence interval 8%, 22%), 15% (9%, 24%) after vaginal delivery without sphincter tear, and 5% (1%, 17%) after cesarean without labor (p=0.23). A study of 132 women per group would be required for 80% power to test differences between 5% and 15%.
Conclusions
While these data provide insufficient power to dismiss a difference in pelvic organ support between modes of delivery, they add to our understanding of support following childbirth.
doi:10.1007/s00192-009-0937-3
PMCID: PMC4064938  PMID: 19777148
Pelvic organ prolapse quantification; Uterine prolapse; Childbirth; Cesarean; Obstetrical anal sphincter laceration
Background
The long-term ingestion of alcohol diminishes hypothalamic–pituitary–adrenal (HPA) axis reactivity in alcohol-dependent men, potentially altering future relapse risk. Although sex differences in HPA axis functioning are apparent in healthy controls, disruptions in this system have received little attention in alcohol-dependent women. In this study, we assessed the basal secretory profile of adrenocorticotropic hormone (ACTH) and cortisol, adrenocortical sensitivity in both the presence and absence of endogenous corticotropic pituitary activation, and feedback pituitary glucocorticoid sensitivity to dexamethasone.
Methods
Seven women 4- to 8-week abstinent alcohol-only dependent subjects and 10 age-matched female healthy controls were studied. All subjects were between 30 and 50 years old, not taking oral contraceptives, and were studied during the early follicular phase of their menstrual cycle. Circulating concentrations of ACTH and cortisol were measured in blood samples collected at frequent intervals from 2000 to 0800 hour. A submaximal dose of cosyntropin (0.01 μg/kg), a synthetic ACTH (1–24), was administered at 0800 hour to assess adrenocortical sensitivity. In a separate session, low-dose cosyntropin was also administered following high-dose dexamethasone (8 mg intravenous) to assess adrenocortical sensitivity in the relative absence of endogenous ACTH. In addition, the ACTH response to dexamethasone was measured to determine the pituitary glucocorticoid negative feedback. Sessions were 5 days apart, and blood draws were obtained every 5 to 10 minutes.
Results
Mean concentrations and pulsatile characteristics of ACTH and cortisol over 12 hours were not statistically different between the 2 groups. Healthy controls had a somewhat higher (p < 0.08) net peak, but not net integrated, cortisol response to cosyntropin relative to the alcohol-dependent women. There were no significant group differences in either the ACTH or cortisol response to dexamethasone nor in the net cortisol response to cosyntropin following dexamethasone.
Conclusion
Significant differences in pituitary–adrenal function were not apparent between alcohol-dependent women and matched controls. Despite the small n, it appears that alcohol-dependent women do not show the same disruptions in HPA activity as alcohol-dependent men. These findings may have relevance for gender-specific treatment effectiveness.
doi:10.1111/j.1530-0277.2010.01164.x
PMCID: PMC4038906  PMID: 20331575
Adrenal Cortex; Alcoholism; Cosyntropin; Dexamethasone; Pituitary-Adrenal System; Gender; Female
Neurogenic bladder is a common complication of spinal cord injury and results in urinary bladder dysfunction through lost control of micturition, or urination. Although several treatment options exist, the efficacies of many of these treatments are unknown. In particular, electroacupuncture and bladder training have had some success as individual treatments. The aim of this study was to explore effects of electroacupuncture combined with bladder training on bladder function of patients with neurogenic bladder after spinal cord injury (SCI) above the sacral segment. Forty-two patients with neurogenic bladder after SCI were evenly divided into two groups (n=21) and given only bladder function training (control group) or electroacupuncture combined with bladder function training (treatment group). Urodynamic changes, IPSS score, and therapeutic efficacy were compared between groups pre- and post-treatment. After either treatment, patients had higher bladder volume and bladder compliance, but lower residual urine volume, bladder pressure, rectal pressure, and detrusor pressure, compared to pre-treatment (P<0.05). Compared to controls, treatment group patients had significantly increased bladder volume and bladder compliance, but significantly decreased residual urine volume, bladder pressure, rectal pressure, and detrusor pressure (P<0.05). Treatment group patients had lower IPSS scores post-treatment (P<0.05) and better therapeutic efficacy (P<0.05) than control group patients. Altogether, our results suggest that electroacupuncture combined with bladder function training can clinically improve bladder function of patients with neurogenic bladder after SCI above the sacral segment.
PMCID: PMC4073754  PMID: 24995093
Bladder function; spinal cord injury; neurogenic bladder; electroacupuncture
PLoS ONE  2014;9(3):e90664.
Objectives
This study was conducted to generate knowledge useful for developing public health interventions for more effective tuberculosis control in Arkansas.
Methods
The study population included 429 culture-confirmed reported cases (January 1, 2004–December 31, 2010). Mycobacterium tuberculosis genotyping data were used to identify cases likely due to recent transmission (clustered) versus reactivation (non-clustered). Poisson regression models estimated average decline rate in incidence over time and assessed the significance of differences between subpopulations. A multinomial logistic model examined differences between clustered and non-clustered incidence.
Results
A significant average annual percent decline was found for the overall incidence of culture-confirmed (9%; 95% CI: 5.5%, 16.9%), clustered (6%; 95% CI: 0.5%, 11.6%), and non-clustered tuberculosis cases (12%; 95% CI: 7.6%, 15.9%). However, declines varied among demographic groups. Significant declines in clustered incidence were only observed in males, non-Hispanic blacks, 65 years and older, and the rural population.
Conclusions
These findings suggest that the Arkansas tuberculosis control program must target both traditional and non-traditional risk groups for successful tuberculosis elimination. The present study also demonstrates that a thorough analysis of TB trends in different population subgroups of a given geographic region or state can lead to the identification of non-traditional risk factors for TB transmission. Similar studies in other low incidence populations would provide beneficial data for how to control and eventually eliminate TB in the U.S.
doi:10.1371/journal.pone.0090664
PMCID: PMC3949677  PMID: 24618839
The aim of this present study is to investigate the effect of Zanthoxylum bungeanum oil (essential oil from Z. bungeanum Maxim.) on cytotoxicity and the transdermal permeation of 5-fluorouracil and indomethacin. The cytotoxicity of Z. bungeanum oil on dermal fibroblasts and epidermal keratinocytes was studied using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The rat skin was employed to determine the percutaneous penetration enhancement effect of Z. bungeanum oil on hydrophilic and lipophilic model drugs, i.e., 5-fluorouracil and indomethacin. The secondary structure changes of the rat stratum corneum (SC) were determined using attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), and saturated solubilities and SC/vehicle partition coefficients of two model drugs with and without Z. bungeanum oil were also measured to understand its related mechanisms of action. It was found that the half maximal inhibitory concentration (IC50) values of Z. bungeanum oil were significantly lower in HaCaT and CCC-ESF-1 cell lines compared to the well-established and standard penetration enhancer Azone. The Z. bungeanum oil at various concentrations effectively facilitated the percutaneous penetration of two model drugs across the rat skin. In addition, the mechanisms of permeation enhancement by Z. bungeanum oil could be explained with saturated solubility, SC/vehicle partition coefficient, and secondary structure changes of SC.
doi:10.1631/jzus.B1300230
PMCID: PMC3924391  PMID: 24510708
Zanthoxylum bungeanum Maxim.; Essential oil; Transdermal delivery; Penetration enhancer; HaCaT; Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR)
Hepatology (Baltimore, Md.)  2007;46(5):10.1002/hep.21923.
Malnutrition is a significant clinical problem in infants with biliary atresia. The natural history of poor growth and its potential association with early transplantation or death in children with biliary atresia was determined. Serial weight- and length-for-age z-scores were computed as part of a retrospective study of 100 infants who underwent hepatoportoenterostomy (HPE) for biliary atresia at 9 U.S. pediatric centers between 1997 and 2000. Poor outcome was defined as transplantation or death by 24 months of age (n = 46) and good outcome was defined as survival with native liver at 24 months of age with total serum bilirubin less than 6 mg/dL (n = 54). Growth velocity was significantly slower in the poor outcome group compared to the good outcome group (P < 0.001 for both weight and length). Mean weight z-scores were significantly lower by 6 months after HPE in the poor outcome group (−2.1 ± 1.4) compared to the good outcome group (−1.2 ± 1.4) (P < 0.001). In a subgroup with total bilirubin between 2 and 6 mg/dL at 3 months after HPE (n = 28), the weight z-scores at 3 months after HPE were significantly lower in the poor outcome group (−2.0 ± 1.2) compared to the good outcome group (−1.0 ± 1.2) (P = 0.04) despite similar bilirubin concentrations.
Conclusion
Growth failure after HPE was associated with transplantation or death by 24 months of age. The combination of intermediate bilirubin concentrations and poor mean weight z-scores 3 months after HPE was also associated with poor clinical outcome.
doi:10.1002/hep.21923
PMCID: PMC3881187  PMID: 17929308
Objective
To develop and test a unique, new pelvic floor surgery complication scale and compare it to an existing validated measure.
Study Design
Surgeons from two clinical trials networks rated complications based on perceived patient bother, severity, and duration of disability to develop a pelvic floor complication scale (PFCS). PFCS scores were calculated for subjects in two multicenter pelvic floor surgical trials. The PFCS and modified Clavien-Dindo scores were evaluated for associations with length of hospitalization(LOH), satisfaction, and quality-of-life (QoL) measures {Health Utilities Index(HUI), Short Form-36(SF-36), Urogenital Distress Inventory(UDI) and Incontinence Impact Questionnaire(IIQ)}.
Results
We calculated PFCS scores for 977 subjects. Higher PFCS and Clavien-Dindo scores were similarly associated with longer LOH (p<0.01), lower satisfaction (p<0.01); lower HUI (p=0.02), lower SF-36 (p=0.02), higher UDI (p<0.01) and IIQ (p<0.01) scores at 3 months. No associations were present at 1 year.
Conclusion
The PFCS compares favorably to the validated modified Clavien-Dindo instrument.
doi:10.1016/j.ajog.2012.10.889
PMCID: PMC3568397  PMID: 23131463
Complications; Reconstructive Pelvic Surgery; Urogynecology; Surgical Outcomes; Quality-of-life measures; Clavien-Dindo
Molecular Vision  2014;20:1557-1568.
Purpose
Exendin-4 (E4), a long-acting agonist of the hormone glucagon-like peptide 1 receptor (GLP-1R), is administered to treat type II diabetes in the clinical setting and also shows a neuroprotective effect. Our previous studies demonstrated its protective effect in early experimental diabetic retinopathy (DR), but the molecular and cellular mechanisms are largely unknown. This study aimed to investigate the protective mechanism of a GLP-1R agonist E4 against early DR in Goto-Kakizaki (GK) rats.
Methods
Diabetic GK rats and control animals were randomly assigned to receive E4 or vehicle by intravitreal injection. The retinal function and retinal cell counts were evaluated using an electroretinogram and light microscopy. The expressions of retinal GLP-1R, mitochondria-dependent apoptosis-associated genes, reactive gliosis markers, and endoplasmic reticulum stress-related pathway genes were studied by western blotting and immunohistochemistry in vivo and in vitro.
Results
E4 significantly prevented the reduction of the b-wave and oscillatory potential amplitudes and retinal cell loss and maintained the Bcl-2/Bax and Bcl-xL/Bax ratio balances in GK rats. It also downregulated the expression of glial fibrillary acidic protein and reduced retinal reactive gliosis. Similar results were found in primary rat Müller cells under high glucose culture in vitro.
Conclusions
E4 may protect retinal cells from diabetic attacks by activating GLP-1R, decreasing retinal cell apoptosis, and reducing retinal reactive gliosis. Thus, E4 treatment may be a novel approach for early DR.
PMCID: PMC4225140  PMID: 25489228
Chinese Medicine  2013;8:19.
Background
This study aims to isolate the α-glucosidase inhibitory compounds from mulberry leaves (Morus atropurpurea Roxb., Moraceae) and to develop an analytical method for quantification of the compounds.
Methods
Four flavonoids, rutin (1), isoquercetin (2), kaempferol-3-O-rutinoside (3) and astragalin (4), were isolated by column chromatography from mulberry leaf water extracts (MWE). The α-glucosidase inhibitory activities of MWE and the four isolated compounds were evaluated by a microplate-based in vitro assay. The content of the isolated flavonoids in M. atropurpurea leaves purchased from different local herbal stores or collected in different locations was determined by high performance liquid chromatography.
Results
The four flavonoids (1–4) showed α-glucosidase inhibitory activities, with rutin (1) and astragalin (4) showing high α-glucosidase inhibitory activities (IC50 values of 13.19 ± 1.10 and 15.82 ± 1.11 μM, respectively). The total contents of the four flavonoids were different among eight samples examined, ranging from 4.34 mg/g to 0.53 mg/g.
Conclusions
The four flavonoids in M. atropurpurea leaves could inhibit α-glucosidase activity.
doi:10.1186/1749-8546-8-19
PMCID: PMC4016240  PMID: 24125526
PLoS ONE  2013;8(9):e74573.
Natural products are frequently used for adjuvant chemotherapy in cancer treatment. 23-O-(1,4'-bipiperidine-1-carbonyl) betulinic acid (BBA) is a synthetic derivative of 23-hydroxybutulinic acid (23-HBA), which is a natural pentacyclic triterpene and the major active constituent of the root of Pulsatillachinensis. We previously reported that BBA could reverse P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR). In the present study, we investigated whether BBA has the potential to reverse multidrug resistance protein 7 (MRP7/ABCC10)-mediated MDR. We found that BBA concentration-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine. Accumulation and efflux experiments demonstrated that BBA increased the intracellular accumulation of [3H]-paclitaxel by inhibiting the efflux of [3H]-paclitaxel from HEK293/MRP7 cells. In addition, immunoblotting and immunofluorescence analyses indicated no significant alteration of MRP7 protein expression and localization in plasma membranes after treatment with BBA. These results demonstrate that BBA reverses MRP7-mediated MDR through blocking the drug efflux function of MRP7 without affecting the intracellular ATP levels. Our findings suggest that BBA has the potential to be used in combination with conventional chemotherapeutic agents to augment the response to chemotherapy.
doi:10.1371/journal.pone.0074573
PMCID: PMC3775757  PMID: 24069321
Cell Research  2012;22(9):1328-1338.
Interferon-stimulated gene 56 (ISG56) family members play important roles in blocking viral replication and regulating cellular functions, however, their underlying molecular mechanisms are largely unclear. Here, we present the crystal structure of ISG54, an ISG56 family protein with a novel RNA-binding structure. The structure shows that ISG54 monomers have 9 tetratricopeptide repeat-like motifs and associate to form domain-swapped dimers. The C-terminal part folds into a super-helical structure and has an extensively positively-charged nucleotide-binding channel on its inner surface. EMSA results show that ISG54 binds specifically to some RNAs, such as adenylate uridylate (AU)-rich RNAs, with or without 5′ triphosphorylation. Mutagenesis and functional studies show that this RNA-binding ability is important to its antiviral activity. Our results suggest a new mechanism underlying the antiviral activity of this interferon-inducible gene 56 family member.
doi:10.1038/cr.2012.111
PMCID: PMC3434343  PMID: 22825553
structure biology; ISG54
PLoS ONE  2013;8(8):e72099.
Podophyllotoxin (POD) is a lignan-type toxin existing in many herbs used in folk medicine. Until now, no effective strategy is available for the management of POD intoxication. This study aims to determine the protective effects of flavonoids (quercetin and kaempferol) on POD-induced toxicity. In Vero cells, both flavonoids protected POD-induced cytotoxicity by recovering alleviating G2/M arrest, decreasing ROS generation and changes of membrane potential, and recovering microtubule structure. In Swiss mice, the group given both POD and flavonoids group had significantly lower mortality rate and showed less damages in the liver and kidney than the group given POD alone. As compared to the POD group, the POD plus flavonoids group exhibited decreases in plasma transaminases, alkaline phosphatase, lactate dehydrogenase, plasma urea, creatinine and malondialdehyde levels, and increases in superoxide dismutase and glutathione levels. Histological examination of the liver and kidney showed less pathological changes in the treatment of POD plus flavonoids group. The protective mechanisms were due to the antioxidant activity of flavonoids against the oxidative stress induced by POD and the competitive binding of flavonoids against POD for the same colchicines-binding sites. The latter binding was confirmed by the tubulin assembly assay in combination with molecular docking analyses. In conclusion, this study for the first time demonstrated that the coexisting flavonoids have great protective effects against the POD toxicity, and results of this study highlighted the great potential of searching for effective antidotes against toxins based on the pharmacological clues.
doi:10.1371/journal.pone.0072099
PMCID: PMC3749096  PMID: 23991049
Objective
The Activities Assessment Scale (AAS) is a 13-item postoperative functional activity scale validated in men undergoing hernia surgery. We evaluated the psychometric characteristics of the AAS in women undergoing vaginal surgery for prolapse (POP) and stress incontinence (SUI).
Methods
Participants included 163 women with POP and SUI enrolled in a randomized trial comparing sacrospinous ligament fixation to uterosacral vault suspension with and without perioperative pelvic floor muscle training. Participants completed the AAS and SF-36 at baseline and 2-weeks and 6-months post-operatively. Internal reliability of the AAS was evaluated using Cronbach’s alpha. Construct validity and responsiveness were examined in cross-sectional and longitudinal data using Pearson’s correlation coefficient and ANOVA. The AAS is scored from 0–100 (higher scores = better function).
Results
Mean baseline AAS score was 87± 17.3 (range 25 to 100). Functional activity declined from baseline to 2-weeks post-operatively (mean change −4.5; 95% CI −7.6 to −1.42) but improved above baseline at 6-months (mean change +10.9; 95% CI 7.8 to 14.0). Internal reliability of the AAS was excellent (Cronbach’s Alpha = 0.93). Construct validity was demonstrated by a correlation of 0.59–0.60 between the AAS and SF-36 Physical Functioning Scale (p<0.0001) and lower correlations between the AAS and other SF-36 scales. Patients who improved in physical functioning based on the SF-36 between 2-weeks and 6-months postoperatively showed an effect size of 0.86 for change in the AAS over the same time period.
Conclusions
The AAS is a valid, reliable and responsive measure for evaluation of physical function in women after pelvic reconstructive surgery.
doi:10.1097/SPV.0b013e31825e6422
PMCID: PMC3666046  PMID: 22777368
Functional Activity; Postoperative Activity; Scales; Pelvic Reconstructive Surgery; Pelvic Organ Prolapse
Objective
Surgical Pain Scales (SPS) consist of 4 items that measure pain at rest, during normal activities, during work/exercise and quantify unpleasantness of worst pain, which are valid and responsive in men undergoing hernia repair. Our objective was to evaluate the psychometric properties of SPS in women undergoing vaginal surgery for pelvic organ prolapse (POP) and stress urinary incontinence (SUI).
Methods
We modified SPS by converting original response scales from a visual analog scale (VAS) to Numerical Rating Scales (NRS). NRS have lower error rates and higher validity than VAS. The sample included 169 women with stage II–IV POP and SUI in a randomized trial comparing sacrospinous ligament fixation to uterosacral vault suspension with and without pelvic floor muscle training. Participants completed SPS and SF-36 at baseline, 2-weeks and 6-months after surgery. Construct validity and responsiveness were examined in cross-sectional and longitudinal data using Pearson’s correlation and ANOVA.
Results
Pain at rest, during normal activities and during work/exercise worsened at 2-weeks (p<0.05) and all measures of pain improved from baseline to 6 months (p<0.0001). Construct validity was demonstrated by correlations of .51–.74 between SPS and the SF-36 Bodily Pain Scale (p<0.0001). Pain worsened on SF-36 between baseline and 2-weeks in 63% of participants and this group demonstrated a mean increase in pain of 1.9 (SD 2.8) on the SPS (effect size 0.99) confirming responsiveness of the scale.
Conclusions
The modified Surgical Pain Scales are valid and responsive in women after pelvic reconstructive surgery.
doi:10.1097/SPV.0b013e31825d65aa
PMCID: PMC3677159  PMID: 22777367
Postoperative Pain; Scales; Pelvic Reconstructive Surgery; Pelvic Organ Prolapse
Scientific Reports  2013;3:2104.
Secondary metabolites are compounds that are important for the survival and propagation of animals and plants. Our current understanding on the roles and secretion mechanism of secondary metabolites is limited by the existing techniques that typically cannot provide transient and dynamic information about the metabolic processes. In this manuscript, by detecting venoms secreted by living scorpion and toad upon attack and variation of alkaloids in living Catharanthus roseus upon stimulation, which represent three different sampling methods for living organisms, we demonstrated that in vivo and real-time monitoring of secondary metabolites released from living animals and plants could be readily achieved by using field-induced direct ionization mass spectrometry.
doi:10.1038/srep02104
PMCID: PMC3696899  PMID: 23811725
With the increasing burden of chronic diseases on the health care system, Markov-type models are becoming popular to predict the long-term outcomes of early intervention and to guide disease management. However, statisticians have not been actively involved in the development of these models. Typically, the models are developed by using secondary data analysis to find a single “best” study to estimate each transition in the model. However, due to the nature of secondary data analysis, there frequently are discrepancies between the theoretical model and the design of the studies being used. This paper illustrates a likelihood approach to correctly model the design of clinical studies under the conditions where 1) the theoretical model may include an instantaneous state of distinct interest to the researchers, and 2) the study design may be such that study data can not be used to estimate a single parameter in the theoretical model of interest. For example, a study may ignore intermediary stages of disease. Using our approach, not only can we accommodate the two conditions above, but more than one study may be used to estimate model parameters. In the spirit of “If life gives you lemon, make lemonade”, we call this method “Lemonade Method”. Simulation studies are carried out to evaluate the finite sample property of this method. In addition, the method is demonstrated through application to a model of heart disease in diabetes.
doi:10.1016/j.inffus.2010.08.003
PMCID: PMC3341173  PMID: 22563307
diabetes; disease modeling; chronic disease; designed absorption; multi-state model; meta-analysis
Fertility and Sterility  2012;97(3):748-756.
Objective
To investigate the impact of prenatal testosterone excess on the expression of key ovarian regulators implicated in follicular recruitment and persistence using a large animal model of polycystic ovarian syndrome.
Design
Interventional, animal model study.
Setting
Academic research unit.
Animals
25 female fetuses, 14 prepubertal female, and 24 adult female Suffolk sheep.
Interventions
Prenatal testosterone treatment.
Main outcome measures
Immunohistochemical determination of expression of antimullerian hormone (AMH), kit-ligand, and growth differentiation factor 9 (GDF9) in fetal, prepubertal, and adult ovarian tissues.
Results
Prenatal testosterone treatment reduced the AMH protein expression in granulosa cells of preantral follicles and increased its expression in antral follicles compared to age-matched adult controls. These differences were not evident in prepubertal animals. Protein expression of GDF9 and kit-ligand was not altered at any of the developmental time points studied.
Conclusion
Prenatal testosterone exposure is associated with changes in AMH expression in preantral and antral follicles in adult ovaries, similar to findings in PCOS women. These findings indicate that abnormal folliculogenesis in PCOS may be at least in part mediated by changes in AMH expression.
doi:10.1016/j.fertnstert.2011.12.028
PMCID: PMC3292625  PMID: 22245531
PCOS; ovary; folliculogenesis; follicular recruitment; follicular persistence
Purpose: Abnormal growth of vertebral body growth plate (VBGP) is considered as one of the etiologic factors in the adolescent idiopathic scoliosis (AIS). It was well-known that melatonin was correlated with the emergence and development of AIS. This study aimed to investigate the effect of melatonin on rat VBGP chondrocytes in vitro.
Methods:Chondrocytes were isolated from rat VBGP, and treated with or without melatonin. Cell proliferation was measured by the Alamar Blue assay. Gene expression of collagen type II and aggrecan were evaluated by real-time PCR. Expression of the melatonin receptors (MT1, MT2), proliferating cell nuclear antigen (PCNA, a cell proliferation marker), Sox9 (a chondrocytic differentiation marker) and Smad4 (a common mediator in regulating the proliferation and differentiation of chondrocytes) were detected by Western blotting.
Results: Expression of melatonin receptors (MT1, MT2) were detected in the rat VBGP chondrocytes. Melatonin, at 10 and 100 µg/mL concentration, significantly inhibited the proliferation of VBGP-chondrocytes and the gene expression of collagen type II and aggrecan, and down-regulated the protein expression of PCNA, Sox9 and Smad4. In addition, the inhibitory effect of melatonin was reversed by luzindole, a melatonin receptor antagonist.
Conclusions: These results suggest that melatonin at high concentrations can inhibit the proliferation and differentiation of VBGP chondrocytes, which might give some new insight into the pathogenic mechanism of AIS.
doi:10.7150/ijms.5645
PMCID: PMC3752726  PMID: 23983601
melatonin; vertebral body growth plate; adolescent idiopathic scoliosis; proliferating cell nuclear antigen; Sox9; Smad4.
Psychology and aging  2011;26(4):761-777.
This research aims to identify distinct courses of depressive symptoms among middle aged and older Americans and to ascertain how these courses vary by race/ethnicity. Data came from the 1995-2006 Health and Retirement Study which involved a national sample of 17,196 Americans over 50 years of age with up to six repeated observations. Depressive symptoms were measured by an abbreviated version of the Center for Epidemiologic Studies Depression scale. Semi parametric group based mixture models (Proc Traj) were used for data analysis. Six major trajectories were identified: (a) minimal depressive symptoms (15.9%), (b) low depressive symptoms (36.3%), (c) moderate and stable depressive symptoms (29.2%), (d) high but decreasing depressive symptoms (6.6%), (e) moderate but increasing depressive symptoms (8.3%), and (f) persistently high depressive symptoms (3.6%). Adjustment of time-varying covariates (e.g., income and health conditions) resulted in a similar set of distinct trajectories. Relative to white Americans, black and Hispanic Americans were significantly more likely to be in trajectories of more elevated depressive symptoms. In addition, they were more likely to experience increasing and decreasing depressive symptoms. Racial and ethnic variations in trajectory groups were partially mediated by SES, marital status, and health conditions, particularly when both interpersonal and intrapersonal differences in these variables were taken into account.
doi:10.1037/a0023945
PMCID: PMC3495237  PMID: 21875216
Depressive Symptoms; Trajectory; Racial/Ethnic Difference; Hispanic

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