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1.  Determining Electrical Properties Based on B1 Fields Measured in an MR Scanner Using a Multi-channel Transmit/Receive Coil: a General Approach 
Physics in medicine and biology  2013;58(13):4395-4408.
Electrical Property Tomography (EPT) is a recently developed noninvasive technology to image the electrical conductivity and permittivity of biological tissues at Larmor frequency in Magnetic Resonance (MR) scanners. The absolute phase of the complex radio-frequency (RF) magnetic field (B1) is necessary for electrical property calculation. However, due to the lack of practical methods to directly measure the absolute B1 phases, current EPT techniques have been achieved with B1 phase estimation based on certain assumptions on object anatomy, coil structure and/or electromagnetic wave behavior associated with the main magnetic field, limiting EPT from a larger variety of applications. In this study, using a multi-channel transmit/receive coil, the framework of a new general approach for EPT has been introduced, which is independent on the assumptions utilized in previous studies. Using a human head model with realistic geometry, a series of computer simulations at 7T were conducted to evaluate the proposed method under different noise levels. Results showed that the proposed method can be used to reconstruct the conductivity and permittivity images with noticeable accuracy and stability. The feasibility of this approach was further evaluated in a phantom experiment at 7T.
doi:10.1088/0031-9155/58/13/4395
PMCID: PMC3770135  PMID: 23743673
2.  Endocrine Control of Embryonic Diapause in the Australian Sharpnose Shark Rhizoprionodon taylori 
PLoS ONE  2014;9(7):e101234.
The reproductive cycle of the Australian sharpnose shark, Rhizoprionodon taylori, includes a temporary suspension of development at the commencement of embryogenesis termed embryonic diapause. This study investigated levels of 17β-estradiol (E2), testosterone (T) and progesterone (P4) in plasma samples of mature wild female R. taylori captured throughout the reproductive cycle and correlated them with internal morphological changes. Levels of T were elevated through most of the embryonic diapause period, suggesting a role of this hormone in the maintenance of this condition. Increasing plasma T concentrations from late diapause to early active development were associated with a possible role of androgens in the termination of embryonic diapause. As in other elasmobranchs, a concomitant increase of E2 with ovarian follicle size indicated a direct role of this hormone in regulating vitellogenesis, while a peak in P4 suggested this hormone is associated with preovulation and ovulation. Additionally, significant correlations between photoperiod or water temperature and maximum follicular diameter and hepatosomatic index suggest that these abiotic factors may also play a role triggering and regulating the synchrony and timing of reproductive events.
doi:10.1371/journal.pone.0101234
PMCID: PMC4081646  PMID: 24992673
3.  An epigenomic approach to therapy for tamoxifen-resistant breast cancer 
Cell Research  2014;24(7):809-819.
Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer.
doi:10.1038/cr.2014.71
PMCID: PMC4085766  PMID: 24874954
epigenomic; tamoxifen; breast cancer
4.  Two Adjacent and Similar TetR Family Transcriptional Regulator Genes, SAV577 and SAV576, Co-Regulate Avermectin Production in Streptomyces avermitilis 
PLoS ONE  2014;9(6):e99224.
Streptomyces avermitilis is an important bacterial species used for industrial production of avermectins, a family of broad-spectrum anthelmintic agents. We previously identified the protein SAV576, a TetR family transcriptional regulator (TFR), as a downregulator of avermectin biosynthesis that acts by controlling transcription of its major target gene SAV575 (which encodes cytochrome P450/NADPH-ferrihemoprotein reductase) and ave genes. SAV577, another TFR gene, encodes a SAV577 protein that displays high amino acid homology with SAV576. In this study, we examined the effect of SAV577 on avermectin production and the relationships between SAV576 and SAV577. SAV577 downregulated avermectin biosynthesis indirectly, similarly to SAV576. SAV576 and SAV577 both directly repressed SAV575 transcription, and reciprocally repressed each other's expression. SAV575 transcription levels in various S. avermitilis strains were correlated with avermectin production levels. DNase I footprinting and electrophoretic mobility shift assays indicated that SAV576 and SAV577 compete for the same binding regions, and that DNA-binding affinity of SAV576 is much stronger than that of SAV577. GST pull-down assays revealed no direct interaction between the two proteins. Taken together, these findings suggest that SAV577 regulates avermectin production in S. avermitilis by a mechanism similar to that of SAV576, and that the role of SAV576 is dominant over that of SAV577. This is the first report of two adjacent and similar TFR genes that co-regulate antibiotic production in Streptomyces.
doi:10.1371/journal.pone.0099224
PMCID: PMC4051647  PMID: 24915523
5.  Usefulness of Ventricular Endocardial Electric Reconstruction from Body Surface Potential Maps to Noninvasively Localize Ventricular Ectopic Activity in Patients 
Physics in medicine and biology  2013;58(11):3897-3909.
As radio frequency (RF) catheter ablation becomes increasingly prevalent in the management of ventricular arrhythmia in patients, an accurate and rapid determination of the arrhythmogenic site is of important clinical interest. The aim of this study was to test the hypothesis that the inversely reconstructed ventricular endocardial current density distribution from body surface potential maps (BSPMs) can localize the regions critical for maintenance of a ventricular ectopic activity. Patients with isolated and monomorphic premature ventricular contractions (PVCs) were investigated by noninvasive BSPMs and subsequent invasive catheter mapping and ablation. Equivalent current density (CD) reconstruction (CDR) during symptomatic PVCs was obtained on the endocardial ventricular surface in 6 patients (4 men, 2 women, years 23–77), and the origin of the spontaneous ectopic activity was localized at the location of the maximum CD value. Compared with the last (successful) ablation site (LAS), the mean and standard deviation of localization error of the CDR approach were 13.8 mm and 1.3 mm, respectively. In comparison, the distance between the LASs and the estimated locations of an equivalent single moving dipole (SMD) in the heart was 25.5 ± 5.5 mm. The obtained CD distribution of activated sources extending from the catheter ablation site also showed a high consistency with the invasively recorded electroanatomical maps. The noninvasively reconstructed endocardial CD distribution is suitable to predict a region of interest containing or close to arrhythmia source, which may have the potential to guide RF catheter ablation.
doi:10.1088/0031-9155/58/11/3897
PMCID: PMC3776132  PMID: 23681281
electrocardiographic inverse problem; current density reconstruction; radio frequency catheter ablation; premature ventricular contraction; body surface potential mapping
6.  Perturbing the Cellular Levels of Steroid Receptor Coactivator-2 Impairs Murine Endometrial Function 
PLoS ONE  2014;9(6):e98664.
As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes. Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality. Accordingly, an unwarranted increase in the cellular levels of SRC members has been causally linked to the initiation and/or progression of a number of clinical disorders. Although knockout mouse models have underscored the critical non-redundant roles for each SRC member in vivo, there are surprisingly few mouse models that have been engineered to overexpress SRCs. This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression. To address this deficiency, we used recent mouse technology that allows for the targeted expression of human SRC-2 in cells which express the progesterone receptor. Through cre-loxP recombination driven by the endogenous progesterone receptor promoter, a marked elevation in expression levels of human SRC-2 was achieved in endometrial cells that are positive for the progesterone receptor. As a result of this increase in coregulator expression, female mice are severely subfertile due to a dysfunctional uterus, which exhibits a hypersensitivity to estrogen exposure. Our findings strongly support the proposal from clinical observations that increased levels of SRC-2 are causal for a number of endometrial disorders which compromise fertility. Future studies will use this mouse model to decipher the molecular mechanisms that underpin the endometrial defect. We believe such mechanistic insight may provide new molecular descriptors for diagnosis, prognosis, and/or therapy in the clinical management of female infertility.
doi:10.1371/journal.pone.0098664
PMCID: PMC4048228  PMID: 24905738
7.  A Normal Reference of Bone Mineral Density (BMD) Measured by Dual Energy X-Ray Absorptiometry in Healthy Thai Children and Adolescents Aged 5–18 Years: A New Reference for Southeast Asian Populations 
PLoS ONE  2014;9(5):e97218.
Ethnic-specific normative data of bone mineral density (BMD) is essential for the accurate interpretation of BMD measurement. There have been previous reports of normative BMD data for Caucasian and Asian children including Japanese, Chinese, Korean and Indian. However, the normative BMD data for Southeast Asian including Thai children and adolescents are not currently available. The goals of our study were 1) to establish normative data of BMD, bone mineral content (BMC), bone area (BA) and lean body mass (LBM) for healthy Thai children and adolescents; aged 5–18 years measured by dual energy X-ray absorptiometry (DXA, Lunar Prodigy) and 2) to evaluate the relationships between BMD vs. age, sex, puberty, weight, height, calcium intake and the age of menarche in our population. Gender and age-specific BMD (L2-4; LS and total body; TB), BMADLS (apparent BMD of the lumbar spine), BMC (L2-4 and total body), BA (L2-4 and total body) and LBM were evaluated in 367 children (174 boys and 193 girls). All parameters increased progressively with age. A rapid increase in BMD, BMC and BMADLS was observed at earlier ages in girls. Gender and Tanner stage-specific BMD normative data were also generated. The dynamic changes of BMD values from childhood to early and late puberty of Thai children appeared to be consistent with those of Caucasian and Asian populations. Using a multiple-regression, weight and Tanner stage significantly affected BMDLS, BMDTB and BMADLS in both genders. Only in girls, height was found to have significant influence on BMDTB and BMADLS. The positive correlation between BMD and several demographic parameters, except the calcium intake, was observed. In summary, we established a normal BMD reference for Thai children and adolescents and this will be of useful for clinicians and researchers to appropriately assess BMD in Thais and other Southeast Asian children.
doi:10.1371/journal.pone.0097218
PMCID: PMC4029563  PMID: 24847716
8.  Dimorphic Ovary Differentiation in Honeybee (Apis mellifera) Larvae Involves Caste-Specific Expression of Homologs of Ark and Buffy Cell Death Genes 
PLoS ONE  2014;9(5):e98088.
The establishment of the number of repeated structural units, the ovarioles, in the ovaries is one of the critical events that shape caste polyphenism in social insects. In early postembryonic development, honeybee (Apis mellifera) larvae have a pair of ovaries, each one consisting of almost two hundred ovariole primordia. While practically all these ovarioles continue developing in queen-destined larvae, they undergo massive programmed cell death (PCD) in worker-destined larvae. So as to gain insight into the molecular basis of this fundamental process in caste differentiation we used quantitative PCR (qPCR) and fluorescent in situ hybridization (FISH) to investigate the expression of the Amark and Ambuffy genes in the ovaries of the two honeybee castes throughout the fifth larval instar. These are the homologs of ark and buffy Drosophila melanogaster genes, respectively, involved in activating and inhibiting PCD. Caste-specific expression patterns were found during this time-window defining ovariole number. Amark transcript levels were increased when ovariole resorption was intensified in workers, but remained at low levels in queen ovaries. The transcripts were mainly localized at the apical end of all the worker ovarioles, but appeared in only a few queen ovarioles, thus strongly suggesting a function in mediating massive ovariolar cell death in worker larvae. Ambuffy was mainly expressed in the peritoneal sheath cells covering each ovariole. The levels of Ambuffy transcripts increased earlier in the developing ovaries of queens than in workers. Consistent with a protective role against cell death, Ambuffy transcripts were localized in practically all queen ovarioles, but only in few worker ovarioles. The results are indicative of a functional relationship between the expression of evolutionary conserved cell death genes and the morphological events leading to caste-specific ovary differentiation in a social insect.
doi:10.1371/journal.pone.0098088
PMCID: PMC4028266  PMID: 24844304
9.  Androgen receptor agonism promotes an osteogenic gene program in preadipocytes 
Androgens regulate body composition by interacting with the androgen receptor (AR) to control gene expression in a tissue-specific manner. To identify novel regulatory roles for AR in preadipocytes, we created a 3T3-L1 cell line stably expressing human AR. We found AR expression is required for androgen-mediated inhibition of 3T3-L1 adipogenesis. This inhibition is characterized by decreased lipid accumulation, reduced expression of adipogenic genes, and induction of genes associated with osteoblast differentiation. Collectively, our results suggest androgens promote an osteogenic gene program at the expense of adipocyte differentiation.
doi:10.1016/j.bbrc.2013.03.078
PMCID: PMC3763992  PMID: 23567971
Adipocyte; Osteoblast; Androgen receptor; Gene regulation
10.  Complex B1 Mapping and Electrical Properties Imaging of the Human Brain using a 16-channel Transceiver Coil at 7T 
The electric properties (EPs) of biological tissue provide important diagnostic information within radio and microwave frequencies, and also play an important role in specific absorption rate (SAR) calculation which is a major safety concern at ultrahigh field (UHF). The recently proposed electrical properties tomography (EPT) technique aims to reconstruct EPs in biological tissues based on B1 measurement. However, for individual coil element in multi-channel transceiver coil which is increasingly utilized at UHF, current B1-mapping techniques could not provide adequate information (magnitude and absolute phase) of complex transmit and receive B1 which are essential for EPT, electric field, and quantitative SAR assessment. In this study, using a 16-channel transceiver coil at 7T, based on hybrid B1-mapping techniques within the human brain, a complex B1-mapping method has been developed, and in-vivo EPs imaging of the human brain has been demonstrated by applying a logarithm-based inverse algorithm. Computer simulation studies as well as phantom and human experiments have been conducted at 7T. The average bias and standard deviation for reconstructed conductivity in vivo were 28% and 67%, and 10% and 43% for relative permittivity, respectively. The present results suggest the feasibility and reliability of proposed complex B1-mapping technique and EPs reconstruction method.
doi:10.1002/mrm.24358
PMCID: PMC3549472  PMID: 22692921
electric properties; B1-mapping; B1 phase; ultrahigh field MRI; multi-channel transceiver array
11.  Androgens Involvement in the Pathogenesis of Renal Stones Formation 
PLoS ONE  2014;9(4):e93790.
Objective
The potential role for the gonadal steroids in the pathogenesis of urolithiasis, higher mean of plasma oxalate concentration and kidney calcium oxalate deposition influenced by androgens in men has been proposed. In this study, the serum levels of steroid hormones as a pathogenesis of this condition in male patients with active renal stone disease compared with controls was investigated.
Methods
Forty patients diagnosed with renal stones and hospitalized for further clinical treatments or referred to our office after ultrasonographic evaluations participated in the study. Forty six healthy subjects served as controls. Steroid sex hormones in the plasma samples including testosterone, free testosterone, dihydrotestosterone, estradiol, and sex hormone binding globulin were analyzed.
Results
A significant difference was observed between patients and the control subjects regarding serum testosterone, free testosterone, dihydrotestosterone, estradiol, and sex hormone binding globulin.
Conclusions
Based on the results, a higher androgens level was diagnosed in renal stone patients, indicating a possibility of a substantial pathogenic role of testosterone, free testosterone, and dihydrotestosterone involvement in the pathogenesis of renal stones formation. Therefore, data presentation and further investigation on the relation between male steroids and urolithiasis is of importance and should be considered in evaluation of the etiology of the disease.
doi:10.1371/journal.pone.0093790
PMCID: PMC3973622  PMID: 24695421
12.  Elevation of NR4A3 Expression and Its Possible Role in Modulating Insulin Expression in the Pancreatic Beta Cell 
PLoS ONE  2014;9(3):e91462.
Background
NR4A3/NOR-1 is a member of the NR4A orphan nuclear receptor subfamily, which contains early response genes that sense and respond to a variety of stimuli in the cellular environment. The role of NR4A3 in insulin expression in pancreatic beta cells remains unknown.
Methods
Dynamic changes in NR4A3 were examined in a pancreatic beta-cell line, MIN6, treated with thapsigargin (TG), palmitate (PA), tunicamycin (TM), and dithiothreitol (DTT), chemicals that produce cell stress and even apoptosis. We exploited virus infection techniques to induce expression of NR4A3 or three deletion mutants, and determined expression of insulin and insulin regulatory genes in MIN6 cells.
Results
TG and PA, two endoplasmic reticulum (ER) stress inducers, were able to induce unfolded protein response (UPR) activation and elevation of NR4A3 expression in MIN6 cells, whereas TM and DTT, two other ER stress inducers, were able to induce UPR activation but not NR4A3 elevation. MIN6 cells over-expressing NR4A3 protein after adenoviral infection exhibited reduced transcription of the insulin genes Ins1 and Ins2, and reduced insulin protein secretion, which were negatively correlated with NR4A3 expression levels. Functional analysis of different deletion mutants of NR4A3 showed that deleting the activation domain AF1 or the DNA-binding domain abolished the down-regulation of insulin transcription by NR4A3 in MIN6 cells, indicating that this down-regulative role was closely related to the NR4A3 trans-activation activity. Over-expression of NR4A3 in MIN6 cells resulted in reduced mRNA transcription of the insulin positive-regulation genes, Pdx1 and NeuroD1.
Conclusion
Some ER stress inducers, such as TG or PA, are able to elevate NR4A3 expression in MIN6 cells, while others, such as TM or DTT, are not. Over-expression of NR4A3 in MIN6 cells results in down-regulation of insulin gene transcription and insulin secretion. NR4A3 reduces insulin gene expression by modulating the expression of Pdx1 and NeuroD1.
doi:10.1371/journal.pone.0091462
PMCID: PMC3956668  PMID: 24638142
13.  Effect of Demecolcine-Assisted Enucleation on the MPF Level and Cyclin B1 Distribution in Porcine Oocytes 
PLoS ONE  2014;9(3):e91483.
Demecolcine (DEM) treatment of oocytes induces formation of a membrane protrusion containing a mass of condensed maternal chromosomes, which can be removed with minimal damage prior to somatic cell nuclear transfer (SCNT). However, the effect of this method on the distribution of maturation-promoting factor (MPF) in porcine oocytes has not been reported. Here, the level of MPF and the distribution of cyclin B1 were assessed in porcine oocytes following DEM treatment. In addition, the efficiencies of DEM-assisted and mechanical enucleation were compared, as were the development (in vitro and in vivo) of these oocytes following SCNT. MPF was uniformly distributed in oocytes that had been treated with 0.4 μg/ml DEM for 1 h. Immunofluorescence microscopy showed that in untreated oocytes, cyclin B1, the regulatory subunit of MPF, accumulated around the spindle, and was lowly detected in the cytoplasm. DEM treatment disrupted spindle microtubules, induced chromosome condensation, and reduced the level of cyclin B1 in the nuclear region. Cyclin B1 was uniformly distributed in DEM-treated oocytes and the level of MPF was increased. The potential of embryos generated from DEM-treated oocytes to develop in vivo was significantly greater than that of embryos generated from mechanically enucleated oocytes. This is the first study to report the effects of DEM-assisted enucleation of porcine oocytes on the distribution of cyclin B1. MPF in mature oocytes is important for the development of reconstructed embryos and for efficient SCNT.
doi:10.1371/journal.pone.0091483
PMCID: PMC3953396  PMID: 24626152
14.  Hip Fractures and Bone Mineral Density in the Elderly—Importance of Serum 25-Hydroxyvitamin D 
PLoS ONE  2014;9(3):e91122.
Background
The significance of serum 25-hydroxyvitamin D [25(OH)D] concentrations for hip fracture risk of the elderly is still uncertain. Difficulties reaching both frail and healthy elderly people in randomized controlled trials or large cohort studies may in part explain discordant findings. We determined hazard ratios for hip fractures of elderly men and women related to serum 25(OH)D, including both the frail and the healthy segment of the elderly population.
Methods
The AGES-Reykjavik Study is a prospective study of 5764 men and women, age 66–96 years, based on a representative sample of the population of Reykjavik, Iceland. Participation was 71.8%. Hazard ratios of incident hip fractures and baseline bone mineral density were determined according to serum concentrations of 25(OH)D at baseline.
Results
Mean follow-up was 5.4 years. Compared with referent values (50–75 nmol/L), hazard ratios for hip fractures were 2.24 (95% CI 1.63, 3.09) for serum 25(OH)D <30 nmol/L, adjusting for age, sex, body mass index, height, smoking, alcohol intake and season, and 2.08 (95% CI 1.51, 2.87), adjusting additionally for physical activity. No difference in risk was associated with 30–50 nmol/L or ≥75 nmol/L in either model compared with referent. Analyzing the sexes separately, hazard ratios were 2.61 (95% CI 1.47, 4.64) in men and 1.93 (95% CI 1.31, 2.84) in women. Values <30 nmol/L were associated with significantly lower bone mineral density of femoral neck compared with referent, z-scores -0.14 (95% CI −0.27, −0.00) in men and −0.11 (95% CI −0.22, −0.01) in women.
Conclusions
Our results lend support to the overarching importance of maintaining serum 25(OH)D above 30 nmol/L for bone health of elderly people while potential benefits of having much higher levels could not be detected.
doi:10.1371/journal.pone.0091122
PMCID: PMC3951316  PMID: 24621578
15.  Microtubule Stabilization by Mdp3 Is Partially Attributed to Its Modulation of HDAC6 in Addition to Its Association with Tubulin and Microtubules 
PLoS ONE  2014;9(3):e90932.
Microtubule-mediated cellular events such as intracellular transport and the maintenance of cell polarity are highly dependent upon microtubule stability, which is controlled by a repertoire of microtubule-associated proteins (MAPs) in the cell. MAP7 domain-containing protein 3 (Mdp3) has recently been identified as a critical regulator of microtubule stability. However, it remains elusive how Mdp3 carries out this function. In this study, by examination of tubulin partitioning between the polymer and soluble dimer forms, we found that Mdp3 could protect microtubules from cold- or nocodazole-induced depolymerization. Immunoblotting and immunofluorescence microscopy showed that knockdown of Mdp3 expression significantly reduced the level of tubulin acetylation. In vitro tubulin polymerization assays revealed that the amino-terminal region of Mdp3 was necessary for its ability to stabilize microtubules. Immunoprecipitation and pulldown experiments showed that the amino-terminal region mediated the interaction of Mdp3 with histone deacetylase 6 (HDAC6), in addition to its association with tubulin and microtubules. Immunofluorescence microscopy further demonstrated that endogenous Mdp3 and HDAC6 colocalized in the cytoplasm. Moreover, depletion of Mdp3 dramatically increased the activity of HDAC6 toward tubulin deacetylation. These findings suggest that Mdp3 controls microtubule stability through its binding to tubulin and microtubules as well as its regulation of HDAC6 activity.
doi:10.1371/journal.pone.0090932
PMCID: PMC3948737  PMID: 24614595
16.  Investigation into the Toxicity of Traditional Uyghur Medicine Quercus Infectoria Galls Water Extract 
PLoS ONE  2014;9(3):e90756.
Objective
Quercus infectoria galls (QIG) is being widely used in Traditional Uyghur Medicine. To gather preclinical safety information for the aqueous extract of QIG, a toxicity study was performed.
Methods
Subject animals were randomized, and devided into exposure and control groups. In the acute toxicity phase, three different doses—5, 7.5, and 10 g/kg, respectively—were administered via enema to imprinting control region (ICR) mice. An experiment using the maximum tolerance dose (MTD) i.e.10 g/kg was also performed. Data were gathered for 14 days, and study parameters were clinical signs, body weight, general behavior, adverse effects and mortality. At the day 14, major organs of the subjects were examined histologically. Chronic toxicity was also evaluated in Wistar rats for over 180 consecutive days. The rats were divided into three groups with different doses of 0.2 g/kg, 0.8 g/kg, and 2 g/kg, QIG. Furthermore, observations were carried out in rabbits to investigate if there were signs of irritation.
Results
In comparison to control group, acute, chronic toxicity and mortality were not significantly increased in exposure group.
Conclusion
Study result suggests that the aqueous extract of QIG is unlikely to have significant toxicity and that clinical trials may proceed safely.
doi:10.1371/journal.pone.0090756
PMCID: PMC3946586  PMID: 24608135
17.  Promoting Female Condoms in the Sex Industry in Four Towns of Southern China: Context Matters 
Sexually transmitted diseases  2013;40(3):264-270.
Background
The female condom (FC) is an effective tool for dual protection, but it remains underused. Individual as well as contextual reasons need to be explored.
Objective
To compare individual and contextual characteristics of FC multi-time users, one-time users and non-users among women in the sex industry of four study sites in China.
Methods
A standardized one-year FC intervention along with male condoms was implemented through outreach to sex establishments. Three serial cross-sectional surveys were conducted at baseline and after each of two six-month intervention phases.
Results
A total of 445, 437 and 290 eligible women were interviewed at three cross-sectional surveys, respectively. At the first and second post-intervention surveys, 83.3% and 81.7% of women reported knowing about FC, and 28.8% and 36.6% had used FC at least once. Women who used FC multiple times reported less unprotected sex than non-users in the last 30 days (3.0% vs. 17.2% at first and 3.2% vs. 16.8% at second post-intervention survey, p<0.01). Polytomous logistic regression showed that both one-time and multi-time users were more likely to come from one particular site (about 3 times more than the reference site). Higher intervention scores (adjusted OR 1.8–4.0) and working in boarding houses (adjusted OR 3.4) were associated with FC use.
Conclusions
Adding FC into male-condom-only intervention may reduce unprotected sex among women in sex establishments in rural and small urban areas of China. Adoption of FC may be related not only to intervention exposure, but also to contextual factors associated with study site and type of sex establishments.
doi:10.1097/OLQ.0b013e31827c58c9
PMCID: PMC3572509  PMID: 23403607
female condom; sex workers; China; HIV/STI prevention; community intervention
18.  Neuromodulation for Brain Disorders: Challenges and Opportunities 
The field of neuromodulation encompasses a wide spectrum of interventional technologies that modify pathological activity within the nervous system to achieve a therapeutic effect. Therapies including deep brain stimulation (DBS), intracranial cortical stimulation (ICS), transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS) have all shown promising results across a range of neurological and neuropsychiatric disorders. While the mechanisms of therapeutic action are invariably different amongst these approaches, there are several fundamental neuroengineering challenges that are commonly applicable to improving neuromodulation efficacy. This article reviews the state-of-the-art of neuromodulation for brain disorders and discusses the challenges and opportunities available for clinicians and researchers interested in advancing neuromodulation therapies.
doi:10.1109/TBME.2013.2244890
PMCID: PMC3724171  PMID: 23380851
neuromodulation; neuroengineering; deep brain stimulation; intracranial cortical stimulation; transcranial magnetic stimulation; transcranial direct current stimulation
19.  Magnetoacoustic Tomography with Magnetic Induction: Bioimepedance reconstruction through vector source imaging 
IEEE transactions on medical imaging  2013;32(3):10.1109/TMI.2013.2239656.
Magneto acoustic tomography with magnetic induction (MAT-MI) is a technique proposed to reconstruct the conductivity distribution in biological tissue at ultrasound imaging resolution. A magnetic pulse is used to generate eddy currents in the object, which in the presence of a static magnetic field induces Lorentz force based acoustic waves in the medium. This time resolved acoustic waves are collected with ultrasound transducers and, in the present work, these are used to reconstruct the current source which gives rise to the MAT-MI acoustic signal using vector imaging point spread functions. The reconstructed source is then used to estimate the conductivity distribution of the object. Computer simulations and phantom experiments are performed to demonstrate conductivity reconstruction through vector source imaging in a circular scanning geometry with a limited bandwidth finite size piston transducer. The results demonstrate that the MAT-MI approach is capable of conductivity reconstruction in a physical setting.
doi:10.1109/TMI.2013.2239656
PMCID: PMC3808985  PMID: 23322761
Electrical impedance imaging; Helmholtz decomposition; Magneto acoustic tomography (MAT-MI); reconstruction
20.  Combined thoracoscopic and laparoscopic minimally invasive esophagectomy 
Journal of Thoracic Disease  2014;6(2):152-155.
With the improvement in thoracoscopic and laparoscopic surgery, thoracoscopic and laparoscopic esophagectomy (TLE), a minimally invasive approach, has attracted increasing attention as an alternative to open three-field esophagectomy. From June 2012 to October 2013, 90 patients underwent laparoscopic and thoracoscopic resection of esophageal carcinoma in our department. The VATS esophagectomy technique described here is the approach currently employed in the department of thoracic surgery at Sichuan Provincial People’s Hospital of China.
doi:10.3978/j.issn.2072-1439.2014.02.04
PMCID: PMC3944189  PMID: 24605230
Thoracoscopic and laparoscopic; minimally invasive; esophagectomy
21.  Human herpes virus 8-unrelated primary effusion lymphoma-like lymphoma in a patient with hepatitis B virus-related liver cirrhosis: A case report 
This study describes a rare case of Human Immunodeficiency Virus and Human Herpes Virus 8 (HHV-8) negative primary effusion lymphoma (PEL)-like lymphoma in a patient with hepatitis B virus-related liver cirrhosis, diagnosed in a 66-year-old male who rapidly progressed to a sense of abdominal fullness. Cytological analysis of the pleural effusion demonstrated large atypical lymphoid cells with rounded nuclei, prominent nucleoli, and abundant cytoplasm. Immunocytochemistry of the pleural effusion detected atypical CD20+ lymphoid cells. The patient was hospitalized, and died following sepsis and multi-organ failure. Our case highlights that HHV-8-unrelated PEL-like lymphoma patients have different pathogenetic mechanisms of causality at the biological level, immunophenotype, clinical behavior, and prognosis.
PMCID: PMC3999608  PMID: 24778676
Hepatitis B virus; human herpes virus 8; liver cirrhosis; primary effusion lymphoma
22.  Relationship between Rad51 G135C and G172T Variants and the Susceptibility to Cancer: A Meta-Analysis Involving 54 Case-Control Studies 
PLoS ONE  2014;9(1):e87259.
Background
The associations between Rad51 gene polymorphisms (G135C and G172T) and risk of cancer have been investigated, but the results were inconclusive. To get a comprehensive evaluation of the association above, we performed a meta-analysis of published studies.
Methods
A computerized search of PubMed, Embase and Web of Knowledge databases for all relevant studies was performed and the data were analyzed in a meta-analysis. The overall odds ratio (OR) with the 95% confidence interval (95% CI) was calculated to assess the strength of the association between Rad51 polymorphisms and cancer risk. Data were analyzed using fixed- or random-effects model when appropriate. Sensitivity analysis and publication bias test were also estimated.
Results
Overall, a total of 54 case-control studies were included in the current meta-analysis, among which 42 studies with 19,142 cases and 20,363 controls for RAD51 G135C polymorphism and 12 studies with 6,646 cases and 6,783 controls for G172T polymorphism. For G135C polymorphism, the pooled results indicated that significantly increased risk was found in overall cancers (homozygote model: OR = 1.776, 95% CI = 1.288–2.449; allelic genetic model: OR = 1.169, 95% CI = 1.016–1.345; recessive model: OR = 1.946, 95% CI = 1.336–2.835), especially in breast cancer (homozygote model: OR = 1.498, 95% CI = 1.026–2.189; recessive model: OR = 1.732, 95% CI  =  1.170–2.562). For G172T polymorphism, a decreased cancer risk was observed in head and neck cancer (homozygote model: OR  =  0.621, 95% CI  =  0.460–0.837; allelic genetic model: OR  =  0.824, 95% CI  =  0.716–0.948; recessive model: OR  =  0.639, 95% CI = 0.488–0.837).
Conclusions
Our results suggested that the Rad51 G135C polymorphism is a candidate for susceptibility to overall cancers, especially to breast cancer, and that the Rad51 G172T might play a protective role in the development of head and neck cancer.
doi:10.1371/journal.pone.0087259
PMCID: PMC3903631  PMID: 24475258
23.  Bisphenol A Exposure Alters Developmental Gene Expression in the Fetal Rhesus Macaque Uterus 
PLoS ONE  2014;9(1):e85894.
Bisphenol A (BPA) exposure results in numerous developmental and functional abnormalities in reproductive organs in rodent models, but limited data are available regarding BPA effects in the primate uterus. To determine if maternal oral BPA exposure affects fetal uterine development in a non-human primate model, pregnant rhesus macaques carrying female fetuses were exposed orally to 400 µg/kg BPA or vehicle control daily from gestation day (GD) 50–100 or GD100–165. Fetal uteri were collected at the completion of treatment (GD100 or GD165); tissue histology, cell proliferation, and expression of estrogen receptor alpha (ERα) and progesterone receptor (PR) were compared to that of controls. Gene expression analysis was conducted using rhesus macaque microarrays. There were no significant differences in histology or in the percentage of cells expressing the proliferation marker Ki-67, ERα, or PR in BPA-exposed uteri compared to controls at GD100 or GD165. Minimal differences in gene expression were observed between BPA-exposed and control GD100 uteri. However, at GD165, BPA-exposed uteri had significant differences in gene expression compared to controls. Several of the altered genes, including HOXA13, WNT4, and WNT5A, are critical for reproductive organ development and/or adult function. We conclude that second or third trimester BPA exposure does not significantly affect fetal uterus development based on morphological, proliferation, and steroid hormone receptor assessments. However, differences in expression of key developmental genes after third trimester exposure suggest that BPA could alter transcriptional signals influencing uterine function later in life.
doi:10.1371/journal.pone.0085894
PMCID: PMC3900442  PMID: 24465770
24.  Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Lines 
PLoS ONE  2014;9(1):e85594.
Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-γ (PPARγ) and PPARα, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPARδ was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor α in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.
doi:10.1371/journal.pone.0085594
PMCID: PMC3899020  PMID: 24465611
25.  Magnetoacoustic Tomography with Magnetic Induction: A Rigorous Theory 
IEEE transactions on bio-medical engineering  2008;55(2 0 2):10.1109/TBME.2007.912674.
We have proposed a new theory on mechanism of the magnetoacoustic signal generation with magnetic induction for an object with an arbitrary shape. An object under a static magnetic field emits acoustic signals when excited by a time-varying magnetic field, and that the acoustic waveform is mainly generated at the conductivity boundaries within the object. The proposed theory on the magnetoacoustic tomography with magnetic induction produced highly consistent results among computational and experimental paradigms in a two-layer sample phantom and suggests the potential applications for bioimpedance imaging.
doi:10.1109/TBME.2007.912674
PMCID: PMC3878613  PMID: 18270025
Electrical impedance imaging; magnetic induction; magnetoacoustic generation; tomography

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