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1.  Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome 
The New England journal of medicine  2014;371(2):119-129.
BACKGROUND
Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes.
METHODS
In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period.
RESULTS
Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P = 0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P = 0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups.
CONCLUSIONS
As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.)
doi:10.1056/NEJMoa1313517
PMCID: PMC4175743  PMID: 25006718
2.  The Pregnancy in Polycystic Ovary Syndrome Study II: Baseline Characteristics and Effects of Obesity from a Multi-Center Randomized Clinical Trial 
Fertility and sterility  2013;101(1):258-269.e8.
Objective
To summarize baseline characteristics from a large multi-center infertility clinical trial.
Design
Cross-sectional baseline data from a double-blind randomized trial of 2 treatment regimens (letrozole vs. clomiphene).
Setting
Academic Health Centers throughout the U.S.
Interventions
None
Main Outcome Measure(s)
Historical, biometric, biochemical and questionnaire parameters.
Participants
750 women with PCOS and their male partners took part in the study.
Results
Females averaged ~30 years old and were obese (BMI 35) with ~20% from a racial/ethnic minority. Most (87%) were hirsute and nulligravid (63%). . Most of the females had an elevated antral follicle count and enlarged ovarian volume on ultrasound. Women had elevated mean circulating androgens, LH:FSH ratio (~2), and AMH levels (8.0 ng/mL). Additionally, women had evidence for metabolic dysfunction with elevated mean fasting insulin and dyslipidemia. Increasing obesity was associated with decreased LH:FSH levels, AMH levels and antral follicle counts but increasing cardiovascular risk factors, including prevalence of the metabolic syndrome. Males were obese (BMI 30) and had normal mean semen parameters.
Conclusions
The treatment groups were well-matched at baseline. Obesity exacerbates select female reproductive and most metabolic parameters. We have also established a database and sample repository that will eventually be accessible to investigators.
doi:10.1016/j.fertnstert.2013.08.056
PMCID: PMC3899700  PMID: 24156957
insulin resistance; hirsutism; infertility; ovulation induction; metabolic syndrome
3.  Stage-Specific Regulation of Oligodendrocyte Development by Wnt/β-Catenin Signaling 
The Journal of Neuroscience  2014;34(25):8467-8473.
Oligodendrocytes are myelin-forming glia that ensheath the axons of neurons in the CNS. Recent studies have revealed that Wnt/β-catenin signaling plays important roles in oligodendrocyte development and myelin formation. However, there are conflicting reports on the specific function of Wnt signaling components in oligodendrocyte specification and differentiation. In the present study, we demonstrate that activation of β-catenin in neural progenitor cells before gliogenesis inhibits the generation of oligodendrocyte progenitors (OLPs) in mice. Once OLPs are formed, β-catenin becomes necessary for oligodendrocyte differentiation. Disruption of β-catenin signaling instead leads to a significant delay of oligodendrocyte maturation. These findings suggest that Wnt/β-catenin pathway regulates oligodendrocyte development in a stage-dependent manner.
doi:10.1523/JNEUROSCI.0311-14.2014
PMCID: PMC4147624  PMID: 24948802
β-catenin; oligodendrocyte differentiation; OLPs; spinal cord; Wnt
4.  Tanshinone IIA Exhibits Anticonvulsant Activity in Zebrafish and Mouse Seizure Models 
ACS Chemical Neuroscience  2013;4(11):1479-1487.
Danshen or Chinese red sage (Salvia miltiorrhiza, Bunge) is used by traditional Chinese medicine (TCM) practitioners to treat neurological, cardiovascular, and cerebrovascular disorders and is included in some TCM formulations to control epileptic seizures. In this study, acetonic crude extracts of danshen inhibited pentylenetetrazol (PTZ)-induced seizure activity in zebrafish larvae. Subsequent zebrafish bioassay-guided fractionation of the extract resulted in the isolation of four major tanshinones, which suppressed PTZ-induced activity to varying degrees. One of the active tanshinones, tanshinone IIA, also reduced c-fos expression in the brains of PTZ-exposed zebrafish larvae. In rodent seizure models, tanshinone IIA showed anticonvulsive activity in the mouse 6-Hz psychomotor seizure test in a biphasic manner and modified seizure thresholds in a complex manner for the mouse i.v. PTZ seizure assay. Interestingly, tanshinone IIA is used as a prescription drug in China to address cerebral ischemia in patients. Here, we provide the first in vivo evidence demonstrating that tanshinone IIA has anticonvulsant properties as well.
doi:10.1021/cn400140e
PMCID: PMC3837379  PMID: 23937066
Tanshinone IIA; Salvia miltiorrhiza; zebrafish PTZ model; mouse seizure models; pentylenetetrazol
5.  Coupling Diffusion Imaging with Histological and Gene Expression Analysis to Examine the Dynamics of Cortical Areas across the Fetal Period of Human Brain Development 
Cerebral Cortex (New York, NY)  2012;23(11):2620-2631.
As a prominent component of the human fetal brain, the structure of the cerebral wall is characterized by its laminar organization which includes the radial glial scaffold during fetal development. Diffusion tensor imaging (DTI) is useful to quantitatively delineate the microstructure of the developing brain and to clearly identify transient fetal layers in the cerebral wall. In our study, the spatio-temporal microstructural changes in the developing human fetal cerebral wall were quantitatively characterized with high-resolution DTI data of postmortem fetal brains from 13 to 21 gestational weeks. Eleven regions of interest for each layer in the entire cerebral wall were included. Distinctive time courses of microstructural changes were revealed for 11 regions of the neocortical plate. A histological analysis was also integrated to elucidate the relationship between DTI fractional anisotropy (FA) and histology. High FA values correlated with organized radial architecture in histological image. Expression levels of 17565 genes were quantified for each of 11 regions of human fetal neocortex from 13 to 21 gestational weeks to identify transcripts showing significant correlation with FA change. These correlations suggest that the heterogeneous and regionally specific microstructural changes of the human neocortex are related to different gene expression patterns.
doi:10.1093/cercor/bhs241
PMCID: PMC3792738  PMID: 22933464
development; diffusion tensor imaging; gene expression; histology; human fetal brain
6.  Dynamic Expression of Secreted Frizzled-related Protein 3 (sFRP3) in the developing mouse spinal cord and dorsal root ganglia 
Neuroscience  2013;0:594-601.
Wnt proteins have been implicated in regulating a variety of developmental processes in the central nervous system (CNS). Secreted Frizzled-related protein 3 (sFRP3) is a member of the sFRP family that can inhibit the Wnt signaling by binding directly to Wnts via their regions of homology to the Wnt-binding domain of Frizzleds. Recent studies suggested that sFRP3 plays an important role in cell proliferation and differentiation in various tissues. To understand the role of sFRP3 in neural development, we carried out detailed studies on the expression of sFRP3 in the developing nervous system. Our results revealed that sFRP3 is initially expressed in the ventricular zone of spinal cord and dorsal root ganglia (DRG), and later in the dorsal horn of spinal cord and subpopulation of DRG neurons. The spatiotemporally dynamic expression of sFRP3 strongly suggests that sFRP3 has potential functions in the sensory neuron genesis and sensory circuitry formation.
doi:10.1016/j.neuroscience.2013.06.044
PMCID: PMC3844105  PMID: 23827310
secreted frizzled-related protein 3; spinal cord; dorsal root ganglia; sensory circuit
7.  Transcriptional Landscape of the Prenatal Human Brain 
Miller, Jeremy A. | Ding, Song-Lin | Sunkin, Susan M. | Smith, Kimberly A | Ng, Lydia | Szafer, Aaron | Ebbert, Amanda | Riley, Zackery L. | Aiona, Kaylynn | Arnold, James M. | Bennet, Crissa | Bertagnolli, Darren | Brouner, Krissy | Butler, Stephanie | Caldejon, Shiella | Carey, Anita | Cuhaciyan, Christine | Dalley, Rachel A. | Dee, Nick | Dolbeare, Tim A. | Facer, Benjamin A. C. | Feng, David | Fliss, Tim P. | Gee, Garrett | Goldy, Jeff | Gourley, Lindsey | Gregor, Benjamin W. | Gu, Guangyu | Howard, Robert E. | Jochim, Jayson M. | Kuan, Chihchau L. | Lau, Christopher | Lee, Chang-Kyu | Lee, Felix | Lemon, Tracy A. | Lesnar, Phil | McMurray, Bergen | Mastan, Naveed | Mosqueda, Nerick F. | Naluai-Cecchini, Theresa | Ngo, Nhan-Kiet | Nyhus, Julie | Oldre, Aaron | Olson, Eric | Parente, Jody | Parker, Patrick D. | Parry, Sheana E. | Player, Allison Stevens | Pletikos, Mihovil | Reding, Melissa | Royall, Joshua J. | Roll, Kate | Sandman, David | Sarreal, Melaine | Shapouri, Sheila | Shapovalova, Nadiya V. | Shen, Elaine H. | Sjoquist, Nathan | Slaughterbeck, Clifford R. | Smith, Michael | Sodt, Andy J. | Williams, Derric | Zöllei, Lilla | Fischl, Bruce | Gerstein, Mark B. | Geschwind, Daniel H. | Glass, Ian A. | Hawrylycz, Michael J. | Hevner, Robert F. | Huang, Hao | Jones, Allan R. | Knowles, James A. | Levitt, Pat | Phillips, John W. | Sestan, Nenad | Wohnoutka, Paul | Dang, Chinh | Bernard, Amy | Hohmann, John G. | Lein, Ed S.
Nature  2014;508(7495):199-206.
Summary
The anatomical and functional architecture of the human brain is largely determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and postmitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and human-expanded outer subventricular zones. Both germinal and postmitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in frontal lobe. Finally, many neurodevelopmental disorder and human evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.
doi:10.1038/nature13185
PMCID: PMC4105188  PMID: 24695229
Human brain; Transcriptome; Microarray; Development; Gene expression; Evolution
8.  Control of Astrocyte Progenitor Specification, Migration and Maturation by Nkx6.1 Homeodomain Transcription Factor 
PLoS ONE  2014;9(10):e109171.
Although astrocytes are the most abundant cell type in the central nervous system (CNS), little is known about their molecular specification and differentiation. It has previously been reported that transcription factor Nkx6.1 is expressed in neuroepithelial cells that give rise to astrocyte precursors in the ventral spinal cord. In the present study, we systematically investigated the function of Nkx6.1 in astrocyte development using both conventional and conditional Nkx6.1 mutant mice. At early postnatal stages, Nkx6.1 was expressed in a subpopulation of astrocytes in the ventral spinal cord. In the conventional Nkx6.1KO spinal cord, the initial specification of astrocyte progenitors was affected by the mutation, and subsequent migration and differentiation were disrupted in newborn mice. In addition, the development of VA2 subtype astrocytes was also inhibited in the white matter. Further studies with Nkx6.1 conditional mutants revealed significantly delayed differentiation and disorganized arrangement of fibrous astrocytes in the ventral white matter. Together, our studies indicate that Nkx6.1 plays a vital role in astrocyte specification and differentiation in the ventral spinal cord.
doi:10.1371/journal.pone.0109171
PMCID: PMC4186865  PMID: 25285789
9.  Paralysis following stereotactic spinal irradiation in pigs suggests a tolerance constraint for single-session irradiation of the spinal nerve 
Background and Purpose
Paralysis observed during a study of vertebral bone tolerance to single-session irradiation led to further study of the dose-related incidence of motor peripheral neuropathy.
Materials and Methods
During a bone tolerance study, cervical spinal nerves of 15 minipigs received bilateral irradiation to levels C5–C8 distributed into three dose groups with mean maximum spinal nerve doses of 16.9±0.3Gy(n=5), 18.7±0.5Gy(n=5), and 24.3±0.8Gy(n=5). Changes developing in the gait of the group of pigs receiving a mean maximum dose of 24.3 Gy after 10 – 15 weeks led to the irradiation of two additional animals. They received mean maximum dose of 24.9±0.2 Gy(n=2), targeted to the left spinal nerves of C5 – C8. The followup period was one year. Histologic sections from spinal cords and available spinal nerves were evaluated. MR imaging was performed on pigs in the 24.9Gy group.
Results
No pig that received a maximum spinal nerve point dose ≤19.0Gy experienced a change in gait while all pigs that received ≥24.1Gy experienced paralysis. Extensive degeneration and fibrosis were observed in irradiated spinal nerves from the 24.9Gy animals. All spinal cord sections were normal. Irradiated spinal nerve regions showed increased thickness and hypointensity on MR imaging.
Conclusion
The single-session tolerance dose of the cervical spinal nerves lies between 19.0 and 24.1 Gy for this model.
doi:10.1016/j.radonc.2013.08.025
PMCID: PMC3840915  PMID: 24060168
spinal nerve; radiation neuropathy; stereotactic ablative radiotherapy; stereotactic body radiation therapy; swine
10.  Comparative Transcriptomic Characterization of the Early Development in Pacific White Shrimp Litopenaeus vannamei 
PLoS ONE  2014;9(9):e106201.
Penaeid shrimp has a distinctive metamorphosis stage during early development. Although morphological and biochemical studies about this ontogeny have been developed for decades, researches on gene expression level are still scarce. In this study, we have investigated the transcriptomes of five continuous developmental stages in Pacific white shrimp (Litopenaeus vannamei) with high throughput Illumina sequencing technology. The reads were assembled and clustered into 66,815 unigenes, of which 32,398 have putative homologues in nr database, 14,981 have been classified into diverse functional categories by Gene Ontology (GO) annotation and 26,257 have been associated with 255 pathways by KEGG pathway mapping. Meanwhile, the differentially expressed genes (DEGs) between adjacent developmental stages were identified and gene expression patterns were clustered. By GO term enrichment analysis, KEGG pathway enrichment analysis and functional gene profiling, the physiological changes during shrimp metamorphosis could be better understood, especially histogenesis, diet transition, muscle development and exoskeleton reconstruction. In conclusion, this is the first study that characterized the integrated transcriptomic profiles during early development of penaeid shrimp, and these findings will serve as significant references for shrimp developmental biology and aquaculture research.
doi:10.1371/journal.pone.0106201
PMCID: PMC4157780  PMID: 25197823
11.  Plasmon-induced broadband fluorescence enhancement on Al-Ag bimetallic substrates 
Scientific Reports  2014;4:6014.
Surface enhanced fluorescence (SEF) utilizes the local electromagnetic environment to enhance fluorescence from the analyte on the surface of a solid substrate with nanostructures. While the detection sensitivity of SEF is improved with the development of nano-techniques, detection of multiple analytes by SEF is still a challenge due to the compromise between the high enhancing efficiency and broad response bandwidth. In this article, a high-efficiency SEF substrate with broad response bandwidth is obtained by embedding silver in an aluminum film to produce additional bonding and anti-bonding hybridized states. The bimetallic film is fabricated by ion implantation and the ion energy and fluence are tailored to control subsurface location of the fabricated bimetallic nanostructures. The process circumvents the inherent limit of aluminum materials and extends the plasmon band of aluminum from deep UV to visible range. Fluorescence from different dyes excited by 310 nm to 555 nm is enhanced by up to 11 folds on the single bimetallic film and the result is theoretically confirmed by finite-difference time-domain simulations. This work demonstrates that bimetallic film can be used for optical detection of multiple analytes.
doi:10.1038/srep06014
PMCID: PMC4127495  PMID: 25109261
12.  MiR-124 suppresses tumor growth and metastasis by targeting Foxq1 in nasopharyngeal carcinoma 
Molecular Cancer  2014;13(1):186.
Background
The molecular mechanisms underlying dysregulation of microRNAs have been documented in nasopharyngeal carcinoma (NPC). Our previous study demonstrated that plasma miR-124 was down-regulated in NPC using microarray analysis and quantitative PCR validation. Though growing studies showed that down-regulated miR-124 was closely related to tumourigenesis in various types of cancers, the role of miR-124 in NPC remains largely unknown.
Methods
The expression level of miR-124 was evaluated in NPC cell lines and patient specimens using quantitative reverse transcription-PCR (Real-time qPCR). The clinicopathological significance of the resultant data was later analyzed. Then, we explored the role of miR-124 in NPC tumorigenesis by in vitro and in vivo experiments. Homo sapiens forkhead box Q1 (Foxq1) was confirmed as a novel direct target gene of miR-124 by the dual-luciferase assay and western bolt.
Results
We found that miR-124 was commonly down-regulated in NPC specimens and NPC cell lines. The expression of miR-124 was inversely correlation with clinical stages and marked on T stages. Then, the ectopic expression of miR-124 dramatically inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as tumor growth and metastasis in vivo. Furthermore, we identified Foxq1 as a novel direct target of miR-124. Functional studies showed that knockdown of Foxq1 inhibited cell growth, migration and invasion, whereas Foxq1 overexpression partially rescued the suppressive effect of miR-124 in NPC. In clinical specimens, Foxq1 was commonly up-regulated in NPC, and the level increased with clinical stages and T stages. Additionally, the level of Foxq1 was inversely correlated with miR-124.
Conclusions
Our results demonstrate that miR-124 functions as a tumor-suppressive microRNA in NPC, and that its suppressive effects are mediated chiefly by repressing Foxq1 expression. MiR-124 could serve as an independent biomarker to identify patients with different clinical characteristics. Therefore, our findings provide valuable clues toward the understanding the of mechanisms of NPC pathogenesis and provide an opportunity to develop new effective clinical therapies in the future.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-186) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-4598-13-186
PMCID: PMC4267157  PMID: 25098939
MicroRNA-124; Tumor growth; Metastasis; Nasopharyngeal carcinoma; Foxq1
13.  E2 enzyme inhibition by stabilization of a low affinity interface with ubiquitin 
Nature chemical biology  2013;10(2):156-163.
Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small molecule inhibitor of the E2 ubiquitin conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester, without overtly affecting the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities.
doi:10.1038/nchembio.1412
PMCID: PMC3905752  PMID: 24316736
14.  Transcriptome Profiling and Physiological Studies Reveal a Major Role for Aromatic Amino Acids in Mercury Stress Tolerance in Rice Seedlings 
PLoS ONE  2014;9(5):e95163.
Mercury (Hg) is a serious environmental pollution threat to the planet. The accumulation of Hg in plants disrupts many cellular-level functions and inhibits growth and development, but the mechanism is not fully understood. To gain more insight into the cellular response to Hg, we performed a large-scale analysis of the rice transcriptome during Hg stress. Genes induced with short-term exposure represented functional categories of cell-wall formation, chemical detoxification, secondary metabolism, signal transduction and abiotic stress response. Moreover, Hg stress upregulated several genes involved in aromatic amino acids (Phe and Trp) and increased the level of free Phe and Trp content. Exogenous application of Phe and Trp to rice roots enhanced tolerance to Hg and effectively reduced Hg-induced production of reactive oxygen species. Hg induced calcium accumulation and activated mitogen-activated protein kinase. Further characterization of the Hg-responsive genes we identified may be helpful for better understanding the mechanisms of Hg in plants.
doi:10.1371/journal.pone.0095163
PMCID: PMC4026224  PMID: 24840062
15.  Streptomyces coelicolor Encodes a Urate-Responsive Transcriptional Regulator with Homology to PecS from Plant Pathogens 
Journal of Bacteriology  2013;195(21):4954-4965.
Many transcriptional regulators control gene activity by responding to specific ligands. Members of the multiple-antibiotic resistance regulator (MarR) family of transcriptional regulators feature prominently in this regard, and they frequently function as repressors in the absence of their cognate ligands. Plant pathogens such as Dickeya dadantii encode a MarR homolog named PecS that controls expression of a gene encoding the efflux pump PecM in addition to other virulence genes. We report here that the soil bacterium Streptomyces coelicolor also encodes a PecS homolog (SCO2647) that regulates a pecM gene (SCO2646). S. coelicolor PecS, which exists as a homodimer, binds the intergenic region between pecS and pecM genes with high affinity. Several potential PecS binding sites were found in this intergenic region. The binding of PecS to its target DNA can be efficiently attenuated by the ligand urate, which also quenches the intrinsic fluorescence of PecS, indicating a direct interaction between urate and PecS. In vivo measurement of gene expression showed that activity of pecS and pecM genes is significantly elevated after exposure of S. coelicolor cultures to urate. These results indicate that S. coelicolor PecS responds to the ligand urate by attenuated DNA binding in vitro and upregulation of gene activity in vivo. Since production of urate is associated with generation of reactive oxygen species by xanthine dehydrogenase, we propose that PecS functions under conditions of oxidative stress.
doi:10.1128/JB.00854-13
PMCID: PMC3807492  PMID: 23995633
16.  Label-free blood plasma test based on surface-enhanced Raman scattering for tumor stages detection in nasopharyngeal cancer 
Scientific Reports  2014;4:4751.
This study aims to evaluate the feasibility of a label-free nanobiosensor based on blood plasma surface-enhanced Raman spectroscopy (SERS) method for exploring variability of different tumor (T) stages in nasopharyngeal cancer (NPC). Au nanoparticles as the SERS-active nanostructures were directly mixed with human blood plasma to enhance the Raman scattering signals. High quality SERS spectra can be acquired from blood plasma samples belong to 60 healthy volunteers, 25 NPC patients with T1 stage and 75 NPC patients with T2–T4 stage. A diagnostic accuracy of 83.5% and 93.3%, respectively, can be achieved for classification between early T (T1) stage cancer and normal; and advanced T (T2–T4) stage cancer and normal blood groups. This exploratory study demonstrates that the nanobiosensor based on SERS technique in conjunction with PCA-LDA has great potential as a clinical complement for different T stages detection in nasopharyngeal cancer.
doi:10.1038/srep04751
PMCID: PMC3996462  PMID: 24756153
17.  Transcriptome profiling of genes and pathways associated with arsenic toxicity and tolerance in Arabidopsis 
BMC Plant Biology  2014;14:94.
Background
Arsenic (As) is a toxic metalloid found ubiquitously in the environment and widely considered an acute poison and carcinogen. However, the molecular mechanisms of the plant response to As and ensuing tolerance have not been extensively characterized. Here, we report on transcriptional changes with As treatment in two Arabidopsis accessions, Col-0 and Ws-2.
Results
The root elongation rate was greater for Col-0 than Ws-2 with As exposure. Accumulation of As was lower in the more tolerant accession Col-0 than in Ws-2. We compared the effect of As exposure on genome-wide gene expression in the two accessions by comparative microarray assay. The genes related to heat response and oxidative stresses were common to both accessions, which indicates conserved As stress-associated responses for the two accessions. Most of the specific response genes encoded heat shock proteins, heat shock factors, ubiquitin and aquaporin transporters. Genes coding for ethylene-signalling components were enriched in As-tolerant Col-0 with As exposure. A tolerance-associated gene candidate encoding Leucine-Rich Repeat receptor-like kinase VIII (LRR-RLK VIII) was selected for functional characterization. Genetic loss-of-function analysis of the LRR-RLK VIII gene revealed altered As sensitivity and the metal accumulation in roots.
Conclusions
Thus, ethylene-related pathways, maintenance of protein structure and LRR-RLK VIII-mediated signalling may be important mechanisms for toxicity and tolerance to As in the species. Here, we provide a comprehensive survey of global transcriptional regulation for As and identify stress- and tolerance-associated genes responding to As.
doi:10.1186/1471-2229-14-94
PMCID: PMC4021232  PMID: 24734953
Arsenate; Arabidopsis accession; Microarray
18.  Berberine Attenuates Axonal Transport Impairment and Axonopathy Induced by Calyculin A in N2a Cells 
PLoS ONE  2014;9(4):e93974.
Berberine is a primary component of the most functional extracts of Coptidis rhizome used in traditional Chinese medicine for centuries. Recent reports indicate that Berberine has the potential to prevent and treat Alzheimer's disease (AD). The previous studies reported that Calyculin A (CA) impaired the axonal transport in neuroblastoma-2a (N2a) cells. Berberine attenuated tau hyperphosphorylation and cytotoxicity induced by CA. Our study aimed at investigating the effects of Berberine on the axonal transport impairment induced by CA in N2a cells. The results showed that Berberine could protect the cell from CA -induced toxicity in metabolism and viability, as well as hyperphosphorylation of tau and neurofilaments (NFs). Furthermore, Berberine could reverse CA-induced axonal transport impairment significantly. Berberine also partially reversed the phosphorylation of the catalytic subunit of PP-2A at Tyrosine 307, a crucial site negatively regulating the activity of PP-2A, and reduced the levels of malondialdehyde and the activity of superoxide dismutase, markers of oxidative stress, induced by CA. The present work for the first time demonstrates that Berberine may play a role in protecting against CA-induced axonal transport impairment by modulating the activity of PP-2A and oxidative stress. Our findings also suggest that Berberine may be a potential therapeutic drug for AD.
doi:10.1371/journal.pone.0093974
PMCID: PMC3979860  PMID: 24713870
19.  Identification of a 24-Gene Prognostic Signature That Improves the European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: An International Collaborative Study 
Journal of Clinical Oncology  2013;31(9):1172-1181.
Purpose
To identify a robust prognostic gene expression signature as an independent predictor of survival of patients with acute myeloid leukemia (AML) and use it to improve established risk classification.
Patients and Methods
Four independent sets totaling 499 patients with AML carrying various cytogenetic and molecular abnormalities were used as training sets. Two independent patient sets composed of 825 patients were used as validation sets. Notably, patients from different sets were treated with different protocols, and their gene expression profiles were derived using different microarray platforms. Cox regression and Kaplan-Meier methods were used for survival analyses.
Results
A prognostic signature composed of 24 genes was derived from a meta-analysis of Cox regression values of each gene across the four training sets. In multivariable models, a higher sum value of the 24-gene signature was an independent predictor of shorter overall (OS) and event-free survival (EFS) in both training and validation sets (P < .01). Moreover, this signature could substantially improve the European LeukemiaNet (ELN) risk classification of AML, and patients in three new risk groups classified by the integrated risk classification showed significantly (P < .001) distinct OS and EFS.
Conclusion
Despite different treatment protocols applied to patients and use of different microarray platforms for expression profiling, a common prognostic gene signature was identified as an independent predictor of survival of patients with AML. The integrated risk classification incorporating this gene signature provides a better framework for risk stratification and outcome prediction than the ELN classification.
doi:10.1200/JCO.2012.44.3184
PMCID: PMC3595425  PMID: 23382473
20.  53BP1 is a reader of the DNA damage-induced H2A Lys15 ubiquitin mark 
Nature  2013;499(7456):50-54.
53BP1 (TP53BP1) is a chromatin-associated factor that promotes immunoglobulin class switching and DNA double-strand break (DSB) repair by non-homologous end joining. To accomplish its function in DNA repair, 53BP1 accumulates at DSB sites downstream of the RNF168 ubiquitin ligase. How ubiquitin recruits 53BP1 to break sites remains enigmatic since its relocalization involves recognition of H4 Lys20 (H4K20) methylation by its Tudor domain. Here we elucidate how 53BP1 is recruited to the chromatin that flanks DSB sites. We show that 53BP1 recognizes mono-nucleosomes containing dimethylated H4K20 (H4K20me2) and H2A ubiquitylated on Lys15 (H2AK15ub), the latter being a product of RNF168 action on chromatin. 53BP1 binds to nucleosomes minimally as a dimer using its previously characterized methyl-lysine-binding Tudor domain and a C-terminal extension, termed the ubiquitylation-dependent recruitment (UDR) motif, which interacts with the epitope formed by H2AK15ub and its surrounding residues on the H2A tail. 53BP1 is therefore a bivalent histone modification reader that recognizes a histone “code” produced by DSB signaling.
doi:10.1038/nature12318
PMCID: PMC3955401  PMID: 23760478 CAMSID: cams3939
21.  Application of Highly Purified Electrolyzed Chlorine Dioxide for Tilapia Fillet Disinfection 
The Scientific World Journal  2014;2014:619038.
This research aimed to develop an electrolysis method to generate high-concentration chlorine dioxide (ClO2) for tilapia fillet disinfection. The designed generator produced up to 3500 ppm of ClO2 at up to 99% purity. Tilapia fillets were soaked in a 400 ppm ClO2 solution for 5, 10, and 25 min. Results show that total plate counts of tilapia, respectively, decreased by 5.72 to 3.23, 2.10, and 1.09 log CFU/g. In addition, a 200 ppm ClO2 solution eliminated coliform bacteria and Escherichia coli in 5 min with shaking treatment. Furthermore, ClO2 and trihalomethanes (THMs) residuals on tilapia fillets were analyzed by GC/MS and were nondetectable (GC-MS detection limit was 0.12 ppb). The results conform to Taiwan's environmental protection regulations and act governing food sanitation.
doi:10.1155/2014/619038
PMCID: PMC3947783  PMID: 24696651
22.  Microstructure, Length, and Connection of Limbic Tracts in Normal Human Brain Development 
The cingulum and fornix play an important role in memory, attention, spatial orientation, and feeling functions. Both microstructure and length of these limbic tracts can be affected by mental disorders such as Alzheimer’s disease, depression, autism, anxiety, and schizophrenia. To date, there has been little systematic characterization of their microstructure, length, and functional connectivity in normally developing brains. In this study, diffusion tensor imaging (DTI) and resting state functional MRI (rs-fMRI) data from 65 normally developing right-handed subjects from birth to young adulthood was acquired. After cingulate gyrus part of the cingulum (cgc), hippocampal part of the cingulum (cgh) and fornix (fx) were traced with DTI tractography, absolute and normalized tract lengths and DTI-derived metrics including fractional anisotropy, mean, axial, and radial diffusivity were measured for traced limbic tracts. Free water elimination (FWE) algorithm was adopted to improve accuracy of the measurements of DTI-derived metrics. The role of these limbic tracts in the functional network at birth and adulthood was explored. We found a logarithmic age-dependent trajectory for FWE-corrected DTI metric changes with fast increase of microstructural integrity from birth to 2 years old followed by a slow increase to 25 years old. Normalized tract length of cgc increases with age, while no significant relationship with age was found for normalized tract lengths of cgh and fx. Stronger microstructural integrity on the left side compared to that of the right side was found. With integrated DTI and rs-fMRI, the key connectional role of cgc and cgh in the default mode network was confirmed as early as birth. Systematic characterization of length and DTI metrics after FWE correction of limbic tracts offers insight into their morphological and microstructural developmental trajectories. These trajectories may serve as a normal reference for pediatric patients with mental disorders.
doi:10.3389/fnagi.2014.00228
PMCID: PMC4147394  PMID: 25221509
limbic tract; development; trajectory; length; microstructure; DTI; connectivity; free water elimination
23.  Chondroprotective Activity of Murraya exotica through Inhibiting β-Catenin Signaling Pathway 
Osteoarthritis (OA) is a degenerative joint disease that affects millions of people. Currently, there is no effective drug treatment for it. The purpose of this study is to investigate the chondroprotective effects of Murraya exotica (L.) on OA. The rat OA models were duplicated to prepare for separating OA chondrocytes, synovial fluid (SF), and serum containing M. exotica (50 mg/kg, 100 mg/kg, and 200 mg/kg), M. exotica showed the activity of decreasing the contents of TNF-α and IL-1β in SF and the chondrocyte apoptosis in a dose-dependent manner. To investigate the probable mechanism, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to determine gene expression and protein profiles, respectively. The results reveal that M. exotica can downregulate mRNA and protein expressions of β-catenin and COX-2 and reporter activity significantly. Conclusively, M. exotica exhibits antiapoptotic chondroprotective activity probably through inhibiting β-catenin signaling.
doi:10.1155/2013/752150
PMCID: PMC3880701  PMID: 24454514
24.  The Ginger-shaped Asteroid 4179 Toutatis: New Observations from a Successful Flyby of Chang'e-2 
Scientific Reports  2013;3:3411.
On 13 December 2012, Chang'e-2 conducted a successful flyby of the near-Earth asteroid 4179 Toutatis at a closest distance of 770 ± 120 meters from the asteroid's surface. The highest-resolution image, with a resolution of better than 3 meters, reveals new discoveries on the asteroid, e.g., a giant basin at the big end, a sharply perpendicular silhouette near the neck region, and direct evidence of boulders and regolith, which suggests that Toutatis may bear a rubble-pile structure. Toutatis' maximum physical length and width are (4.75 × 1.95 km) ±10%, respectively, and the direction of the +z axis is estimated to be (250 ± 5°, 63 ± 5°) with respect to the J2000 ecliptic coordinate system. The bifurcated configuration is indicative of a contact binary origin for Toutatis, which is composed of two lobes (head and body). Chang'e-2 observations have significantly improved our understanding of the characteristics, formation, and evolution of asteroids in general.
doi:10.1038/srep03411
PMCID: PMC3860288  PMID: 24336501
25.  Optical imaging of head and neck squamous cell carcinoma in vivo using arginine-glycine-aspartic acid peptide conjugated near-infrared quantum dots 
OncoTargets and therapy  2013;6:1779-1787.
Molecular imaging plays a key role in personalized medicine and tumor diagnosis. Quantum dots with near-infrared emission spectra demonstrate excellent tissue penetration and photostability, and have recently emerged as important tools for in vivo tumor imaging. Integrin αvβ3 has been shown to be highly and specifically expressed in endothelial cells of tumor angiogenic vessels in almost all types of tumors, and specifically binds to the peptide containing arginine-glycine-aspartic acid (RGD). In this study, we conjugated RGD with quantum dots with emission wavelength of 800 nm (QD800) to generate QD800-RGD, and used it via intravenous injection as a probe to image tumors in nude mice bearing head and neck squamous cell carcinoma (HNSCC). Twelve hours after the injection, the mice were still alive and were sacrificed to isolate tumors and ten major organs for ex vivo analysis to localize the probe in these tissues. The results showed that QD800-RGD was specifically targeted to integrin αvβ3 in vitro and in vivo, producing clear tumor fluorescence images after the intravenous injection. The tumor-to-background ratio and size of tumor image were highest within 6 hours of the injection and declined significantly at 9 hours after the injection, but there was still a clearly visible tumor image at 12 hours. The greatest amount of QD800-RGD was found in liver and spleen, followed by tumor and lung, and a weak fluorescence signal was seen in tibia. No detectable signal of QD800-RGD was found in brain, heart, kidney, testis, stomach, or intestine. Our study demonstrated that using integrin αvβ3 as target, it is possible to use intravenously injected QD800-RGD to generate high quality images of HNSCC, and the technique offers great potential in the diagnosis and personalized therapy for HNSCC.
doi:10.2147/OTT.S53901
PMCID: PMC3855103  PMID: 24324343
nanotechnology; near-infrared fluorescence; tumor angiogenic vessel; head and neck cancer; in vivo imaging

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