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1.  GSH2 promoter methylation in pancreatic cancer analyzed by quantitative methylation-specific polymerase chain reaction 
Oncology Letters  2015;10(1):387-391.
Tumor suppressor gene silencing via promoter hypermethylation is an important event in pancreatic cancer pathogenesis. Aberrant DNA hypermethylation events are highly tumor specific, and may provide a diagnostic tool for pancreatic cancer patients. The objective of the current study was to identify novel methylation-related genes that may potentially be used to establish novel therapeutic and diagnostic strategies against pancreatic cancer. The methylation status of the GS homeobox 2 (GSH2) gene was analyzed using the sodium bisulfite sequencing method. The GSH2 methylation ratio was examined in primary carcinomas and corresponding normal tissues derived from 47 patients with pancreatic cancer, using quantitative methylation-specific polymerase chain reaction. Methylation ratios were found to be associated with the patient's clinicopathological features. GSH2 gene methylation was detected in 26 (55.3%) of the 47 pancreatic cancer patients, indicating that it occurs frequently in pancreatic cancer. A significant association with methylation was observed for tumor-node-metastasis stage (P=0.031). GSH2 may be a novel methylation-sensitive tumor suppressor gene in pancreatic cancer and may be a tumor-specific biomarker of the disease.
PMCID: PMC4487178  PMID: 26171036
pancreatic cancer; GSH2; methylation
2.  A simple method for RNA isolation from various tissues of the tree Neolamarckia cadamba  
Plant tissues contain abundant polysaccharides, phenolic compounds and other metabolites, which makes it difficult to isolate high-quality RNA from them. In addition, Neolamarckia cadamba contains large quantities of other components, particularly RNA-binding alkaloids, which makes the isolation even more challenging. Here, we describe a concise and efficient RNA isolation method that combines the cetyltrimethyl ammonium bromide (CTAB) and Plant RNA Kit (Omega) protocols. Gel electrophoresis showed that RNA extracted from all tissues, using this protocol, was of good integrity and without DNA contamination. Furthermore, the isolated RNA was of high purity, with an A 260/A 280 ratio of 2.1 and an A 260/A 230 ratio of >2.0. The isolated RNA was also suitable for downstream applications, such as reverse transcription-polymerase chain reaction (RT-PCR) and quantitative RT-PCR (RT-qPCR). The RNA isolation method was also efficient for recalcitrant plant tissues.
PMCID: PMC4434054  PMID: 26019587
Neolamarckia cadamba; RNA extraction; CTAB; spermidine; recalcitrant plant tissues
3.  The Association between Triglyceride/High-Density Lipoprotein Cholesterol Ratio and All-Cause Mortality in Acute Coronary Syndrome after Coronary Revascularization 
PLoS ONE  2015;10(4):e0123521.
High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are cardiovascular risk factors. A positive correlation between elevated TG/HDL-C ratio and all-cause mortality and cardiovascular events exists in women. However, utility of TG to HDL-C ratio for prediction is unknown among acute coronary syndrome (ACS).
Fasting lipid profiles, detailed demographic data, and clinical data were obtained at baseline from 416 patients with ACS after coronary revascularization. Subjects were stratified into three levels of TG/HDL-C. We constructed multivariate Cox-proportional hazard models for all-cause mortality over a median follow-up of 3 years using log TG to HDL-C ratio as a predictor variable and analyzing traditional cardiovascular risk factors. We constructed a logistic regression model for major adverse cardiovascular events (MACEs) to prove that the TG/HDL-C ratio is a risk factor.
The subject’s mean age was 64 ± 11 years; 54.5% were hypertensive, 21.8% diabetic, and 61.0% current or prior smokers. TG/HDL-C ratio ranged from 0.27 to 14.33. During the follow-up period, there were 43 deaths. In multivariate Cox models after adjusting for age, smoking, hypertension, diabetes, and severity of angiographic coronary disease, patients in the highest tertile of ACS had a 5.32-fold increased risk of mortality compared with the lowest tertile. After adjusting for conventional coronary heart disease risk factors by the logistic regression model, the TG/HDL-C ratio was associated with MACEs.
The TG to HDL-C ratio is a powerful independent predictor of all-cause mortality and is a risk factor of cardiovascular events.
PMCID: PMC4399840  PMID: 25880982
4.  Ecological genomics in Xanthomonas: the nature of genetic adaptation with homologous recombination and host shifts 
BMC Genomics  2015;16(1):188.
Comparative genomics provides insights into the diversification of bacterial species. Bacterial speciation usually takes place with lasting homologous recombination, which not only acts as a cohering force between diverging lineages but brings advantageous alleles favored by natural selection, and results in ecologically distinct species, e.g., frequent host shift in Xanthomonas pathogenic to various plants.
Using whole-genome sequences, we examined the genetic divergence in Xanthomonas campestris that infected Brassicaceae, and X. citri, pathogenic to a wider host range. Genetic differentiation between two incipient races of X. citri pv. mangiferaeindicae was attributable to a DNA fragment introduced by phages. In contrast to most portions of the genome that had nearly equivalent levels of genetic divergence between subspecies as a result of the accumulation of point mutations, 10% of the core genome involving with homologous recombination contributed to the diversification in Xanthomonas, as revealed by the correlation between homologous recombination and genomic divergence. Interestingly, 179 genes were under positive selection; 98 (54.7%) of these genes were involved in homologous recombination, indicating that foreign genetic fragments may have caused the adaptive diversification, especially in lineages with nutritional transitions. Homologous recombination may have provided genetic materials for the natural selection, and host shifts likely triggered ecological adaptation in Xanthomonas. To a certain extent, we observed positive selection nevertheless contributed to ecological divergence beyond host shifting.
Altogether, mediated with lasting gene flow, species formation in Xanthomonas was likely governed by natural selection that played a key role in helping the deviating populations to explore novel niches (hosts) or respond to environmental cues, subsequently triggering species diversification.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1369-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4372319  PMID: 25879893
Xanthomonas; Adaptive diversification; Host shift; Parapatric speciation; Homologous recombination; Comparative genomics
5.  Quantitative assessment of global cerebral metabolic rate of oxygen (CMRO2) in neonates using MRI 
NMR in biomedicine  2014;27(3):332-340.
Cerebral metabolic rate of oxygen (CMRO2) is the rate of oxygen consumption by the brain and is thought to be a direct index of energy homeostasis and brain health. However, in vivo measurement of CMRO2 has been challenging, in particular for neonatal population in whom conventional radiotracer methods are not applicable due to safety concerns. In this study, we propose a method to quantify global CMRO2 in neonates based on arteriovenous differences in oxygen content and employ separate measurements of oxygenation and CBF parameters. Specifically, arterial and venous oxygenation levels were determined with pulse oximetry and a novel T2-Relaxation-Under-Spin-Tagging (TRUST) MRI, respectively. Global CBF was measured with a phase-contrast (PC) flow velocity MRI. The proposed method was implemented on a standard 3T MRI without the need of any exogenous tracers and the total scan duration was less than 5 minutes. We demonstrated the feasibility of this method in twelve healthy neonates within an age range of 35–42 gestational weeks. CMRO2 values were successfully obtained from ten neonates. It was found that average CMRO2 in this age range was 38.3±17.7 μmol/100g/min and was positively correlated with age (p=0.007, slope 5.2 μmol/100g/min per week), although the highest CMRO2 value in this age range was still less than half of the adult level. Test-retest studies showed a coefficient of variation of 5.8±2.2 % between repeated CMRO2 measurements. Additionally, given the highly variable blood flow velocity within this age range, it is recommended that the TRUST labeling thickness and position should be determined on a subject-by-subject basis, and an automatic algorithm was developed for this purpose. Although this method provides a global CMRO2 measure only, the clinical significance of an energy consumption marker and the convenience of this technique may make it a useful tool in functional assessment of neonatal population.
PMCID: PMC3970939  PMID: 24399806
CMRO2; brain; fetus; baby; TRUST; energy consumption
6.  Prior exposure to imatinib does not impact outcome of allogeneic hematopoietic transplantation for chronic myeloid leukemia patients: a single-center experience in china 
Objective: We conducted a retrospective single-center study of 106 patients to investigate the impact of prior exposure to imatinib before allogeneic hematopoietic stem cell transplantation (allo-HSCT) on outcome of HSCT for chronic myeloid leukemia (CML) in china. Methods: Patients were divided into imatinib and non-imatinib group according to whether receiving imatinib therapy before transplantation or not. Hematopoietic engraftment, prognosis, congestive heart failure (CHF), hepatic veno-occlusive disease (HVOD), graft versus host disease (GVHD), hemorrhagic cystitis and infections were compared between the two groups in early stage of transplantation (within 100 days after transplantation). Results: Compared to non-imatinib group, imatinib group neither had a significantly longer engraftment time nor higher incidence of HVOD, GVHD, hemorrhagic cystitis and infections (P > 0.05). However, imatinib group tended to have a statistically higher incidence of CHF (29.6% vs 8.6%, P = 0.037) and a higher 0.5-year transplant-related mortality (TRM) (27.8% vs 5.9%, P = 0.001). The estimated 10-year relapse-free survival (RFS) and 10-year overall survival (OS) were not statistically significant between the two groups (79.6% vs 62.4% P = 0.432, 68.9% vs 55.5% P = 0.086, respectively). Conclusion: Thus, prior exposure to imatinib before transplantation does not influence the hematopoietic engraftment and incidence of early transplant-related complications. While, imatinib therapy pre-HSCT probably increases the risk of CHF and TRM in early stage of post-HSCT, and this effect can be enhanced in older age patients. However, Imatinib therapy doesn’t impact RFS and OS on a long view.
PMCID: PMC4402842  PMID: 25932195
Imatinib; chronic myelogenous leukemia; allogeneic hematopoietic stem cell transplantation; early transplant-related complications; congestive heart failure
7.  Protein expression of phospho-lim kinase-1 in patients and an experimental rat model with intractable temporal lobe epilepsy 
Lim kinase-1 (LIMK1) plays a critical role in dendritic spine morphogenesis and brain function. The protein expression pattern of phospho-LIMK1 (p-LIMK1), the active form of LIMK1, in intractable temporal lobe epilepsy (TLE), however, is unknown. Here we measured p-LIMK1 protein expression in thirty temporal neocortex tissue samples from intractable TLE patients, fifteen histologically normal temporal neocortex tissue samples from trauma patients without epilepsy, in the hippocampi of lithium chloride/pilocarpine-induced TLE rats, and in controls. We found that p-LIMK1 was expressed mainly in the cytoplasm of neurons. The protein expression of p-LIMK1 was significantly higher in the TLE patients and rats than in the control groups. Our results suggest that p-LIMK1 might be involved in the pathogenesis of intractable TLE.
PMCID: PMC4358492  PMID: 25785037
Lim kinase-1; phospho-LIMK1; intractable temporal lobe epilepsy; lithium chloride; pilocarpine
8.  Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome 
The New England journal of medicine  2014;371(2):119-129.
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.
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.
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.
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; number, NCT00719186.)
PMCID: PMC4175743  PMID: 25006718
9.  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.
To summarize baseline characteristics from a large multi-center infertility clinical trial.
Cross-sectional baseline data from a double-blind randomized trial of 2 treatment regimens (letrozole vs. clomiphene).
Academic Health Centers throughout the U.S.
Main Outcome Measure(s)
Historical, biometric, biochemical and questionnaire parameters.
750 women with PCOS and their male partners took part in the study.
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.
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.
PMCID: PMC3899700  PMID: 24156957
insulin resistance; hirsutism; infertility; ovulation induction; metabolic syndrome
10.  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.
PMCID: PMC4147624  PMID: 24948802
β-catenin; oligodendrocyte differentiation; OLPs; spinal cord; Wnt
11.  Upregulation of D site of albumin promoter binding protein in the brain of patients with intractable epilepsy 
Molecular Medicine Reports  2014;11(4):2486-2492.
The mechanisms that underlie the pathogenesis of intractable epilepsy (IE) remain to be elucidated. The present study aimed to investigate the expression of D site of albumin promoter binding protein (DBP) and mitogen-activated protein kinases (MAPKs) in the temporal lobes of patients with IE, in order to examine the possible roles of DBP in the pathogenesis of IE. The expression of DBP and MAPK was detected by immunohistochemistry and double-label immunofluorescence staining against DBP/MAPK in 35 patients with IE, and the data were compared with those of the 15 controls. The results demonstrated that DBP expression in IE group (0.31±0.03) was significantly higher compared with that in the controls (0.18±0.02; P<0.05) and MAPK expression in the IE group (0.19±0.03) was also higher compared with that in the controls (0.12±0.02; P<0.05). DBP and MAPK were mainly expressed in the cytoplasm of neurons and the double-label immunofluorescence staining demonstrated that DBP and MAPK expression occurred in the same neurons. Therefore, the expression of DBP and MAPK in epilepsy patients was upregulated, suggesting a possible pathogenetic role in IE.
PMCID: PMC4337482  PMID: 25503293
intractable epilepsy; temporal lobe; D site of albumin promoter binding protein; mitogen-activated protein kinases
12.  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.
PMCID: PMC3837379  PMID: 23937066
Tanshinone IIA; Salvia miltiorrhiza; zebrafish PTZ model; mouse seizure models; pentylenetetrazol
13.  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.
PMCID: PMC3792738  PMID: 22933464
development; diffusion tensor imaging; gene expression; histology; human fetal brain
14.  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.
PMCID: PMC3844105  PMID: 23827310
secreted frizzled-related protein 3; spinal cord; dorsal root ganglia; sensory circuit
15.  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.
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.
PMCID: PMC4105188  PMID: 24695229
Human brain; Transcriptome; Microarray; Development; Gene expression; Evolution
16.  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.
PMCID: PMC4186865  PMID: 25285789
17.  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.
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.
The single-session tolerance dose of the cervical spinal nerves lies between 19.0 and 24.1 Gy for this model.
PMCID: PMC3840915  PMID: 24060168
spinal nerve; radiation neuropathy; stereotactic ablative radiotherapy; stereotactic body radiation therapy; swine
18.  High-capacity millimetre-wave communications with orbital angular momentum multiplexing 
Nature Communications  2014;5:4876.
One property of electromagnetic waves that has been recently explored is the ability to multiplex multiple beams, such that each beam has a unique helical phase front. The amount of phase front ‘twisting’ indicates the orbital angular momentum state number, and beams with different orbital angular momentum are orthogonal. Such orbital angular momentum based multiplexing can potentially increase the system capacity and spectral efficiency of millimetre-wave wireless communication links with a single aperture pair by transmitting multiple coaxial data streams. Here we demonstrate a 32-Gbit s−1 millimetre-wave link over 2.5 metres with a spectral efficiency of ~16 bit s−1 Hz−1 using four independent orbital–angular momentum beams on each of two polarizations. All eight orbital angular momentum channels are recovered with bit-error rates below 3.8 × 10−3. In addition, we demonstrate a millimetre-wave orbital angular momentum mode demultiplexer to demultiplex four orbital angular momentum channels with crosstalk less than −12.5 dB and show an 8-Gbit s−1 link containing two orbital angular momentum beams on each of two polarizations.
High speed data transmission using orbital angular momentum beams has been recently demonstrated. Here, Yan et al. demonstrate a 32 Gbit/s millimetre-wave communication link using eight coaxially propagating independent orbital angular momentum beams with four orbital angular momentum states on two orthogonal polarizations.
PMCID: PMC4175588  PMID: 25224763
19.  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.
PMCID: PMC4157780  PMID: 25197823
20.  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.
PMCID: PMC4127495  PMID: 25109261
21.  MiR-124 suppresses tumor growth and metastasis by targeting Foxq1 in nasopharyngeal carcinoma 
Molecular Cancer  2014;13:186.
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.
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.
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.
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.
PMCID: PMC4267157  PMID: 25098939
MicroRNA-124; Tumor growth; Metastasis; Nasopharyngeal carcinoma; Foxq1
22.  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.
PMCID: PMC3905752  PMID: 24316736
23.  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.
PMCID: PMC4026224  PMID: 24840062
24.  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.
PMCID: PMC3807492  PMID: 23995633
25.  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.
PMCID: PMC3996462  PMID: 24756153

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