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1.  Spin and field squeezing in a spin-orbit coupled Bose-Einstein condensate 
Scientific Reports  2015;5:8006.
Recently, strong spin-orbit coupling with equal Rashba and Dresselhaus strength has been realized in neutral atomic Bose-Einstein condensates via a pair of Raman lasers. In this report, we investigate spin and field squeezing of the ground state in spin-orbit coupled Bose-Einstein condensate. By mapping the spin-orbit coupled BEC to the well-known quantum Dicke model, the Dicke type quantum phase transition is presented with the order parameters quantified by the spin polarization and occupation number of harmonic trap mode. This Dicke type quantum phase transition may be captured by the spin and field squeezing arising from the spin-orbit coupling. We further consider the effect of a finite detuning on the ground state and show the spin polarization and the quasi-momentum exhibit a step jump at zero detuning. Meanwhile, we also find that the presence of the detuning enhances the occupation number of harmonic trap mode, while it suppresses the spin and the field squeezing.
PMCID: PMC4306133  PMID: 25620051
2.  An effective approach to prevent immune rejection of human ESC-derived allografts 
Cell stem cell  2014;14(1):121-130.
Human embryonic stem cells (hESCs) hold great promise for cell therapy as a source of diverse differentiated cell types. One key bottleneck to realizing such potential is allogenic immune rejection of hESC-derived cells by recipients. Here, we optimized humanized mice (Hu-mice) reconstituted with a functional human immune system that mounts a vigorous rejection of hESCs and their derivatives. We established knock-in hESCs that constitutively express CTLA4-Ig and PD-L1 before and after differentiation, denoted CP hESCs. We then demonstrated that allogenic CP hESC-derived teratomas, fibroblasts, and cardiomyocytes are immune protected in Hu-mice, while cells derived from parental hESCs are effectively rejected. Expression of both CTLA4-Ig, which disrupts T-cell co-stimulatory pathways, and PD-L1, which activates T-cell inhibitory pathway, is required to confer immune protection as neither was sufficient on their own. These findings are instrumental for developing a strategy to protect hESC-derived cells from allogenic immune responses without requiring systemic immune suppression.
PMCID: PMC4023958  PMID: 24388175
3.  Disruption of human papillomavirus 16 E6 gene by clustered regularly interspaced short palindromic repeat/Cas system in human cervical cancer cells 
OncoTargets and therapy  2014;8:37-44.
High-risk human papillomavirus (HPV), especially HPV16, is considered a main causative agent of cervical cancer. Upon HPV infection, the viral oncoprotein E6 disrupts the host tumor-suppressor protein p53, thus promoting malignant transformation of normal cervical cells. Here, we used the newly developed programmable ribonucleic acid-guided clustered regularly interspaced short palindromic repeat (CRISPR)/Cas system to disrupt the HPV16 E6 gene. We showed that HPV16 E6 deoxyribonucleic acid was cleaved at specific sites, leading to apoptosis and growth inhibition of HPV16-positive SiHa and CaSki cells, but not HPV-negative C33A or human embryonic kidney 293 cells. We also observed downregulation of the E6 protein and restoration of the p53 protein. These data proved that the HPV16 E6 ribonucleic acid-guided CRISPR/Cas system might be an effective therapeutic agent in treating HPV infection-related cervical malignancy.
PMCID: PMC4278796  PMID: 25565864
CRISPR/Cas system; E6; p53; SiHa; CaSki; cervical cancer
4.  Boost Up Carrier Mobility for Ferroelectric Organic Transistor Memory via Buffering Interfacial Polarization Fluctuation 
Scientific Reports  2014;4:7227.
Ferroelectric organic field-effect transistors (Fe-OFETs) have been attractive for a variety of non-volatile memory device applications. One of the critical issues of Fe-OFETs is the improvement of carrier mobility in semiconducting channels. In this article, we propose a novel interfacial buffering method that inserts an ultrathin poly(methyl methacrylate) (PMMA) between ferroelectric polymer and organic semiconductor layers. A high field-effect mobility (μFET) up to 4.6 cm2 V−1 s−1 is obtained. Subsequently, the programming process in our Fe-OFETs is mainly dominated by the switching between two ferroelectric polarizations rather than by the mobility-determined charge accumulation at the channel. Thus, the “reading” and “programming” speeds are significantly improved. Investigations show that the polarization fluctuation at semiconductor/insulator interfaces, which affect the charge transport in conducting channels, can be suppressed effectively using our method.
PMCID: PMC4245676  PMID: 25428665
5.  Five New Secondary Metabolites Produced by a Marine-Associated Fungus, Daldinia eschscholzii 
Marine Drugs  2014;12(11):5563-5575.
Five new compounds, including a benzopyran ribonic glycoside, daldiniside A (1), two isocoumarin ribonic glycosides, daldinisides B (2) and C (3), and two alkaloids, 1-(3-indolyl)-2R,3-dihydroxypropan-1-one (4) and 3-ethyl-2,5-pyrazinedipropanoic acid (5), along with five known compounds (6–10), were isolated from the EtOAc extract of the marine-associated fungus, Daldinia eschscholzii. Their structures were elucidated by extensive physicochemical and spectroscopic properties, besides comparison with literature data. The absolute configurations of compounds 1–3 were corroborated by chemical transformation, GC analysis and X-ray crystallographic analysis. Meanwhile, the absolute configuration of compound 4 and the planar structure of compound 6 were also determined based on the X-ray diffraction analysis. The cytotoxicity of compounds 1–10, antifungal and anti-HIV activities of compounds 1–5 and the in vitro assay for glucose consumption of compounds 1–3 were done in the anti-diabetic model, whereas none showed obvious activity.
PMCID: PMC4245545  PMID: 25419997
marine-associated fungus; Daldinia eschscholzii; secondary metabolites; hydrolysis; GC analysis; X-ray diffraction analysis
6.  Meta-analysis of nonsteroidal anti-inflammatory drug intake and prostate cancer risk 
Epidemiological studies of the association between nonsteroidal anti-inflammatory drug (NSAID) intake and the risk of prostate cancer still remain controversial. Therefore, we conducted a meta-analysis to evaluate the potential association between NSAID intake and prostate cancer risk.
Eligible studies were retrieved by both computerized searches and reviews of references. Subgroup analyses on country and design of study were also performed. Random or fixed-effect models were used to pool estimates of odds ratios (ORs) with 95% confidence intervals (CIs).
We observed that the intake of aspirin was associated with a marginally decreased risk of prostate cancer (OR =0.95, 95% CI =0.93 to 0.98). A similar result was found between nonaspirin NSAIDs and prostate cancer risk (OR =0.94, 95% CI =0.90 to 0.98). However, a positive relation between all-NSAID intake and prostate cancer risk was observed (OR =1.18, 95% CI =1.15 to 1.22).
We observed a marginally inverse correlation between the intake of aspirin and prostate cancer risk. On the contrary, a positive relationship between all-NSAID intake and prostate cancer was detected. Further research needs to be conducted to better clarify potential biological mechanisms.
PMCID: PMC4194408  PMID: 25282624
Etiology; Meta-analysis; NSAIDs; Prostate cancer
7.  Genetic Diagnosis of Two Dopa-Responsive Dystonia Families by Exome Sequencing 
PLoS ONE  2014;9(9):e106388.
Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.
PMCID: PMC4152247  PMID: 25181484
8.  Exploring MicroRNA-Like Small RNAs in the Filamentous Fungus Fusarium oxysporum 
PLoS ONE  2014;9(8):e104956.
RNA silencing such as quelling and meiotic silencing by unpaired DNA (MSUD) and several other classes of special small RNAs have been discovered in filamentous fungi recently. More than four different mechanisms of microRNA-like RNAs (milRNAs) production have been illustrated in the model fungus Neurospora crassa including a dicer-independent pathway. To date, very little work focusing on small RNAs in fungi has been reported and no universal or particular characteristic of milRNAs were defined clearly. In this study, small RNA and degradome libraries were constructed and subsequently deep sequenced for investigating milRNAs and their potential cleavage targets on the genome level in the filamentous fungus F. oxysporum f. sp. lycopersici. As a result, there is no intersection of conserved miRNAs found by BLASTing against the miRBase. Further analysis showed that the small RNA population of F. oxysporum shared many common features with the small RNAs from N. crassa and other fungi. According to the known standards of miRNA prediction in plants and animals, milRNA candidates from 8 families (comprising 19 members) were screened out and identified. However, none of them could trigger target cleavage based on the degradome data. Moreover, most major signals of cleavage in transcripts could not match appropriate complementary small RNAs, suggesting that other predominant modes for milRNA-mediated gene regulation could exist in F. oxysporum. In addition, the PAREsnip program was utilized for comprehensive analysis and 3 families of small RNAs leading to transcript cleavage were experimentally validated. Altogether, our findings provided valuable information and important hints for better understanding the functions of the small RNAs and milRNAs in the fungal kingdom.
PMCID: PMC4139310  PMID: 25141304
9.  Analytical and Numerical Investigations into Hemisphere-Shaped Electrostatic Sensors 
Sensors (Basel, Switzerland)  2014;14(8):14021-14037.
Electrostatic sensors have been widely used in many applications due to their advantages of low cost and robustness. Their spatial sensitivity and time-frequency characteristics are two important performance parameters. In this paper, an analytical model of the induced charge on a novel hemisphere-shaped electrostatic sensor was presented to investigate its accurate sensing characteristics. Firstly a Poisson model was built for electric fields produced by charged particles. Then the spatial sensitivity and time-frequency response functions were directly derived by the Green function. Finally, numerical calculations were done to validate the theoretical results. The results demonstrate that the hemisphere-shaped sensors have highly 3D-symmetrical spatial sensitivity expressed in terms of elementary function, and the spatial sensitivity is higher and less homogeneous near the hemispherical surface and vice versa. Additionally, the whole monitoring system, consisting of an electrostatic probe and a signal conditioner circuit, acts as a band-pass filter. The time-frequency characteristics depend strongly on the spatial position and velocity of the charged particle, the radius of the probe as well as the equivalent resistance and capacitance of the circuit.
PMCID: PMC4179042  PMID: 25090419
electrostatic monitoring; hemisphere-shaped sensors; Green function; spatial sensitivity; induced charge
10.  Disruption of HPV16-E7 by CRISPR/Cas System Induces Apoptosis and Growth Inhibition in HPV16 Positive Human Cervical Cancer Cells 
BioMed Research International  2014;2014:612823.
High-risk human papillomavirus (HR-HPV) has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR-) associated protein system (CRISPR/Cas system), a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA) guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.
PMCID: PMC4127252  PMID: 25136604
11.  Highly efficient generation of airway and lung epithelial cells from human pluripotent stem cells 
Nature biotechnology  2013;32(1):84-91.
The ability to generate lung and airway epithelial cells from human pluripotent stem cells (hPSCs) would have applications in regenerative medicine, drug screening and modeling of lung disease, and studies of human lung development. We established, based on developmental paradigms, a highly efficient method for directed differentiation of hPSCs into lung and airway epithelial cells. Long-term differentiation in vivo and in vitro yielded basal, goblet, Clara, ciliated, type I and type II alveolar epithelial cells. Type II alveolar epithelial cells generated were capable of surfactant protein-B uptake and stimulated surfactant release, providing evidence of specific function. Inhibiting or removing agonists to signaling pathways critical for early lung development in the mouse—retinoic acid, Wnt and BMP—recapitulated defects in corresponding genetic mouse knockouts. The capability of this protocol to generate most cell types of the respiratory system suggests its utility for deriving patient-specific therapeutic cells.
PMCID: PMC4101921  PMID: 24291815
12.  Enhanced Cold Field Emission of Large-area Arrays of Vertically Aligned ZnO-nanotapers via Sharpening: Experiment and Theory 
Scientific Reports  2014;4:4676.
Large-area arrays of vertically aligned ZnO-nanotapers with tailored taper angle and height are electrodeposited on planar Zn-plate via continuously tuning the Zn(NH3)4(NO3)2 concentration in the electrolyte. Experimental measurements reveal that the field-emission performance of the ZnO-nanotaper arrays is enhanced with the sharpness and height of the ZnO-nanotapers. Theoretically, the ZnO-nanotaper is simplified to a “charge disc” model, based on which the characteristic macroscopic field enhancement factor (γC) is quantified. The theoretically calculated γC values are in good agreement with the experimental ones measured from arrays of ZnO-nanotapers with a series of geometrical parameters. The ZnO-nanotaper arrays have promising potentials in field-emission. The electrochemical synthetic strategy we developed may be extended to nanotaper arrays of other materials that are amenable to electrodeposition, and the “charge disc” model can be used for quasi-one-dimensional field emitters of other materials with nano-sized diameters.
PMCID: PMC3985081  PMID: 24728408
13.  Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma 
Molecular Cancer  2014;13:65.
The success of using glycolytic inhibitors for cancer treatment relies on better understanding the roles of each frequently deregulated glycolytic genes in cancer. This report analyzed the involvement of a key glycolytic enzyme, alpha-enolase (ENO1), in tumor progression and prognosis of human glioma.
ENO1 expression levels were examined in glioma tissues and normal brain (NB) tissues. The molecular mechanisms of ENO1 expression and its effects on cell growth, migration and invasion were also explored by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, Transwell chamber assay, Boyden chamber assay, Western blot and in vivo tumorigenesis in nude mice.
ENO1 mRNA and protein levels were upregulated in glioma tissues compared to NB. In addition, increased ENO1 was associated disease progression in glioma samples. Knocking down ENO1 expression not only significantly decreased cell proliferation, but also markedly inhibited cell migration and invasion as well as in vivo tumorigenesis. Mechanistic analyses revealed that Cyclin D1, Cyclin E1, pRb, and NF-κB were downregulated after stable ENO1 knockdown in glioma U251 and U87 cells. Conversely, knockdown of ENO1 resulted in restoration of E-cadherin expression and suppression of mesenchymal cell markers, such as Vimentin, Snail, N-Cadherin, β-Catenin and Slug. Furthermore, ENO1 suppression inactivated PI3K/Akt pathway regulating the cell growth and epithelial-mesenchymal transition (EMT) progression.
Overexpression of ENO1 is associated with glioma progression. Knockdown of ENO1 expression led to suppressed cell growth, migration and invasion progression by inactivating the PI3K/Akt pathway in glioma cells.
PMCID: PMC3994408  PMID: 24650096
ENO1; Glioma; Cell growth; EMT; PI3K/Akt
14.  Genome sequence of the anaerobic bacterium Bacillus sp. strain ZYK, a selenite and nitrate reducer from paddy soil 
Standards in Genomic Sciences  2014;9(3):646-654.
Bacillus sp. strain ZYK, a member of the phylum Firmicutes, is of interest for its ability to reduce nitrate and selenite and for its resistance to arsenic under anaerobic conditions. Here we describe some key features of this organism, together with the complete genome sequence and annotation. The 3,575,797 bp long chromosome with its 3,454 protein-coding and 70 RNA genes, and the information gained from its sequence will be relevant to the elucidation of microbially-mediated transformations of nitrogen, selenium and arsenic in paddy soil.
PMCID: PMC4148952  PMID: 25197451
anaerobic; spore-forming; Gram-positive; nitrate-reduction; selenite-reduction; arsenic resistance; paddy soil; Bacillaceae
15.  Tea consumption and prostate cancer: an updated meta-analysis 
Tea is supposed to have chemopreventive effect against various cancers. However, the protective role of tea in prostate cancer is still controversial. The aim of this study is to elucidate the association between tea consumption and prostate cancer risk by meta-analysis.
A total of 21 published articles were retrieved via both computerized searches and review of references. Estimates of OR/RR for highest versus non/lowest tea consumption levels were pooled on the basis of random effect model or fixed effect model as appropriate. Stratified analyses on tea type, population and study design were also conducted.
No statistical significance was detected between tea consumption and prostate cancer risk in meta-analysis of all included studies (odds ratio (OR) = 0.86, 95% CI (0.69-1.04)). Furthermore, stratified analyses on population (Asian, OR = 0.81, 95% CI (0.55-1.08); non-Asian, OR = 0.89, 95% CI (0.72-1.07)) and tea type (green tea, OR = 0.79, 95% CI (0.43-1.14); black tea, OR = 0.88, 95% CI (0.73-1.02)) also yielded non-significant association. Only the case–control study subgroup demonstrated a borderline protective effect for tea consumption against prostate cancer (OR = 0.77, 95% CI (0.55-0.98)).
Our analyses did not support the conclusion that tea consumption could reduce prostate cancer risk. Further epidemiology studies are needed.
PMCID: PMC3925323  PMID: 24528523
Prostate cancer; Tea; Meta-analysis
16.  Analysis of promoters of microRNAs from a Glycine max degradome library* #  
Objective: MicroRNAs (miRNAs) are genome-encoded, small non-coding RNAs that play important functions in development, biotic and abiotic stress responses, and other processes. Our aim was to explore the regulation of miRNA expression. Methods: We used bioinformatics methods to predict the core promoters of 440 miRNAs identified from a soybean (Glycine max) degradome library and to analyze cis-acting elements for 369 miRNAs. Results: The prediction results showed that 83.86% of the 440 miRNAs contained promoters in their upstream sequences, and 8.64% (38 loci) in their downstream sequences. The distributions of two core promoter elements, TATA-boxes and transcription start sites (TSSs), were similar. The cis-acting elements were examined to provide clues to the function and regulation of spatiotemporal expression of the miRNAs. Analyses of miRNA cis-elements and targets indicated a potential auxin response factor (ARF)- and gibberellin response factor (GARF)-mediated negative feedback loop for miRNA expression. Conclusions: The features of miRNAs from a Glycine max degradome library obtained here provide insights into the transcription regulation and functions of miRNAs in soybean.
PMCID: PMC3924388  PMID: 24510705
Glycine max; MicroRNA (miRNA); Promoter; Cis-acting element; Prediction
17.  Age-Dependent Transition from Cell-Level to Population-Level Control in Murine Intestinal Homeostasis Revealed by Coalescence Analysis 
PLoS Genetics  2013;9(2):e1003326.
In multi-cellular organisms, tissue homeostasis is maintained by an exquisite balance between stem cell proliferation and differentiation. This equilibrium can be achieved either at the single cell level (a.k.a. cell asymmetry), where stem cells follow strict asymmetric divisions, or the population level (a.k.a. population asymmetry), where gains and losses in individual stem cell lineages are randomly distributed, but the net effect is homeostasis. In the mature mouse intestinal crypt, previous evidence has revealed a pattern of population asymmetry through predominantly symmetric divisions of stem cells. In this work, using population genetic theory together with previously published crypt single-cell data obtained at different mouse life stages, we reveal a strikingly dynamic pattern of stem cell homeostatic control. We find that single-cell asymmetric divisions are gradually replaced by stochastic population-level asymmetry as the mouse matures to adulthood. This lifelong process has important developmental and evolutionary implications in understanding how adult tissues maintain their homeostasis integrating the trade-off between intrinsic and extrinsic regulations.
Author Summary
In multi-cellular organisms, there is a static equilibrium maintaining cells of various forms. This homeostasis is achieved by an exquisite balance between stem cell proliferation and differentiation. Understanding how different species and organ types maintain this dynamic equilibrium has been an interesting question for both evolutionary and developmental biologists. Using population genetic theory together with previously published single-cell sequencing data collected from mouse intestinal crypts at two points in development, we have revealed a dynamic picture of stem cell renewal in intestinal crypts. We found that intestinal equilibrium is maintained at the single-cell level through predominantly asymmetric stem cell divisions at early life stages, but progressively switches to a population level homeostasis with only symmetric divisions as the mouse matures to adulthood. This dynamic process, likely to be conserved across species, has important developmental and evolutionary implications in understanding how adult tissues maintain their homeostasis integrating lifelong trade-offs between intrinsic and extrinsic factors.
PMCID: PMC3585040  PMID: 23468655
18.  Human lymphohematopoietic reconstitution and immune function in immunodeficient mice receiving cotransplantation of human thymic tissue and CD34+ cells 
Cellular & molecular immunology  2012;9(3):232-236.
Small animal models with functional human lymphohematopoietic systems are highly valuable for the study of human immune function under physiological and pathological conditions. Over the last two decades, numerous efforts have been devoted towards the development of such humanized mouse models. This review is focused on human lymphohematopoietic reconstitution and immune function in humanized mice by cotransplantation of human fetal thymic tissue and CD34+ cells. The potential use of these humanized mice in translational biomedical research is also discussed.
PMCID: PMC3346882  PMID: 22307039
19.  Human lymphohematopoietic reconstitution and immune function in immunodeficient mice receiving cotransplantation of human thymic tissue and CD34+ cells 
Small animal models with functional human lymphohematopoietic systems are highly valuable for the study of human immune function under physiological and pathological conditions. Over the last two decades, numerous efforts have been devoted towards the development of such humanized mouse models. This review is focused on human lymphohematopoietic reconstitution and immune function in humanized mice by cotransplantation of human fetal thymic tissue and CD34+ cells. The potential use of these humanized mice in translational biomedical research is also discussed.
PMCID: PMC3346882  PMID: 22307039
humanized mouse; hematopoiesis; immune system; immunodeficient mouse; thymopoiesis
20.  Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias 
Brain  2011;134(12):3490-3498.
Paroxysmal kinesigenic dyskinesias is a paroxysmal movement disorder characterized by recurrent, brief attacks of abnormal involuntary movements induced by sudden voluntary movements. Although several loci, including the pericentromeric region of chromosome 16, have been linked to paroxysmal kinesigenic dyskinesias, the causative gene has not yet been identified. Here, we identified proline-rich transmembrane protein 2 (PRRT2) as a causative gene of paroxysmal kinesigenic dyskinesias by using a combination of exome sequencing and linkage analysis. Genetic linkage mapping with 11 markers that encompassed the pericentromeric of chromosome 16 was performed in 27 members of two families with autosomal dominant paroxysmal kinesigenic dyskinesias. Then, the whole-exome sequencing was performed in three patients from these two families. By combining the defined linkage region (16p12.1–q12.1) and the results of exome sequencing, we identified an insertion mutation c.649_650InsC (p.P217fsX7) in one family and a nonsense mutation c.487C>T (p.Q163X) in another family. To confirm our findings, we sequenced the exons and flanking introns of PRRT2 in another three families with paroxysmal kinesigenic dyskinesias. The c.649_650InsC (p.P217fsX7) mutation was identified in two of these families, whereas a missense mutation, c.796C>T (R266W), was identified in another family with paroxysmal kinesigenic dyskinesias. All of these mutations completely co-segregated with the phenotype in each family. None of these mutations was identified in 500 normal unaffected individuals of matched geographical ancestry. Thus, we have identified PRRT2 as the first causative gene of paroxysmal kinesigenic dyskinesias, warranting further investigations to understand the pathogenesis of this disorder.
PMCID: PMC3235563  PMID: 22120146
proline-rich transmembrane protein 2; paroxysmal kinesigenic dyskinesias; whole-exome sequencing; linkage analysis
21.  Hepato-specific microRNA-122 facilitates accumulation of newly synthesized miRNA through regulating PRKRA 
Nucleic Acids Research  2011;40(2):884-891.
microRNAs (miRNAs) are a versatile class of non-coding RNAs involved in regulation of various biological processes. miRNA-122 (miR-122) is specifically and abundantly expressed in human liver. In this study, we employed 3′-end biotinylated synthetic miR-122 to identify its targets based on affinity purification. Quantitative RT-PCR analysis of the affinity purified RNAs demonstrated a specific enrichment of several known miR-122 targets such as CAT-1 (also called SLC7A1), ADAM17 and BCL-w. Using microarray analysis of affinity purified RNAs, we also discovered many candidate target genes of miR-122. Among these candidates, we confirmed that protein kinase, interferon-inducible double-stranded RNA-dependent activator (PRKRA), a Dicer-interacting protein, is a direct target gene of miR-122. miRNA quantitative-RT–PCR results indicated that miR-122 and small interfering RNA against PRKRA may facilitate the accumulation of newly synthesized miRNAs but did not detectably affect endogenous miRNAs levels. Our findings will lead to further understanding of multiple functions of this hepato-specific miRNA. We conclude that miR-122 could repress PRKRA expression and facilitate accumulation of newly synthesized miRNAs.
PMCID: PMC3258128  PMID: 21937511
22.  Overexpression and Small Molecule-Triggered Downregulation of CIP2A in Lung Cancer 
PLoS ONE  2011;6(5):e20159.
Lung cancer is the leading cause of cancer deaths worldwide, with a five-year overall survival rate of only 15%. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies. However, whether CIP2A can be a new drug target for lung cancer is largely unclear.
Methodology/Principal Findings
Normal and malignant lung tissues were derived from 60 lung cancer patients from southern China. RT-PCR, Western blotting and immunohistochemistry were used to evaluate the expression of CIP2A. We found that among the 60 patients, CIP2A was undetectable or very low in paratumor normal tissues, but was dramatically elevated in tumor samples in 38 (63.3%) patients. CIP2A overexpression was associated with cigarette smoking. Silencing CIP2A by siRNA inhibited the proliferation and clonogenic activity of lung cancer cells. Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down-regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells.
Our findings strongly indicate that CIP2A could be an effective target for lung cancer drug development, and the therapeutic potentials of CIP2A-targeting agents warrant further investigation.
PMCID: PMC3105001  PMID: 21655278
23.  Putative EPHX1 Enzyme Activity Is Related with Risk of Lung and Upper Aerodigestive Tract Cancers: A Comprehensive Meta-Analysis 
PLoS ONE  2011;6(3):e14749.
EPHX1 is a key enzyme in metabolizing some exogenous carcinogens such as products of cigarette-smoking. Two functional polymorphisms in the EPHX1 gene, Tyr113His and His139Arg can alter the enzyme activity, suggesting their possible association with carcinogenesis risk, particularly of some tobacco-related cancers.
Methodology/Principal Findings
A comprehensive systematic review and meta-analysis was performed of available studies on these two polymorphisms and cancer risk published up to November 2010, consisting of 84 studies (31144 cases and 42439 controls) for Tyr113His and 77 studies (28496 cases and 38506 controls) for His139Arg primarily focused on lung cancer, upper aerodigestive tract (UADT) cancers (including oral, pharynx, larynx and esophagus cancers), colorectal cancer or adenoma, bladder cancer and breast cancer. Results showed that Y113H low activity allele (H) was significantly associated with decreased risk of lung cancer (OR = 0.88, 95%CI = 0.80–0.96) and UADT cancers (OR = 0.86, 95%CI = 0.77–0.97) and H139R high activity allele (R) with increased risk of lung cancer (OR = 1.18, 95%CI = 1.04–1.33) but not of UADT cancers (OR = 1.05, 95%CI = 0.93–1.17). Pooled analysis of lung and UADT cancers revealed that low EPHX1 enzyme activity, predicted by the combination of Y113H and H139R showed decreased risk of these cancers (OR = 0.83, 95%CI = 0.75–0.93) whereas high EPHX1 activity increased risk of the cancers (OR = 1.20, 95%CI = 0.98–1.46). Furthermore, modest difference for the risk of lung and UADT cancers was found between cigarette smokers and nonsmokers both in single SNP analyses (low activity allele H: OR = 0.77/0.85 for smokers/nonsmokers; high activity allele R: OR = 1.20/1.09 for smokers/nonsmokers) and in combined double SNP analyses (putative low activity: OR = 0.73/0.88 for smokers/nonsmokers; putative high activity: OR = 1.02/0.93 for smokers/ nonsmokers).
Putative low EPHX1 enzyme activity may have a potential protective effect on tobacco-related carcinogenesis of lung and UADT cancers, whereas putative high EPHX1 activity may have a harmful effect. Moreover, cigarette-smoking status may influence the association of EPHX1 enzyme activity and the related cancer risk.
PMCID: PMC3060809  PMID: 21445251
24.  Association of EPHA2 polymorphisms and age-related cortical cataract in a Han Chinese population 
Molecular Vision  2011;17:1553-1558.
The gene for Eph-receptor tyrosinekinase-type A2 (EPHA2) has been shown to be involved in the pathogenesis of age-related cataract (ARC). The aim of this study was to examine whether EPHA2 polymorphisms were associated with the susceptibility to age-related cortical cataract in a Han Chinese population.
Five single-nucleotide polymorphisms (SNPs)—rs3768293, rs3754334, rs7548209, rs707455, and rs477558—in the EPHA2 gene were genotyped in 422 Han Chinese patients with age-related cortical cataract and 317 age-, sex-, and ethnically matched healthy controls using a PCR restriction fragment length polymorphism (PCR-RFLP) assay. Data were analyzed by χ2 analysis.
The results showed that the five analyzed polymorphisms in EPHA2 were in Hardy–Weinberg equilibrium both in the patients and in the controls. The frequency of the rs477558 AA genotype was significantly increased in ARC patients compared with controls (χ2=8.649, pc=0.045, odds ratio [OR] 1.555, 95% CI 1.158 to 2.089). The frequency of the rs477558 AG genotype was significantly decreased in ARC patients compared with controls (χ2=9.281, pc=0.030, OR 0.626, 95% CI 0.463 to 0.847). Significantly higher frequencies of the GG genotype and the G allele of rs7548209 were observed in ARC patients compared with controls (χ2=10.430, pc=0.015, OR 1.660, 95% CI 1.219 to 2.261 and χ2=8.537, pc=0.015, OR 1.486, 95% CI 1.138 to 1.940, respectively). On the other hand, significantly decreased frequencies of the rs7548209 CG genotype and the C allele were observed in ARC patients compared with controls (χ2=9.999, pc=0.030, OR 0.603, 95% CI 0.440 to 0.826 and χ2=8.537, pc=0.015, OR 0.673, 95% CI 0.515 to 0.879, respectively). There was no difference in the frequencies of the genotype and allele of the rs3768293, rs3754334, and rs707455 SNPs between the patients with ARC and the controls.
Our study suggests that both SNP rs477558 and SNP rs7548209 of EPHA2 are associated with age-related cortical cataract in a Han Chinese population.
PMCID: PMC3115745  PMID: 21686326
25.  Assessment of immunogenicity of romiplostim in clinical studies with ITP subjects 
Annals of Hematology  2010;89(Suppl 1):75-85.
Romiplostim is an Fc-peptide fusion protein that activates intracellular transcriptional pathways via the thrombopoietin (TPO) receptor leading to increased platelet production. Romiplostim has been engineered to have no amino acid sequence homology to endogenous TPO. Recombinant protein therapeutics can be at a risk of development of an antibody response that can impact efficacy and safety. Hence, a strategy to detect potential antibody formation to the drug and to related endogenous molecules can be useful. The immunogenicity assessment strategy involved both the detection and characterization of binding and neutralizing antibodies. The method for detection was based on a surface plasmon resonance biosensor platform using the Biacore 3000. Samples that tested positive for binding antibodies in the Biacore immunoassay were then tested in a neutralization assay. Serum samples from 225 subjects with immune thrombocytopenic purpura (ITP) dosed with romiplostim and 45 ITP subjects dosed with placebo were tested for romiplostim and TPO antibodies. Prior to romiplostim treatment, 17 subjects (7%) tested romiplostim antibody positive and 12 subjects (5%) tested TPO antibody positive for pre-existing binding antibodies. After romiplostim exposure, 11% of the subjects exhibited binding antibodies against romiplostim and 5% of the subjects with ITP showed binding antibodies against TPO. The antibodies against romiplostim did not cross-react with TPO and vice versa. No cases of anti-TPO neutralizing antibodies were detected in romiplostim-treated subjects. The incidence of anti-romiplostim neutralizing antibodies to romiplostim was 0.4% (one subject); this subject tested negative at the time of follow-up 4 months later. No impact on platelet profiles were apparent in subjects that had antibodies to romiplostim to date. In summary, administration of romiplostim in ITP subjects resulted in the development of a binding antibody response against romiplostim and TPO ligand. One subject developed a neutralizing antibody response to romiplostim that impacted the platelet counts of this subject. No neutralizing antibodies to endogenous TPO were observed.
PMCID: PMC2900600  PMID: 19484238
Immune thrombocytopenic purpura (ITP); Romiplostim; Immunogenicity; TPO; Platelet

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