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1.  Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome 
Blood Cancer Journal  2014;4(1):e177-.
Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.
doi:10.1038/bcj.2013.74
PMCID: PMC3913943  PMID: 24442206
ASXL1 mutation; myelodysplastic syndrome; sequential analyses; prognosis
2.  Association between tuberculosis infections and non-pulmonary malignancies: a nationwide population-based study 
British Journal of Cancer  2013;109(1):229-234.
Background:
In addition to lung cancers, tuberculosis infections have been associated with increased risk of non-pulmonary malignancies in case reports. Our population-based study employed standardized incidence ratios (SIRs) to systemically survey non-pulmonary cancer risks after tuberculosis infections.
Methods:
Data of patients who had newly diagnosed tuberculosis, were aged 20 years or older, and had no prior cancer or tuberculosis were sampled from the Taiwan National Health Insurance database between 2000 and 2010. SIRs compared cancer incidence in patients with tuberculosis infections to the general population. SIRs of specific cancers were further analyzed with respect to gender and time after tuberculosis infections.
Results:
After a follow-up period of 28 866 person–years, 530 tuberculosis cases developed cancers compared with 256 cases in the general populations (2.07, 95% confidence interval (CI), 1.90–2.26). The SIR of non-pulmonary malignancies was also increased (1.71, 95% CI, 1.54–1.90). For males, SIRs were increased within 1 year after tuberculosis diagnosis for the following cancers: head and neck, esophageal, colorectal, liver, lung, melanomas, and Hodgkin's disease. SIRs were increased for liver, biliary, lung, and bladder cancers beyond the first year after tuberculosis diagnosis. For females, SIRs were increased for leukemia, esophageal, and lung cancers within the first year, and only for leukemia beyond 1 year post diagnosis.
Conclusion:
Having found increased risks of several cancers that differ with gender and time after tuberculosis diagnosis, physicians may consider these factors in patients following tuberculosis diagnosis.
doi:10.1038/bjc.2013.220
PMCID: PMC3708573  PMID: 23652313
tuberculosis infections; standardized incidence ratios
3.  Evidence for a motor gamma-band network governing response interference✰ 
NeuroImage  2013;74:10.1016/j.neuroimage.2013.02.013.
The gamma-band response is thought to represent a key neural signature of information processing in the human brain. These brain signals have been associated with a variety of sensory modalities (vision, sensation, and audition) and also following basic motor responses, yet the functional significance of the motor gamma-band response remains unclear. We used the Multi-Source Interference Task (MSIT) to assess the sensitivity of these cortical motor gamma-band rhythms to stimuli producing response interference. We recorded MEG from adult participants (N=24) during MSIT task performance and compared motor gamma-band activity on Control and Interference trials.
Reaction time on MSIT Interference trials was significantly longer (∼0.2 s) for all subjects. Response interference produced a significant increase in motor gamma-band activity including ∼0.5 s sustained increase in gamma-band activity from contralateral primary motor area directly preceding the response. In addition, activation of increased right Inferior Frontal Gyrus (R-IFG) was observed at gamma-band frequencies ∼0.2 s prior to the button press response. Post-hoc analysis of R-IFG gamma-band activity was observed to correlate with reaction time increases to response interference.
Our study is the first to record MEG during MSIT task performance. We observed novel activity of the motor gamma-band on interference trials which was sustained prior to the response and in novel locations including contralateral (BA6), and R-IFG. Our results support the idea that R-IFG is specialized structure for response control that also functions at gamma-band frequencies. Together, these data provide evidence for a motor gamma-band network for response selection and maintenance of planned behavior.
doi:10.1016/j.neuroimage.2013.02.013
PMCID: PMC3817211  PMID: 23454050
MEG; Magnetoencephalography; Motor cortex; amma-band response; Multi-source interference task (MSIT); Response interference
4.  Synergistic effect of trichostatin A and scriptaid on the development of cloned rabbit embryos 
Theriogenology  2013;79(9):1284-1293.
The first successful rabbit SCNT was achieved more than one decade ago, yet rabbits remain one of the most difficult species to clone. The present study was designed to evaluate the effects of two histone deacetylase inhibitors (HDACi), namely trichostatin A (TSA) and scriptaid (SCP), on cloning efficiency in rabbits. The in vitro development, acetylation levels of histone H4 lysine 5 (H4K5ac), and Oct-4 protein expression patterns of cloned embryos were systemically examined after various HDACi treatments. Supplementation of TSA (50 nM) or SCP (250 nM) in the culture medium for 6 h improved blastocyst development rates of cloned embryos compared to treatment without HDACi. The combined treatment with TSA (50 nM) and SCP (250 nM) further enhanced morula (58.6%) and blastocyst (49.4%) rates in vitro. More importantly, compared to single HDACi treatments, embryos with the combined treatment had a higher level of H4K5ac and an increased total cell number (203.7±14.4 vs 158.9±9.0 or 162.1±8.2, P<0.05) with better Oct-4 expression pattern in hatching blastocysts, indicating substantially improved embryo quality. This was apparently the first report regarding Oct-4 expression in cloned rabbit embryos. We inferred that the majority of cloned rabbit embryos had an aberrant ICM structure accompanied with abnormal spatial distribution of Oct-4 signals. This study demonstrated a synergistic effect of TSA and SCP treatments on cloned rabbit embryos, which may be useful to improve cloning efficiency in rabbits.
doi:10.1016/j.theriogenology.2013.03.003
PMCID: PMC3677057  PMID: 23566670
Rabbit; SCNT; HDACi; TSA; SCP
5.  Non-viral FoxM1 gene delivery to hepatocytes enhances liver repopulation 
Cell Death & Disease  2014;5(5):e1252-.
Hepatocyte transplantation as a substitute strategy of orthotopic liver transplantation is being studied for treating end-stage liver diseases. Several technical hurdles must be overcome in order to achieve the therapeutic liver repopulation, such as the problem of insufficient expansion of the transplanted hepatocytes in recipient livers. In this study, we analyzed the application of FoxM1, a cell-cycle regulator, to enhance the proliferation capacity of hepatocytes. The non-viral sleeping beauty (SB) transposon vector carrying FoxM1 gene was constructed for delivering FoxM1 into the hepatocytes. The proliferation capacities of hepatocytes with FoxM1 expression were examined both in vivo and in vitro. Results indicated that the hepatocytes with FoxM1 expression had a higher proliferation rate than wild-type (WT) hepatocytes in vitro. In comparison with WT hepatocytes, the hepatocytes with FoxM1 expression had an enhanced level of liver repopulation in the recipient livers at both sub-acute injury (fumaryl acetoacetate hydrolase (Fah)–/– mice model) and acute injury (2/3 partial hepatectomy mice model). Importantly, there was no increased risk of tumorigenicity with FoxM1 expression in recipients even after serial transplantation. In conclusion, expression of FoxM1 in hepatocytes enhanced the capacity of liver repopulation without inducing tumorigenesis. FoxM1 gene delivered by non-viral SB vector into hepatocytes may be a viable approach to promote therapeutic repopulation after hepatocyte transplantation.
doi:10.1038/cddis.2014.230
PMCID: PMC4047909  PMID: 24853430
FoxM1; sleeping beauty transposon; non-viral; hepatocyte transplantation; liver repopulation
6.  IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation 
Cell Death & Disease  2014;5(5):e1239-.
Bone morphogenetic protein 2 (BMP2) is known to activate unfolded protein response (UPR) signaling molecules, such as BiP (IgH chain-binding protein), PERK (PKR-like ER-resistant kinase), and IRE1α. Inositol-requiring enzyme-1a (IRE1a), as one of three unfolded protein sensors in UPR signaling pathways, can be activated during ER stress. Granulin-epithelin precursor (GEP) is an autocrine growth factor that has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation. However, the influence on IRE1a in BMP2-induced osteoblast differentiation has not yet been elucidated. Herein we demonstrate that overexpression of IRE1a inhibits osteoblast differentiation, as revealed by reduced activity of alkaline phosphatase (ALP) and osteocalcin; however, knockdown of IRE1a via the RNAi approach stimulates osteoblastogenesis. Mechanistic studies revealed that the expression of IRE1a during osteoblast was a consequence of JunB transcription factor binding to several AP1 sequence (TGAG/CTCA) in the 5′-flanking regulatory region of the IRE1a gene, followed by transcription. In addition, GEP induces IRE1a expressions and this induction of IRE1a by GEP depends on JunB. Furthermore, IRE1a inhibition of GEP-induced osteoblastogenesis relies on JunB. Besides, GEP is required for IRE1a inhibition of BMP2-induced bone formation. Collectively, these findings demonstrate that IRE1a negatively regulates BMP2-induced osteoblast differentiation and this IRE1a inhibition effect depends on GEP growth factor. Thus, IRE1a, BMP2, GEP growth factor, and JunB transcription factor form a regulatory loop and act in concert in the course of osteoblastogenesis.
doi:10.1038/cddis.2014.194
PMCID: PMC4047903  PMID: 24853417
inositol-requiring enzyme-1a; osteoblastogenesis; GEP; BMP2; unfolded protein response
7.  Superior Tensile Ductility in Bulk Metallic Glass with Gradient Amorphous Structure 
Scientific Reports  2014;4:4757.
Over centuries, structural glasses have been deemed as a strong yet inherently ‘brittle’ material due to their lack of tensile ductility. However, here we report bulk metallic glasses exhibiting both a high strength of ~2 GPa and an unprecedented tensile elongation of 2–4% at room temperature. Our experiments have demonstrated that intense structural evolution can be triggered in theses glasses by the carefully controlled surface mechanical attrition treatment, leading to the formation of gradient amorphous microstructures across the sample thickness. As a result, the engineered amorphous microstructures effectively promote multiple shear banding while delay cavitation in the bulk metallic glass, thus resulting in superior tensile ductility. The outcome of our research uncovers an unusual work-hardening mechanism in monolithic bulk metallic glasses and demonstrates a promising yet low-cost strategy suitable for producing large-sized, ultra-strong and stretchable structural glasses.
doi:10.1038/srep04757
PMCID: PMC3996486  PMID: 24755683
8.  The atomic-scale mechanism for the enhanced glass-forming-ability of a Cu-Zr based bulk metallic glass with minor element additions 
Scientific Reports  2014;4:4648.
It is known that the glass forming-ability (GFA) of bulk metallic glasses (BMGs) can be greatly enhanced via minor element additions. However, direct evidence has been lacking to reveal its structural origin despite different theories hitherto proposed. Through the high-resolution transmission-electron-microscopy (HRTEM) analysis, here we show that the content of local crystal-like orders increases significantly in a Cu-Zr-Al BMG after a 2-at% Y addition. Contrasting the previous studies, our current results indicate that the formation of crystal-like order at the atomic scale plays an important role in enhancing the GFA of the Cu-Zr-Al base BMG.
doi:10.1038/srep04648
PMCID: PMC3983660  PMID: 24721927
9.  Research on Dynamic Routing Mechanisms in Wireless Sensor Networks 
The Scientific World Journal  2014;2014:165694.
WirelessHART is the most widely applied standard in wireless sensor networks nowadays. However, it does not provide any dynamic routing mechanism, which is important for the reliability and robustness of the wireless network applications. In this paper, a collection tree protocol based, dynamic routing mechanism was proposed for WirelessHART network. The dynamic routing mechanism was evaluated through several simulation experiments in three aspects: time for generating the topology, link quality, and stability of network. Besides, the data transmission efficiency of this routing mechanism was analyzed. The simulation and evaluation results show that this mechanism can act as a dynamic routing mechanism for the TDMA-based wireless sensor network.
doi:10.1155/2014/165694
PMCID: PMC4005053  PMID: 24982927
10.  Loss of TACSTD2 contributed to squamous cell carcinoma progression through attenuating TAp63-dependent apoptosis 
Wang, F | Liu, X | Yang, P | Guo, L | Liu, C | Li, H | Long, S | Shen, Y | Wan, H
Cell Death & Disease  2014;5(3):e1133-.
Tumor-associated calcium signal transducer 2 (TACSTD2), a calcium signal transducer, is universally expressed in stratified squamous epithelia of many organs, including skin, esophagus and cervix. Although TACSTD2, was reported to be overexpressed in many epithelial tumors, which has increased interest in using it as a molecular target for cancer therapy, the role of TACSTD2 in carcinogenesis of squamous cell carcinoma (SCC) is largely unclear and controversial. To explore the role of TACSTD2, temporal-spatial expression of TACSTD2 was analyzed in both normal and SCC tissues. Our data demonstrate that Tacstd2 expression and membrane localization are tightly associated with stratified epithelial homeostasis, while loss of TACSTD2 was identified in poorly differentiated SCC tissues collected from cervix, esophagus, head and neck. Gradual loss of TACSTD2 was correlated with stepwise progression of SCC. Consistent with these in vivo observations, our data show that inhibition of Tacstd2 expression significantly inhibited chemotherapeutic reagent-induced apoptosis, and TACSTD2 regulated apoptotic gene expression through P63 containing the transactivation domain (TAp63). These findings indicated that loss of TACSTD2 could promote SCC progression and treatment resistance through attenuating chemotherapeutic reagent-induced apoptosis through TAp63, and TACSTD2 could be used as a marker for pathological grading of SCC.
doi:10.1038/cddis.2014.96
PMCID: PMC3973208  PMID: 24651436
TACSTD2; squamous cell carcinoma; apoptosis; TAp63; tumor progression
11.  MiRNA-210 modulates a nickel-induced cellular energy metabolism shift by repressing the iron–sulfur cluster assembly proteins ISCU1/2 in Neuro-2a cells 
He, M | Lu, Y | Xu, S | Mao, L | Zhang, L | Duan, W | Liu, C | Pi, H | Zhang, Y | Zhong, M | Yu, Z | Zhou, Z
Cell Death & Disease  2014;5(2):e1090-.
The cellular energy metabolism shift, characterized by the inhibition of oxidative phosphorylation (OXPHOS) and enhancement of glycolysis, is involved in nickel-induced neurotoxicity. MicroRNA-210 (miR-210) is regulated by hypoxia-inducible transcription factor-1α (HIF-1α) under hypoxic conditions and controls mitochondrial energy metabolism by repressing the iron–sulfur cluster assembly protein (ISCU1/2). ISCU1/2 facilitates the assembly of iron–sulfur clusters (ISCs), the prosthetic groups that are critical for mitochondrial oxidation-reduction reactions. This study aimed to investigate whether miR-210 modulates alterations in energy metabolism after nickel exposure through suppressing ISCU1/2 and inactivating ISCs-containing metabolic enzymes. We determined that NiCl2 exposure leads to a significant accumulation of HIF-1α, rather than HIF-1β, in Neuro-2a cells. The miR-210 overexpression and ISCU1/2 downregulation was observed in a dose- and time-dependent manner. The gain-of-function and loss-of-dysfunction assays revealed that miR-210 mediated the ISCU1/2 suppression, energy metabolism alterations, and ISC-containing metabolic enzyme inactivation after nickel exposure. In addition, the impact of miR-210 on ISC-containing metabolic enzymes was independent from cellular iron regulation. Overall, these data suggest that repression of miR-210 on ISCU1/2 may contribute to HIF-1α-triggered alterations in energy metabolism after nickel exposure. A better understanding of how nickel impacts cellular energy metabolism may facilitate the elucidation of the mechanisms by which nickel affects the human health.
doi:10.1038/cddis.2014.60
PMCID: PMC3944272  PMID: 24577088
nickel; energy metabolism shift; miR-210; ISCU1/2; glycolysis
13.  Accumulation of heavy metals in leaf vegetables from agricultural soils and associated potential health risks in the Pearl River Delta, South China 
This study investigated the extent of heavy metal accumulation in leaf vegetables and associated potential health risks in agricultural areas of the Pearl River Delta (PRD), South China. Total concentrations of mercury (Hg), cadmium (Cd), lead (Pb), chromium (Cr) and arsenic (As) were determined in 92 pairs of soil and leaf vegetable (flowering Chinese cabbage, lettuce, pakchoi, Chinese cabbage, loose-leaf lettuce, and Chinese leaf mustard) samples collected from seven agricultural areas (cities). The bioconcentration factors (BCF) of heavy metals from soil to vegetables were estimated, and the potential health risks of heavy metal exposure to the PRD residents through consumption of local leaf vegetables were assessed. Results showed that among the six leaf vegetables, pakchoi had the lowest capacity for heavy metal enrichment, whereas among the five heavy metals, Cd had the highest capacity for transferring from soil into vegetables, with BCF values 30-fold those of Hg and 50-fold those of Cr, Pb and As. Sewage irrigation and fertilization were likely the main sources of heavy metals accumulated in leaf vegetables grown in agricultural areas of the PRD region. Different from previous findings, soil pH had no clear effect on metal accumulation in leaf vegetables. Despite a certain degree of metal enrichment from soil to leaf vegetables, the PRD residents were not exposed to significant health risks associated with consumption of local leaf vegetables. Nevertheless, more attention should be paid to children due to their sensitivity to metal pollutants.
doi:10.1007/s10661-013-3472-0
PMCID: PMC3902199  PMID: 24185814
Pearl River Delta; Leaf vegetables; Heavy metals; Bioconcentration factor; Target hazard quotient
14.  Blue-blocking intraocular implants should be used routinely during phacoemulsification surgery – No 
Eye  2012;26(11):1400-1401.
doi:10.1038/eye.2012.177
PMCID: PMC3496097  PMID: 22955038
15.  Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource 
Diabetologia  2012;55(11):2970-2984.
Aims/hypothesis
Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs.
Methods
We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (Fsts) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ±250 kb around each EuA SNP in AfAs.
Results
Allele frequency differences ranged from 0.6% to 54%. Fst exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p=5.8 × 10-8; MTNR1B, p=8.5 × 10-9; and FADS1, p=2.2 × 10-4) or FI (GCKR, p=5.9 × 10-4). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r2<0.2), suggesting allelic heterogeneity for association with FG at these loci.
Conclusions/interpretation
Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.
doi:10.1007/s00125-012-2656-4
PMCID: PMC3804308  PMID: 22893027
African ancestry; Genetics; Genome-wide association; LD mapping; Minorities; Type 2 diabetes
16.  Fabrication of 200 nanometer period centimeter area hard x-ray absorption gratings by multilayer deposition 
We describe the design and fabrication trials of x-ray absorption gratings of 200 nm period and up to 100:1 depth-to-period ratios for full-field hard x-ray imaging applications. Hard x-ray phase-contrast imaging relies on gratings of ultra-small periods and sufficient depth to achieve high sensitivity. Current grating designs utilize lithographic processes to produce periodic vertical structures, where grating periods below 2.0 μm are difficult due to the extreme aspect ratios of the structures. In our design, multiple bilayers of x-ray transparent and opaque materials are deposited on a staircase substrate, and mostly on the floor surfaces of the steps only. When illuminated by an x-ray beam horizontally, the multilayer stack on each step functions as a micro-grating whose grating period is the thickness of a bilayer. The array of micro-gratings over the length of the staircase works as a single grating over a large area when continuity conditions are met. Since the layers can be nanometers thick and many microns wide, this design allows sub-micron grating periods and sufficient grating depth to modulate hard x-rays. We present the details of the fabrication process and diffraction profiles and contact radiography images showing successful intensity modulation of a 25 keV x-ray beam.
doi:10.1088/0960-1317/22/10/105007
PMCID: PMC3468157  PMID: 23066175
17.  Discrimination between neoplastic and non-neoplastic lesions in cirrhotic liver using contrast-enhanced ultrasound 
The British Journal of Radiology  2012;85(1018):1376-1384.
Objectives
To assess the value of contrast-enhanced ultrasound (CEUS) in differentiating hepatocellular carcinoma (HCC) from non-neoplastic lesion in cirrhotic liver in comparison with baseline ultrasound.
Methods
A total of 147 nodules (diameter ≤5.0 cm) in 133 cirrhotic patients (mean age±standard deviation: 52±13 years, range 20–82 years; gender: 111 males and 22 females) were examined with CEUS. There were 116 HCCs, 26 macroregenerative nodules and 5 high-grade dysplastic nodules. CEUS was performed with a real-time contrast-specific mode and a sulphur hexafluoride-filled microbubble contrast agent.
Results
Hypervascularity was observed in 94.8% (110/116) HCCs, 3.8% (1/26) macroregenerative nodules and 60.0% (3/5) high-grade dysplastic nodules during arterial phase on CEUS. Detection rates of typical vascular pattern (i.e. hypervascularity during arterial phase and subsequent washout) in HCCs with a diameter of ≤2.0 cm, 2.1–3.0 cm and 3.1–5.0 cm were 69.2% (27/39), 97.1% (33/34) and 100.0% (43/43), respectively. CEUS significantly improved the sensitivity [88.8% (103/116) vs 37.1% (43/116), p<0.001], negative predictive value [70.5% (31/44) vs 31.5% (29/92), p<0.001], and accuracy [91.2% (134/147) vs 49.0% (72/147), p<0.001] in differentiating HCCs from non-neoplastic lesions when compared with baseline ultrasound. However, the sensitivity and accuracy of CEUS for HCCs ≤2.0 cm in diameter were significantly lower than those for HCCs of 2.1–3.0 cm and 3.1–5.0 cm in diameter.
Conclusions
CEUS improves diagnostic performance in differentiating HCCs from non-neoplastic nodules in cirrhotic patients compared with baseline ultrasound. Diagnosis of HCCs ≤2.0 cm diameter by CEUS is still a clinical concern, and thus needs further investigation.
doi:10.1259/bjr/19932596
PMCID: PMC3474036  PMID: 22553290
18.  Enrichment of Cis-Regulatory Gene Expression SNPs and Methylation Quantitative Trait Loci Among Bipolar Disorder Susceptibility Variants 
Molecular psychiatry  2012;18(3):340-346.
We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of Bipolar Disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as mQTLs. Bipolar Disorder susceptibility variants that cis-regulate both cerebellar expression and methylation of the same gene are a very small proportion of Bipolar Disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of SNPs studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, Pbonferroni<0.05) from two other GWA studies (TGen+GAIN; 2,191 cases and 1,434 controls) of Bipolar Disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance biological understanding of Bipolar Disorder.
doi:10.1038/mp.2011.174
PMCID: PMC3601550  PMID: 22212596
19.  SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-κB pathway 
Chronic inflammation induced by amyloid-beta (Aβ) plays a key role in the development of age-related macular degeneration (AMD), and matrix metalloproteinase-9 (MMP-9), interleukin (IL)-6, and IL-8 may be associated with chronic inflammation in AMD. Sirtuin 1 (SIRT1) regulates inflammation via inhibition of nuclear factor-kappa B (NF-κB) signaling, and resveratrol has been reported to prevent Aβ-induced retinal degeneration; therefore, we investigated whether this action was mediated via activation of SIRT1 signaling. Human adult retinal pigment epithelial (RPE) cells were exposed to Aβ, and overactivation and knockdown of SIRT1 were performed to investigate whether SIRT1 is required for abrogating Aβ-induced inflammation. We found that Aβ-induced RPE barrier disruption and expression of IL-6, IL-8, and MMP-9 were abrogated by the SIRT1 activator SRT1720, whereas alterations induced by Aβ in SIRT1-silenced RPE cells were not attenuated by SRT1720. In addition, SRT1720 inhibited Aβ-mediated NF-κB activation and decrease of the NF-κB inhibitor, IκBα. Our findings suggest a protective role for SIRT1 signaling in Aβ-dependent retinal degeneration and inflammation in AMD.
doi:10.1590/1414-431X20132903
PMCID: PMC3854412  PMID: 24036938
Amyloid-beta; SRT1720; Age-related macular degeneration; Barrier integrity; Tight junction; Matrix metalloproteinase-9
20.  Identification of the IFITM3 gene as an inhibitor of hepatitis C viral translation in a stable STAT1 cell line 
Journal of viral hepatitis  2011;18(10):e523-e529.
SUMMARY
To investigate the functions of signal transducers and activators of transcription 1 (STAT1)-induced anti-hepatitis C viral (HCV) effects, a stable Huh7.5 cell line (Huh7.5-STAT1ER) was established that constitutively expresses a fusion protein (STAT1ER) of STAT1 and the mouse oestrogen receptor (ER), which forms STAT1ER homodimers after 4-hydroxytamoxifen (4-HT) treatment. This inducible and cytokine/receptor-independent STAT1 activation system allowed us to investigate the anti-HCV effects of STAT1ER activation after inducing IFN-stimulated gene (ISG) expression. The anti-HCV effects of dimerized STAT1ER fusion protein were determined by real-time PCR in a time-dependent fashion post-HCV (JFH-1) infection. HCV (JFH-1) RNA decreased 48% at 72 h after 4-HT treatment. To distinguish the inhibitory effects of STAT1ER activation on HCV RNA replication or HCV internal ribosomal entry site (IRES)–mediated translation, a dicistronic pRL-HL construct was used in the studies. Both cellular (Cap-dependent) and HCV IRES–mediated (Cap-independent) translation were decreased by 63% and 57% at 72 h post-STAT1ER activation in the STAT1ER cell line. In our previous studies, interferon-induced transmembrane protein 3 [(IFITM3) (1-8U)] was found to inhibit HCV RNA replication. Subsequently, elevated expression of the 1-8U gene was confirmed by Western blotting in the Huh7.5-STAT1ER cell line. To further investigate the 1-8U function with both in vivo and in vitro studies, the 1-8U gene was found to suppress cellular and HCV IRES–mediated translation.
doi:10.1111/j.1365-2893.2011.01452.x
PMCID: PMC3736357  PMID: 21914072
HCV IRES; hepatitis C virus; IFITM3 (1-8U); mouse oestrogen receptor; STAT1 dimerization
21.  ‘Bilateral same-day cataract surgery should routinely be offered to patients' – Yes 
Eye  2012;26(8):1031-1032.
doi:10.1038/eye.2012.91
PMCID: PMC3420059  PMID: 22627478
22.  Contrast-enhanced ultrasound of intrahepatic cholangiocarcinoma: correlation with pathological examination 
The British Journal of Radiology  2012;85(1016):1029-1037.
Objective
To investigate the correlation between enhancement patterns of intrahepatic cholangiocarcinoma (ICC) on contrast-enhanced ultrasound (CEUS) and pathological findings.
Methods
The CEUS enhancement patterns of 40 pathologically proven ICC lesions were retrospectively analysed. Pathologically, the degree of tumour cell and fibrosis distribution in the lesion was semi-quantitatively evaluated.
Results
4 enhancement patterns were observed in the arterial phase for 32 mass-forming ICCs: peripheral rim-like hyperenhancement (n=19); heterogeneous hyperenhancement (n=6); homogeneous hyperenhancement (n=3); and heterogeneous hypo-enhancement (n=4). Among the four enhancement patterns, the differences in tumour cell distribution were statistically significant (p<0.05). The hyperenhancing area on CEUS corresponded to more tumour cells for mass-forming ICCs. Heterogeneous hyperenhancement (n=2) and heterogeneous hypo-enhancement (n=2) were observed in the arterial phase for four periductal infiltrating ICCs. In this subtype, fibrosis was more commonly found in the lesions. Heterogeneous hyperenhancement (n=1) and homogeneous hyperenhancement (n=3) were observed in the arterial phase for four intraductal growing ICCs. This subtype tended to have abundant tumour cells.
Conclusion
The CEUS findings of ICC relate to the degree of carcinoma cell proliferation at pathological examination. Hyperenhancing areas in the tumour always indicated increased density of cancer cells.
doi:10.1259/bjr/21653786
PMCID: PMC3587094  PMID: 22374276
23.  First-principles prediction and experimental verification of glass-forming ability in Zr-Cu binary metallic glasses 
Scientific Reports  2013;3:2124.
In the field of metallic materials with amorphous structures, it is vitally important to understand the glass formation and to predict glass-forming ability (GFA) in terms of constituent elements and alloy compositions. In this study, an expression has been formulated from first-principles calculations to predict the trend of GFA by hybridizing both internal energies and atomic-scale defect structures. The prediction of GFA from compositions has been verified successfully by available experimental data in the model Zr-Cu alloy system. The physical scenario revealed here has extensive implications for the design of bulk metallic glasses with superior GFA.
doi:10.1038/srep02124
PMCID: PMC3699808  PMID: 23821016
24.  The current practice trends in pediatric bone-anchored hearing aids in Canada: a national clinical and surgical practice survey 
Background
Since the introduction of bone-anchored hearing aids (BAHAs) in the 1980s, the practices of surgeons who implant these hearing aids have become varied; different indications and surgical techniques are utilized depending on the surgeon and institution. The objective of the current study is to describe the clinical and surgical practices of otolaryngologists in Canada who perform pediatric BAHA operations.
Methods
A detailed practice questionnaire was devised and sent to all members of the Canadian Society of Otolaryngology-Head and Neck Surgery. Those who performed pediatric BAHA surgeries were asked to participate.
Results
Twelve responses were received (response rate of 80%). All of the respondents identified congenital aural atresia to be an indication for pediatric BAHAs. Other indications were chronic otitis externa or media with hearing loss (92%), allergic reactions to conventional hearing aids (75%), congenital fixation or anomaly of ossicular chain (67%), and unilateral deafness (25%). Minor complications, such as skin reactions, were reported in 25% of cases, while major complications were very rare. There was great variability with regards to surgical techinque and post-operative management. The extent of financial support for the BAHA hardware and device also varied between provinces, and even within the same province.
Conclusion
There is a lack of general consensus regarding pediatric BAHA surgeries in Canada. With such a small community of otolaryngologists performing this procedure, we are hopeful that this survey can serve as an impetus for a national collaboration to establish a set of general management principles and inspire multi-site research ventures.
doi:10.1186/1916-0216-42-43
PMCID: PMC3702399  PMID: 23815797
Bone-anchored hearing aid; BAHA; Surgical practice; Clinical practice; Practice survey; Pediatrics
25.  miR-874 regulates myocardial necrosis by targeting caspase-8 
Cell Death & Disease  2013;4(7):e709-.
Cardiomyocyte death is an important reason for the cardiac syndromes, such as heart failure (HF) and myocardial infarction (MI). In the heart diseases, necrosis is one of the main forms of cell death. MicroRNAs (miRNAs) are a class of small non-coding RNAs that mediate post-transcriptional gene silencing. Hitherto, it is not yet clear whether miRNA can regulate necrosis in cardiomyocyte. In this work, we performed a microarray to detect miRNAs in response to H2O2 treatment, and the results showed that miR-874 was substantially increased. We further studied the function of miR-874, and observed that knockdown of miR-874 attenuated necrosis in the cellular model and also MI in the animal model. We searched for the downstream mediator of miR-874 and identified that caspase-8 was a target of miR-874. Caspase-8 was able to antagonize necrosis. When suppressed by miR-874, caspase-8 lost the ability to repress necrotic program. In exploring the molecular mechanism by which miR-874 expression is regulated, we identified that Foxo3a could transcriptionally repress miR-874 expression. Foxo3a transgenic or knockout mice exhibited a low or high expression level of miR-874, and a reduced or enhanced necrosis and MI. Our present study reveals a novel myocardial necrotic regulating model, which is composed of Foxo3a, miR-874 and caspase-8. Modulation of their levels may provide a new approach for tackling myocardial necrosis.
doi:10.1038/cddis.2013.233
PMCID: PMC3730407  PMID: 23828572
myocardial necrosis; miR-874; caspase-8

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