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1.  Cognitive trio: relationship with major depression and clinical predictors in Han Chinese women 
Psychological Medicine  2013;43(11):2265-2275.
Previous studies support Beck's cognitive model of vulnerability to depression. However, the relationship between his cognitive triad and other clinical features and risk factors among those with major depression (MD) has rarely been systematically studied.
The three key cognitive symptoms of worthlessness, hopelessness and helplessness were assessed during their lifetime worst episode in 1970 Han Chinese women with recurrent MD. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Compared to patients who did not endorse the cognitive trio, those who did had a greater number of DSM-IV A criteria, more individual depressive symptoms, an earlier age at onset, a greater number of episodes, and were more likely to meet diagnostic criteria for melancholia, postnatal depression, dysthymia and anxiety disorders. Hopelessness was highly related to all the suicidal symptomatology, with ORs ranging from 5.92 to 6.51. Neuroticism, stressful life events (SLEs) and a protective parental rearing style were associated with these cognitive symptoms.
During the worst episode of MD in Han Chinese women, the endorsement of the cognitive trio was associated with a worse course of depression and an increased risk of suicide. Individuals with high levels of neuroticism, many SLEs and high parental protectiveness were at increased risk for these cognitive depressive symptoms. As in Western populations, symptoms of the cognitive trio appear to play a central role in the psychopathology of MD in Chinese women.
PMCID: PMC3807662  PMID: 23425530
Cognitive trio; Han Chinese women; major depression; suicide; symptoms
2.  β-Arrestin1 promotes the progression of chronic myeloid leukaemia by regulating BCR/ABL H4 acetylation 
Qin, R | Li, K | Qi, X | Zhou, X | Wang, L | Zhang, P | Zou, L
British Journal of Cancer  2014;111(3):568-576.
β-Arrestins are scaffold proteins that interact with various cellular signals. Although β-arrestin2 mediates the initiation and progression of myeloid leukaemia, the critical role of β-arrestin1 in the chronic myeloid leukaemia (CML) is still unknown. The aim of this study is to investigate the essential function of β-arrestin1 in CML.
The expressions of β-arrestin1 and BCR/ABL in CML patients, animal models and K562 cells were measured by RT–PCR, immunofluorescence and western blotting. The effect of β-arrestin1 on CML animal models and K562 cells by colony formation, MTT and survival analysis were assessed. BCR/ABL H4 acetylation was analysed through the use of Chromatin-immunoprecipitation (ChIP) -on-chip and confirmed by ChIP respectively. Co-immunoprecipitation and confocal were examined for the binding of β-arrestin1 with enhancer of zeste homologue 2 (EZH2).
The higher expression of β-arrestin1 is positively correlated with clinical phases of CML patients. Depletion of β-arrestin1 decelerates progression of K562 and primary cells, and increases survival of CML mice. Importantly, silenced β-arrestin1 results in the decrease of BCR/ABL H4 acetylation level in K562 cells. Further data illustrate that nuclear β-arrestin1 binds to EZH2 to mediate BCR/ABL acetylation and thus regulates cell progression in K562 cells and the survival of CML mice.
Our findings reveal a novel function of β-arrestin1 binding to EZH2 to promote CML progression by regulating BCR/ABL H4 acetylation.
PMCID: PMC4119990  PMID: 24937675
β-arrestin1; chronic myeloid leukaemia (CML); BCR/ABL; acetylation; enhancer of zeste homologue 2 (EZH2)
3.  MRI Methods for Evaluating the Effects of Tyrosine Kinase Inhibitor Administration Used to Enhance Chemotherapy Efficiency in a Breast Tumor Xenograft Model 
To evaluate whether quantitative MRI parameters are sensitive to the effects of the tyrosine kinase inhibitor gefitinib and can discriminate between two different treatment protocols.
Materials and Methods
Untreated mice with BT474 breast tumor xenografts were characterized in a preliminary study. Subsequently, tumor volume, apparent diffusion coefficient (ADC), transendothelial permeability (Kps), and fractional plasma volume (fPV) were measured in three groups of mice receiving: 1) control vehicle for 10 days, or gefitinib as 2) a single daily dose for 10 days or 3) a 2-day pulsed dose.
Gefitinib treatment resulted in significant tumor growth inhibition (pulsed: 439 ± 93; daily: 404 ± 53; control: 891 ± 174 mm3, P < 0.050) and lower cell density (pulsed: 0.15 ± 0.01, daily: 0.17 ± 0.01, control: 0.24 ± 0.01, P < 0.050) after 9 days. Tumor ADC increased in treated groups but decreased in controls (P > 0.050). Tumor Kps decreased with pulsed treatment but rebounded afterwards and increased with daily treatment (P > 0.050). Tumor fPV increased in both treated groups, decreasing afterwards with pulsed treatment (P > 0.050).
Quantitative MRI can provide a sensitive measure of gefitinib-induced tumor changes, potentially distinguish between treatment regimens, and may be useful for determining optimal treatment scheduling for enhancing chemotherapy delivery.
PMCID: PMC4511711  PMID: 19388114
chemotherapy; dynamic contrast enhanced; diffusion weighted imaging; gefitinib; tyrosine kinase inhibitor; xenograft tumor model
4.  Efficacy and toxicity of external-beam radiation therapy for localised prostate cancer: a network meta-analysis 
Zhu, Z | Zhang, J | Liu, Y | Chen, M | Guo, P | Li, K
British Journal of Cancer  2014;110(10):2396-2404.
Many radiation regimens for treating prostate cancer have been used over the years, but which regimen is optimal for localised or locally advanced prostate cancer lacks consensus. We performed a network meta-analysis to identify the optimal radiation regimen.
We systematically reviewed data from 27 randomised controlled trials and could group seven radiation regimens as follows: low- and high-dose radiation therapy (LDRT and HDRT), LDRT+ short- or long-term androgen deprivation therapy (LDRT+SADT and LDRT+LADT), HDRT+SADT, hypofractionated radiotherapy (HFRT), and HFRT+SADT. The main outcomes were overall mortality (OM), prostate-specific antigen (PSA) failure, cancer-specific mortality, and adverse events.
For the network meta-analysis of 27 trials, LDRT+LADT and LDRT+SADT were associated with decreased risk of OM as compared with LDRT alone as was LDRT+LADT compared with HDRT. Apart from HFRT, all other treatments were associated with decreased risk of PSA failure as compared with LDRT. HFRT+SADT was associated with decreased risk of cancer-specific mortality as compared with HFRT, LDRT+SADT, HDRT, and LDRT.
HFRT+SADT therapy might be the most efficacious treatment but with worst toxicity for localised or locally advanced prostate cancer, and HDRT showed excellent efficacy but more adverse events.
PMCID: PMC4021530  PMID: 24736585
EBRT; prostate cancer; network meta-analysis
5.  The miR-106b∼25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300 
Cell Death and Differentiation  2013;21(3):462-474.
Resistance to chemotherapeutic treatment, which is indirectly responsible for many cancer deaths, is normally associated with an aggressive phenotype including increased cell motility and acquisition of invasive properties. Here we describe how breast cancer cells overcome doxorubicin-induced senescence and become drug resistant by overexpression of the microRNA (miR)-106b∼25 cluster. Although all three miRs in the cluster contribute to the generation of doxorubicin resistance, miR-25 is the major contributor to this phenotype. All three miRs in this cluster target EP300, a transcriptional activator of E-cadherin, resulting in cells acquiring a phenotype characteristic of cells undergoing epithelial-to-mesenchymal transition (EMT), including an increase in both cell motility and invasion, as well as the ability to proliferate after treatment with doxorubicin. These findings provide a novel drug resistance/EMT regulatory pathway controlled by the miR-106b∼25 cluster by targeting a transcriptional activator of E-cadherin.
PMCID: PMC3921594  PMID: 24270410
doxorubicin-induced senescence; EMT; cancer stem cells; E-cadherin; EP300
6.  MRI findings of solitary fibrous tumours in the head and neck region 
Liu, Y | Tao, X | Shi, H | Li, K
Dentomaxillofacial Radiology  2014;43(3):20130415.
To analyse the MRI findings of solitary fibrous tumours in the head and neck region.
We retrospectively reviewed MR images in eight patients with solitary fibrous tumours proven on histological examination. All the patients underwent conventional MRI, and four patients also underwent dynamic contrast-enhanced MRI and diffusion-weighted imaging in five cases. Image characteristics were analysed.
All lesions were found as solitary well-defined masses ranging in size from 1.9 to 6.8 cm (mean, 4.1 cm). They were mostly homogeneous and isointense to the muscle on T1 weighted images and heterogeneous and mildly hyperintense on T2 weighted images. After gadolinium administration, areas that were mildly hyperintense on T2 weighted images were strongly enhanced. They were mildly hyperintense on diffusion-weighted imaging. The average tumour-apparent diffusion coefficient values were 0.001 157 ± 0.000 304 9 mm s−2 compared with the muscle 0.000 760 ± 0.000 265 0 mm s−2, and there was a statistical difference of p = 0.002. The time–intensity curves exhibited a rapidly enhancing and a slow washout pattern on dynamic contrast-enhanced MRI.
Solitary fibrous tumours should be considered in cases of heterogeneous hypervascular tumours in the head and neck region. Areas of mild hyperintense intensity on T2 weighted images that are strongly enhanced after gadolinium injection are suggestive of this diagnosis. Non-restricted diffusion and rapidly enhancing and slow washout pattern time–intensity curves may be additional valuable features.
PMCID: PMC4064629  PMID: 24720608
solitary fibrous tumours; head and neck; magnetic resonance imaging; dynamic contrast-enhanced imaging; diffusion-weighted imaging
7.  Electrowetting on liquid-infused film (EWOLF): Complete reversibility and controlled droplet oscillation suppression for fast optical imaging 
Scientific Reports  2014;4:6846.
Electrowetting on dielectric (EWOD) has emerged as a powerful tool to electrically manipulate tiny individual droplets in a controlled manner. Despite tremendous progress over the past two decades, current EWOD operating in ambient conditions has limited functionalities posing challenges for its applications, including electronic display, energy generation, and microfluidic systems. Here, we demonstrate a new paradigm of electrowetting on liquid-infused film (EWOLF) that allows for complete reversibility and tunable transient response simultaneously. We determine that these functionalities in EWOLF are attributed to its novel configuration, which allows for the formation of viscous liquid-liquid interfaces as well as additional wetting ridges, thereby suppressing the contact line pinning and severe droplet oscillation encountered in the conventional EWOD. Finally, by harnessing these functionalities demonstrated in EWOLF, we also explore its application as liquid lens for fast optical focusing.
PMCID: PMC4213809  PMID: 25355005
8.  Retinotopic maps in the pulvinar of bush baby (Otolemur garnettii) 
The Journal of comparative neurology  2013;521(15):10.1002/cne.23358.
Despite its anatomical prominence, the function of primate pulvinar is poorly understood. A few electrophysiological studies in simian primates have investigated the functional organization of pulvinar by examining visuotopic maps. Multiple visuotopic maps have been found in all studied simians, with differences in organization reported between New and Old World simians. Given that prosimians are considered closer to the common ancestors of New and Old World primates, we investigated the visuotopic organization of pulvinar in the prosimian bush baby (Otolemur garnettii). Single electrode extracellular recording was used to find the retinotopic maps in the lateral (PL) and inferior (PI) pulvinar. Based on recordings across cases a 3D model of the map was constructed. From sections stained for Nissl bodies, myelin, acetylcholinesterase, calbindin or cytochrome oxidase, we identified three PI chemoarchitectonic subdivisions, lateral central (PIcl), medial central (PIcm) and medial (PIm) inferior pulvinar. Two major retinotopic maps were identified that cover PL and PIcl, the dorsal one in dorsal PL and the ventral one in PIcl and ventral PL. Both maps represent the central vision at the posterior end of the border between the maps, the upper visual field in the lateral half and the lower visual field in the medial half. They share many features with the maps reported in the pulvinar of simians, including location in pulvinar and the representation of the upper-lower and central-peripheral visual field axes. The second order representation in the lateral map and a laminar organization are likely features specific to Old World simians.
PMCID: PMC3775912  PMID: 23640865
electrophysiology; greater galago; chemoarchitecture; single unit; thalamus; vision
9.  Higher order Arabidopsis 14-3-3 mutants show 14-3-3 involvement in primary root growth both under control and abiotic stress conditions 
Journal of Experimental Botany  2014;65(20):5877-5888.
Our research shows that there is isoform specificity and redundancy among 6 out of 13 14-3-3 members in root growth under control and abiotic stress conditions.
Arabidopsis 14-3-3 proteins are a family of conserved proteins that interact with numerous partner proteins in a phospho-specific manner, and can affect the target proteins in a number of ways; e.g. modification of enzymatic activity. We isolated T-DNA insertion lines in six 14-3-3 genes within the non-epsilon group that phylogenetically group in three closely related gene pairs. In total, 6 single, 3 double, 12 triple, and 3 quadruple mutants were generated. The mutants were phenotyped for primary root growth on control plates: single and double mutants were indistinguishable from WT, whereas six triples and all quadruples showed a shorter primary root. In addition, length of the first epidermal cell with a visible root hair bulge (LEH) was used to determine primary root elongation on medium containing mannitol and 1-aminocyclopropane-1-carboxylic acid (ACC). This analysis showed clear differences depending on the stress and 14-3-3 gene combinations. Next to the phenotypic growth analyses, a 14-3-3 pull-down assay on roots treated with and without mannitol showed that mannitol stress strongly affects the 14-3-3 interactome. In conclusion, we show gene specificity and functional redundancy among 14-3-3 proteins in primary root elongation under control and under abiotic stress conditions and changes in the 14-3-3 interactome during the onset of stress adaptation.
PMCID: PMC4203132  PMID: 25189593
Redundancy; 14-3-3; abiotic stress; LEH; stress-interactome; primary root.
10.  Zinc finger protein 637 protects cells against oxidative stress-induced premature senescence by mTERT-mediated telomerase activity and telomere maintenance 
Cell Death & Disease  2014;5(7):e1334-.
Oxidative stress is believed to be an important inducer of cellular senescence and aging. Zinc finger protein 637 (Zfp637), which belongs to the Krüppel-like protein family, has been hypothesized to play a role in oxidative stress. Nevertheless, the precise function of Zfp637 has seldom been reported, and it remains unclear whether Zfp637 is involved in oxidative stress-induced premature senescence. In this study, we show that the endogenous expression levels of Zfp637 and mouse telomerase reverse transcriptase (mTERT) are downregulated during oxidative stress-induced premature senescence and in senescent tissues from naturally aged mice. The overexpression of Zfp637 markedly increases mTERT expression and telomerase activity, maintains telomere length, and inhibits both H2O2 and D-galactose-induced senescence accompanied by a reduction in the production of reactive oxygen species (ROS). In contrast, the knockdown of Zfp637 significantly aggravates cellular senescence by downregulating mTERT and telomerase activity, accelerating telomere shortening, and increasing ROS accumulation. In addition, the protective effect of Zfp637 against premature senescence is abrogated in the absence of mTERT. We further confirm that Zfp637 binds to and transactivates the mTERT promoter (−535/−502) specifically. As a result, the mTERT-mediated telomerase activity and telomere maintenance are responsible for the protective effect of Zfp637 against oxidative stress-induced senescence. We therefore propose that Zfp637 prevents oxidative stress-induced premature senescence in an mTERT-dependent manner, and these results provide a new foundation for the investigation of cellular senescence and aging.
PMCID: PMC4123090  PMID: 25032857
11.  Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy 
Translational Psychiatry  2014;4(6):e400-.
Autism spectrum disorders (ASDs) now affect 1–2% of the children born in the United States. Hundreds of genetic, metabolic and environmental factors are known to increase the risk of ASD. Similar factors are known to influence the risk of schizophrenia and bipolar disorder; however, a unifying mechanistic explanation has remained elusive. Here we used the maternal immune activation (MIA) mouse model of neurodevelopmental and neuropsychiatric disorders to study the effects of a single dose of the antipurinergic drug suramin on the behavior and metabolism of adult animals. We found that disturbances in social behavior, novelty preference and metabolism are not permanent but are treatable with antipurinergic therapy (APT) in this model of ASD and schizophrenia. A single dose of suramin (20 mg kg−1 intraperitoneally (i.p.)) given to 6-month-old adults restored normal social behavior, novelty preference and metabolism. Comprehensive metabolomic analysis identified purine metabolism as the key regulatory pathway. Correction of purine metabolism normalized 17 of 18 metabolic pathways that were disturbed in the MIA model. Two days after treatment, the suramin concentration in the plasma and brainstem was 7.64 μM pmol μl−1 (±0.50) and 5.15 pmol mg−1 (±0.49), respectively. These data show good uptake of suramin into the central nervous system at the level of the brainstem. Most of the improvements associated with APT were lost after 5 weeks of drug washout, consistent with the 1-week plasma half-life of suramin in mice. Our results show that purine metabolism is a master regulator of behavior and metabolism in the MIA model, and that single-dose APT with suramin acutely reverses these abnormalities, even in adults.
PMCID: PMC4080315  PMID: 24937094
12.  Empirical Selection of Informative Microsatellite Markers within Co-ancestry Pig Populations Is Required for Improving the Individual Assignment Efficiency 
The Lanyu is a miniature pig breed indigenous to Lanyu Island, Taiwan. It is distantly related to Asian and European pig breeds. It has been inbred to generate two breeds and crossed with Landrace and Duroc to produce two hybrids for laboratory use. Selecting sets of informative genetic markers to track the genetic qualities of laboratory animals and stud stock is an important function of genetic databases. For more than two decades, Lanyu derived breeds of common ancestry and crossbreeds have been used to examine the effectiveness of genetic marker selection and optimal approaches for individual assignment. In this paper, these pigs and the following breeds: Berkshire, Duroc, Landrace and Yorkshire, Meishan and Taoyuan, TLRI Black Pig No. 1, and Kaohsiung Animal Propagation Station Black pig are studied to build a genetic reference database. Nineteen microsatellite markers (loci) provide information on genetic variation and differentiation among studied breeds. High differentiation index (FST) and Cavalli-Sforza chord distances give genetic differentiation among breeds, including Lanyu’s inbred populations. Inbreeding values (FIS) show that Lanyu and its derived inbred breeds have significant loss of heterozygosity. Individual assignment testing of 352 animals was done with different numbers of microsatellite markers in this study. The testing assigned 99% of the animals successfully into their correct reference populations based on 9 to 14 markers ranking D-scores, allelic number, expected heterozygosity (HE) or FST, respectively. All miss-assigned individuals came from close lineage Lanyu breeds. To improve individual assignment among close lineage breeds, microsatellite markers selected from Lanyu populations with high polymorphic, heterozygosity, FST and D-scores were used. Only 6 to 8 markers ranking HE, FST or allelic number were required to obtain 99% assignment accuracy. This result suggests empirical examination of assignment-error rates is required if discernible levels of co-ancestry exist. In the reference group, optimum assignment accuracy was achievable achieved through a combination of different markers by ranking the heterozygosity, FST and allelic number of close lineage populations.
PMCID: PMC4093195  PMID: 25049996
Microsatellite Markers; Pigs; Assignment Test
13.  Vertebral body corner oedema vs gadolinium enhancement as biomarkers of active spinal inflammation in ankylosing spondylitis 
The British Journal of Radiology  2012;85(1017):e702-e708.
To investigate the relative performance of T2 weighted short tau inversion–recovery (STIR) and fat-suppressed T1 weighted gadolinium contrast-enhanced sequences in depicting active inflammatory lesions in ankylosing spondylitis (AS).
Whole-spine MRI was performed on 32 patients with AS, who participated in a clinical trial of infliximab treatment, by STIR and contrast-enhanced sequences at baseline and after 30 weeks. The AS spine MRI-activity (ASspiMRI-a) scoring method was used. The images from these two imaging techniques were evaluated separately by two independent readers.
For the pre-treatment lesion status, the intraclass correlation coefficients comparing STIR readings and contrast-enhanced readings were 0.69±0.23 for Reader 1 and 0.65±0.21 for Reader 2. At baseline, the mean ASspiMRI-a score was 15.4% and 17.7% higher for contrast-enhanced images than for STIR images for Reader 1 and Reader 2, respectively. After infliximab treatment, Reader 1 rated an ASspiMRI-a score reduction of 50.8±33.6% and 25.3±35.3% for STIR images and contrast-enhanced images, respectively, whereas Reader 2 rated an ASspiMRI-a score reduction of 42.4±50.4% and 32.9±35.6% for STIR images and contrast-enhanced images, respectively.
While both contrast-enhanced and STIR sequences showed sensitivity to change over a short period of time after infliximab treatment, these two sequences may reflect different disease mechanisms.
PMCID: PMC3487088  PMID: 22595499
14.  Mammalian ncRNA-disease repository: a global view of ncRNA-mediated disease network 
Wang, Y | Chen, L | Chen, B | Li, X | Kang, J | Fan, K | Hu, Y | Xu, J | Yi, L | Yang, J | Huang, Y | Cheng, L | Li, Y | Wang, C | Li, K | Li, X | Xu, J | Wang, D
Cell Death & Disease  2013;4(8):e765-.
PMCID: PMC3763453  PMID: 23928704
15.  The role of musical training in emergent and event-based timing 
Introduction: Musical performance is thought to rely predominantly on event-based timing involving a clock-like neural process and an explicit internal representation of the time interval. Some aspects of musical performance may rely on emergent timing, which is established through the optimization of movement kinematics, and can be maintained without reference to any explicit representation of the time interval. We predicted that musical training would have its largest effect on event-based timing, supporting the dissociability of these timing processes and the dominance of event-based timing in musical performance.
Materials and Methods: We compared 22 musicians and 17 non-musicians on the prototypical event-based timing task of finger tapping and on the typically emergently timed task of circle drawing. For each task, participants first responded in synchrony with a metronome (Paced) and then responded at the same rate without the metronome (Unpaced).
Results: Analyses of the Unpaced phase revealed that non-musicians were more variable in their inter-response intervals for finger tapping compared to circle drawing. Musicians did not differ between the two tasks. Between groups, non-musicians were more variable than musicians for tapping but not for drawing. We were able to show that the differences were due to less timer variability in musicians on the tapping task. Correlational analyses of movement jerk and inter-response interval variability revealed a negative association for tapping and a positive association for drawing in non-musicians only.
Discussion: These results suggest that musical training affects temporal variability in tapping but not drawing. Additionally, musicians and non-musicians may be employing different movement strategies to maintain accurate timing in the two tasks. These findings add to our understanding of how musical training affects timing and support the dissociability of event-based and emergent timing modes.
PMCID: PMC3653057  PMID: 23717275
music; timing; finger tapping; circle drawing; emergent timing; event-based timing
16.  IRS1 gene variants, dysglycaemic metabolic changes and type-2 diabetes risk 
Background and aims
A recent genome-wide association study identified rs2943641C > T, 500 kb from the insulin receptor substrate-1 gene (IRS1), as a type-2 diabetes (T2D) susceptibility locus. We aimed to replicate this association by meta-analysis and examine whether common variants within IRS1, present on the HumanCVD BeadChip, were associated with T2D risk.
Methods and results
We genotyped rs2943641 in 2389 prevalent or incident T2D patients and 6494 controls from two prospective and three case studies based in UK and in the European Atherosclerosis Research Study-II (EARSII; n = 714). Thirty-three IRS1 variants had been genotyped in the prospective Whitehall-II study (n = 4752) using the HumanCVD BeadChip. In a fixed-effects meta-analysis of the UK study cohorts rs2943641T allele was associated with 6% lower risk of T2D (p = 0.18), with T-allele carriers having an odds ratio (OR) of 0.89 (95% confidence interval [CI]: 0.80–1.00, p = 0.056) compared to CC subjects. The T-allele was also associated with lower fasting insulin and homeostasis model assessment index of insulin resistance in Whitehall-II and with lower post-load insulin after an oral glucose tolerance test in EARSII (all p < 0.05). None of the IRS1 variants on the chip showed linkage disequilibrium with rs2943641. In silico analysis with follow-up genotyping (total n = 9313) identified that the rare allele of the IRS1 promoter variant rs6725556A > G showed association with reduced T2D risk (OR per G-allele: 0.82, 95%CI: 0.69–0.96, p = 0.015).
We confirm the association of rs2943641T with T2D protection. There is a possible independent effect on risk of a putative IRS1 promoter variant.
PMCID: PMC3657179  PMID: 21917432
IRS1; GWAS; Genetic variation; Type-2 diabetes; Hyperinsulinemia; Insulin resistance; IRS1, Insulin receptor substrate-1; T2D, Type-2 diabetes; CVD, Cardiovascular disease; GWAS, Genome-wide association studies; SNP, Single nucleotide polymorphism; HOMA-IR, Homeostasis model assessment of insulin resistance; OGTT, Oral glucose tolerance test; LD, Linkage disequilibrium; WHII, Whitehall-II; NPHSII, Northwick Park Heart Study-II; UDACS, UniversityCollege London Diabetes and Cardiovascular Study; EDS, Ealing Diabetes Study; PREDICT, PRospective Evaluation of Diabetic Ischemic heart disease by Computed Tomography; EARSII, European Atherosclerosis Research Study-II; DIAGRAM, Diabetes Genetics Replication and Meta-analysis Consortium
17.  Modeling Focused Ultrasound Exposure for the Optimal Control of Thermal Dose Distribution 
The Scientific World Journal  2012;2012:252741.
Preclinical studies indicate that focused ultrasound at exposure conditions close to the threshold for thermal damage can increase drug delivery at the focal region. Although these results are promising, the optimal control of temperature still remains a challenge. To address this issue, computer-simulated ultrasound treatments have been performed. When the treatments are delivered without taking into account the cooling effect exerted by the blood flow, the resulting thermal dose is highly variable with regions of thermal damage, regions of underdosage close to the vessels, and areas in between these two extremes. When the power deposition is adjusted so that the peak thermal dose remains close to the threshold for thermal damage, the thermal dose is more uniformly distributed but under-dosage is still visible around the thermally significant vessels. The results of these simulations suggest that, for focused ultrasound, as for other delivery methods, the only way to control temperature is to adjust the average energy deposition to compensate for the presence of thermally significant vessels in the target area. By doing this, we have shown that it is possible to reduce the temperature heterogeneity observed in focused ultrasound thermal treatments.
PMCID: PMC3349131  PMID: 22593669
18.  An Optimum Method for Pulsed High Intensity Focused Ultrasound Treatment of Large Volumes using the InSightec ExAblate® 2000 ‡ 
Physics in medicine and biology  2010;55(21):6395-6410.
Pulsed high intensity focused ultrasound (pHIFU) is a method for delivering ultrasound to tissue while avoiding high temperatures. The technique has been suggested for non-destructively enhancing local uptake of drugs. Side effects include thermal necrosis, therefore, realtime monitoring of tissue temperature is advantageous. This paper outlines a method for improving the treatment effciency of (pHIFU) using the MR image guided InSightec ExAblate® 2000, an ultrasound system integrated into a whole body human MRI scanner with the ability to measure temperature at the treatment location in near real-time. Thermal measurements obtained during treatment of a tissue phantom were used to determine appropriate heating parameters, and compared to in vivo treatment of rabbit muscle. Optimization of the treatment procedure and ultrasound transducer steering patterns was then conducted with the goal of minimizing treatment time while avoiding overheating. The optimization was performed on the basis of approximate solutions to the standard bioheat equation. The commercial system software of the Exablate® system was modified to assist in this optimization. Depending on the size of the treatment volume, the presented results demonstrate that it is possible to use the technique described to cut treatment times significantly, up to one third of that required by the current standard treatment cycle.
PMCID: PMC2993179  PMID: 20938069
19.  Orthokeratinized odontogenic cyst in a Hong Kong community: the clinical and radiological features 
Dentomaxillofacial Radiology  2010;39(4):240-245.
The aim was to evaluate the principal clinical and conventional radiological features of a consecutive series of cases of orthokeratinized odontogenic cyst (OOC) affecting a Hong Kong Chinese community and to determine the outcome by follow-up.
All cases were accompanied by appropriate radiography and were confirmed by histopathology.
The clinical and conventional radiological presentations, differential diagnoses and outcomes of follow-up of five consecutive OOCs were reviewed. There were two males and three females. All affected the posterior sextant. The mean age at first presentation was 33.5 years. The mean of their period of prior awareness was 0.11 years. Swelling was the most frequent presenting symptom. All presented as well-defined corticated radiolucencies; three were unilocular and two were multilocular and all displayed expansion. This resulted in displacement and erosion of the lower border of the mandible in one case and the downward displacement past the lower border of a lateral cortex in two others. The inferior dental canal in each mandibular case exhibited both displacement and absence. The antrum was affected in a sole maxillary case. Four patients were followed up for a mean of 8.5 years. The fifth patient discharged himself shortly after surgery. No lesions recurred.
OOCs in this community displayed an expansile character, but did not recur after moderately long follow-up. The time between the prior awareness of their disease and their presentation for diagnosis and treatment was, so far, the shortest for any lesion affecting the jaw in this Hong Kong Chinese community.
PMCID: PMC3520233  PMID: 20395466
orthokeratinized odontogenic cyst; keratocyst; bone; jaw; radiology
20.  Keratocystic odontogenic tumour in a Hong Kong community: the clinical and radiological features 
Dentomaxillofacial Radiology  2010;39(3):167-175.
The aim of this study was to evaluate the clinical and conventional radiological features of a consecutive series of cases of “keratocystic odontogenic tumour” (KCOT) affecting a Hong Kong Chinese community and to determine their outcome by follow-up.
All cases were accompanied by appropriate radiography and were histopathologically confirmed.
33 consecutive KCOTs were reviewed. 18 patients were male. The mean age at first presentation was 30.6 years. Swelling was the most frequent presenting symptom. Those patients first presenting with pain were significantly older, whereas those first presenting with a maxillary lesion were significantly younger. The maxilla and mandible were affected in 13 and 20 cases, respectively. KCOTs were most frequently confined to the posterior sextants of both jaws. KCOTs affecting the maxilla were mainly unilocular, whereas those affecting the mandible were multilocular. Patients with multilocular KCOTs were significantly older. Patients with KCOTs associated with root resorption were significantly older, whereas patients associated with unerupted teeth were significantly younger. 69% displaced teeth, 41% resorbed them and 56% were associated with unerupted teeth. All but two were followed up for at least 2 years. Three lesions recurred.
KCOTs in this community displayed some differences from those reported in the literature.
PMCID: PMC3520223  PMID: 20203279
keratocystic odontogenic tumour; keratocyst; bone; jaw; radiology
21.  Human Karyotyping Using TaqMan Copy Number Assays 
Journal of Biomolecular Techniques : JBT  2010;21(3 Suppl):S44-S45.
Chromosomal or sub-chromosomal changes in genomic copy numbers may lead to various genomic disorders and developmental abnormalities including Down Syndrome etc. In addition, these numerical aberrations, also known as aneuploidy, may also occur in embryos, stem cells, and other cell lines during cell culture. Therefore, karyotyping analysis is crucial for clinical research and diagnosis including prenatal diagnostics, IVF (in vitro fertilization), stem cell and cancer research. Most commonly used technologies for karyotyping analysis are microarray-based comparative genomic hybridization (CGH) and fluorescent in-situ hybridization (FISH). Although they are powerful and have many advantages, their detection of chromosomal gain or loss is not quantitative and may not be reliable. Moreover, the lengthy protocols and cost for sample screening are undesirable. To overcome these problems, we have developed a new method for chromosome karyotyping using TaqMan copy number assays. Since extra or missing chromosomes will cause chromosomal copy number changes, we leverage the existing pre-designed TaqMan Copy Number Assays. We select and validate TaqMan copy number assays that target each of the 24 chromosomes. To cover all the 24 chromosomes on a 384 well plate or a TaqMan Array Card, we select 4 assays per chromosome. We also develop a gene-specific pre-amplification protocol for copy number assays to perform karyotyping analysis using a minute amount of DNA sample. Our preliminary feasibility studies suggest that TaqMan karyotyping assays enable researchers to quantitatively detect chromosome copy number changes for limited quantity of gDNA sample and offer a simple workflow with high sample throughput. As a complementary tool to the existing karyotyping technologies, TaqMan karyotyping is valuable for aneuploidy screening and validating karyotyping results from other platforms.
PMCID: PMC2918123
22.  Role of Retinoic Acid Inducible Gene-I in Human Metapneumovirus-induced Cellular Signaling 
The Journal of general virology  2008;89(Pt 8):1978-1986.
Human metapneumovirus (hMPV) is a recently discovered pathogen causing a significant portion of respiratory infections in young infants, the elderly and immunocompromised patients. Very little is known regarding the cellular signaling elicited by this virus in airway epithelial cells, the target of hMPV infection. In this study, we investigated the role of the RNA helicases RIG-I (retinoic acid inducible gene-I) and MDA-5 (melanoma differentiation-associated gene-5) as the main pattern recognition receptors (PRRs) involved in viral detection and subsequent expression of proinflammatory and antiviral genes. HMPV infection readily induced RIG-I and MDA-5 gene and protein expression in A549 cells, a type II-like alveolar epithelial cell line. Expression of dominant negative (DN) RIG-I or downregulation of RIG-I gene expression using small interfering (si)RNA significantly decreased hMPV-induced Interferon (IFN)-β, Interleukin (IL)-8, and RANTES gene transcription, by inhibiting viral-induced activation of Nuclear Factor (NF)-kB and Interferon Regulatory Factor (IRF), leading to enhanced viral replication. On the other hand, MDA-5 did not seem to play a significant role in hMPV-induced cellular responses. MAVS (mitochondrial antiviral signaling protein), an adaptor protein linking both RIG-I and MDA-5 to downstream activation of IRF-3 and NF-kB, was also necessary for hMPV-induced cellular signaling. Expression of a MAVS DN significantly reduced IFN-β and chemokine gene transcription, by inhibiting NF-kB and IRF-dependent gene transcription, in response to hMPV infection. Our results show that hMPV activates the RIG-I-MAVS signaling pathway in airway epithelial cells, leading to the expression of important proinflammatory and antiviral molecules involved in the innate immune response to viruses.
PMCID: PMC2865242  PMID: 18632970
23.  Agrobacterium-mediated transformation of durum wheat (Triticum turgidum L. var. durum cv Stewart) with improved efficiency 
Journal of Experimental Botany  2010;61(6):1567-1581.
An efficient Agrobacterium-mediated durum wheat transformation system has been developed for the production of 121 independent transgenic lines. This improved system used Agrobacterium strain AGL1 containing the superbinary pGreen/pSoup vector system and durum wheat cv Stewart as the recipient plant. Acetosyringone at 400 μM was added to both the inoculation and cultivation medium, and picloram at 10 mg l−1 and 2 mg l−1 was used in the cultivation and induction medium, respectively. Compared with 200 μM in the inoculation and cultivation media, the increased acetosyringone concentration led to significantly higher GUS (β-glucuronidase) transient expression and T-DNA delivery efficiency. However, no evident effects of acetosyringone concentration on regeneration frequency were observed. The higher acetosyringone concentration led to an improvement in average final transformation efficiency from 4.7% to 6.3%. Furthermore, the concentration of picloram in the co-cultivation medium had significant effects on callus induction and regeneration. Compared with 2 mg l−1 picloram in the co-cultivation medium, increasing the concentration to 10 mg l−1 picloram resulted in improved final transformation frequency from 2.8% to 6.3%, with the highest frequency of 12.3% reached in one particular experiment, although statistical analysis showed that this difference in final transformation efficiency had a low level of significance. Stable integration of foreign genes, their expression, and inheritance were confirmed by Southern blot analyses, GUS assay, and genetic analysis. Analysis of T1 progeny showed that, of the 31 transgenic lines randomly selected, nearly one-third had a segregation ratio of 3:1, while the remainder had ratios typical of two or three independently segregating loci.
PMCID: PMC2852660  PMID: 20202997
Acetosyringone; Agrobacterium tumefaciens; durum wheat cv Stewart; picloram; transformation
24.  The development and genetic diversity of H5N1 influenza virus in China, 1996–2006 
Virology  2008;380(2):243-254.
Since it was first detected in 1996, the Goose/Guangdong/1/1996 (Gs/GD) H5N1 influenza virus and its reassortants have spread to over 60 countries, with over 20 distinct genetic reassortants previously recognized. However, systematic analysis of their interrelationship and the development of genetic diversity have not been explored. As each of those reassortants was first detected in China, here 318 full- length H5N1 virus genomes isolated from 1996–2006 in this region were phylogenetically analyzed. Our findings revealed two major group reassortment events in 2001 and 2002 that were responsible for the generation of the majority of the 44 distinct Gs/GD genotypes identified, excepting those 1997 variants. Genotype replacement and emergence occurred continually, with 34 transient genotypes detected while only 10 variants were persistent. Two major replacements of predominant genotypes were also observed: genotype B replaced by Z in 2002 and then genotype Z replaced by the now predominant genotype V in 2005.
PMCID: PMC2651962  PMID: 18774155
genotype; reassortant; avian influenza
25.  Investigation of the Frequency and Force of Chest Vibration Performed by Physiotherapists 
Physiotherapy Canada  2008;60(4):341-348.
To investigate the frequency and force of chest vibration as applied by 18 physiotherapists working in a teaching hospital.
Chest vibration was applied to a healthy adult male lying supine on a plinth with seven mounted sensors measuring frequency and force, during three test conditions: (1) directly on the chest, (2) on the chest through a layer of sheet, and (3) on the chest through a layer of towelling. The influence of gender and current practice area (physiotherapists working in cardiopulmonary areas [cardiopulmonary physiotherapists] and physiotherapists who presently did not work in the cardiopulmonary area, but had treated cardiopulmonary patients within the last year [general practice physiotherapists]) on the frequency and force of chest vibrations was examined.
Physiotherapists demonstrated a mean frequency of 5.7, 5.3, and 5 Hz and a mean maximum force of 272.78, 273.47, and 271.13 N for conditions 1, 2, and 3 respectively. There were no significant differences in the frequency or forces generated by vibration between cardiopulmonary and general practice physiotherapists, between genders, or among the three test conditions.
Vibration frequency was lower and force higher than previously recorded. Force may vary depending on the patient. The addition of a sheet or towel did not affect the force or frequency of vibration compared to vibration performed directly on the chest.
PMCID: PMC2792789  PMID: 20145766
chest shaking; chest vibration; force; frequency; ébranlement thoracique; force; fréquence; vibration thoracique

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