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1.  The 6q22.33 Locus and Breast Cancer Susceptibility 
Recently, we identified a novel breast cancer (BC) susceptibility locus at 6q22.33 following a genome-wide association study (GWAS) in the Ashkenazi Jewish (AJ) genetic isolate. To replicate these findings, we performed case-control association analysis on 6q22.33 (rs2180341) in additional 487 AJ BC cases and in an independent non-Jewish (non-AJ), predominantly European-American (EU-Am), populations of 1,466 BC cases and 1,467 controls. We have confirmed the 6q22.33 association with BC risk in the replication cohorts (per-allele OR=1.18, 95%CI 1.04–1.33, p=0.0083) with the strongest effect in the aggregate meta-analysis of 3,039 BC cases and 2,616 AJ and non-AJ controls (per-allele OR=1.24, 95%CI 1.13–1.36, P=3.85×10−7).
We have also shown that the association was slightly stronger with ER positive tumors (per-allele OR=1.35, 95%CI 1.20–1.51, p=2.2×10−5) compared to ER negative tumors (per-allele OR=1.19, 95%CI 0.97–1.47, p=0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in BC susceptibility. Due to stronger association of 6q22.33 with ER-positive BC we examined the effect of candidate genes on ER response elements (ERE). Upon transfection of overexpressed RNF146 in the MCF-7 BC cell line, we observed diminished expression of an ERE reporter construct. This study confirms the association of 6q22.33 with BC, with slightly stronger effect in ER positive tumors. Further functional studies of candidate genes are in progress and a large replication analysis is being completed as part of an international consortium.
doi:10.1158/1055-9965.EPI-09-0151
PMCID: PMC4286363  PMID: 19690183
Ashkenazi Jews; Breast Cancer; Genome-wide association studies; SNPs; estrogen receptor
2.  TNF-α-induced cardiomyocyte apoptosis contributes to cardiac dysfunction after coronary microembolization in mini-pigs 
This experimental study was designed to clarify the relationship between cardiomyocyte apoptosis and tumour necrosis factor-alpha (TNF-α) expression, and confirm the effect of TNF-α on cardiac dysfunction after coronary microembolization (CME) in mini-pigs. Nineteen mini-pigs were divided into three groups: sham-operation group (n = 5), CME group (n = 7) and adalimumab pre-treatment group (n = 7; TNF-α antibody, 2 mg/kg intracoronary injection before CME). Magnetic resonance imaging (3.0-T) was performed at baseline, 6th hour and 1 week after procedure. Cardiomyocyte apoptosis was detected by cardiac-TUNEL staining, and caspase-3 and caspase-8 were detected by RT-PCR and immunohistochemistry. Furthermore, serum TNF-α, IL-6 and troponin T were analysed, while myocardial expressions of TNF-α and IL-6 were detected. Both TNF-α expression (serum level and myocardial expression) and average number of apoptotic cardiomyocyte nuclei were significantly increased in CME group compared with the sham-operation group. Six hours after CME, left ventricular end-systolic volume (LVESV) was increased and the left ventricular ejection fraction (LVEF) was decreased in CME group. Pre-treatment with adalimumab not only significantly improved LVEF after CME (6th hour: 54.9 ± 2.3% versus 50.4 ± 3.9%, P = 0.036; 1 week: 56.7 ± 4.2% versus 52.7 ± 2.9%, P = 0.041), but also suppressed cardiomyocyte apoptosis and the expression of caspase-3 and caspase-8. Meanwhile, the average number of apoptotic cardiomyocytes nuclei was inversely correlated with LVEF (r = −0.535, P = 0.022). TNF-α-induced cardiomyocyte apoptosis is likely involved in cardiac dysfunction after CME. TNF-α antibody therapy suppresses cardiomyocyte apoptosis and improves early cardiac function after CME.
doi:10.1111/jcmm.12342
PMCID: PMC4244011  PMID: 25130514
coronary microembolization; apoptosis; tumour necrosis factor-alpha
3.  Developmental Changes in Organization of Structural Brain Networks 
Khundrakpam, Budhachandra S. | Reid, Andrew | Brauer, Jens | Carbonell, Felix | Lewis, John | Ameis, Stephanie | Karama, Sherif | Lee, Junki | Chen, Zhang | Das, Samir | Evans, Alan C. | Ball, William S. | Byars, Anna Weber | Schapiro, Mark | Bommer, Wendy | Carr, April | German, April | Dunn, Scott | Rivkin, Michael J. | Waber, Deborah | Mulkern, Robert | Vajapeyam, Sridhar | Chiverton, Abigail | Davis, Peter | Koo, Julie | Marmor, Jacki | Mrakotsky, Christine | Robertson, Richard | McAnulty, Gloria | Brandt, Michael E. | Fletcher, Jack M. | Kramer, Larry A. | Yang, Grace | McCormack, Cara | Hebert, Kathleen M. | Volero, Hilda | Botteron, Kelly | McKinstry, Robert C. | Warren, William | Nishino, Tomoyuki | Robert Almli, C. | Todd, Richard | Constantino, John | McCracken, James T. | Levitt, Jennifer | Alger, Jeffrey | O'Neil, Joseph | Toga, Arthur | Asarnow, Robert | Fadale, David | Heinichen, Laura | Ireland, Cedric | Wang, Dah-Jyuu | Moss, Edward | Zimmerman, Robert A. | Bintliff, Brooke | Bradford, Ruth | Newman, Janice | Evans, Alan C. | Arnaoutelis, Rozalia | Bruce Pike, G. | Louis Collins, D. | Leonard, Gabriel | Paus, Tomas | Zijdenbos, Alex | Das, Samir | Fonov, Vladimir | Fu, Luke | Harlap, Jonathan | Leppert, Ilana | Milovan, Denise | Vins, Dario | Zeffiro, Thomas | Van Meter, John | Lange, Nicholas | Froimowitz, Michael P. | Botteron, Kelly | Robert Almli, C. | Rainey, Cheryl | Henderson, Stan | Nishino, Tomoyuki | Warren, William | Edwards, Jennifer L. | Dubois, Diane | Smith, Karla | Singer, Tish | Wilber, Aaron A. | Pierpaoli, Carlo | Basser, Peter J. | Chang, Lin-Ching | Koay, Chen Guan | Walker, Lindsay | Freund, Lisa | Rumsey, Judith | Baskir, Lauren | Stanford, Laurence | Sirocco, Karen | Gwinn-Hardy, Katrina | Spinella, Giovanna | McCracken, James T. | Alger, Jeffry R. | Levitt, Jennifer | O'Neill, Joseph
Cerebral Cortex (New York, NY)  2012;23(9):2072-2085.
Recent findings from developmental neuroimaging studies suggest that the enhancement of cognitive processes during development may be the result of a fine-tuning of the structural and functional organization of brain with maturation. However, the details regarding the developmental trajectory of large-scale structural brain networks are not yet understood. Here, we used graph theory to examine developmental changes in the organization of structural brain networks in 203 normally growing children and adolescents. Structural brain networks were constructed using interregional correlations in cortical thickness for 4 age groups (early childhood: 4.8–8.4 year; late childhood: 8.5–11.3 year; early adolescence: 11.4–14.7 year; late adolescence: 14.8–18.3 year). Late childhood showed prominent changes in topological properties, specifically a significant reduction in local efficiency, modularity, and increased global efficiency, suggesting a shift of topological organization toward a more random configuration. An increase in number and span of distribution of connector hubs was found in this age group. Finally, inter-regional connectivity analysis and graph-theoretic measures indicated early maturation of primary sensorimotor regions and protracted development of higher order association and paralimbic regions. Our finding reveals a time window of plasticity occurring during late childhood which may accommodate crucial changes during puberty and the new developmental tasks that an adolescent faces.
doi:10.1093/cercor/bhs187
PMCID: PMC3729193  PMID: 22784607
adolescence; connectivity; connector hub; cortical thickness; maturation
4.  Beta-2 Adrenergic Receptor (ADRB2) Gene Polymorphisms and the Risk of Asthma: A Meta-Analysis of Case-Control Studies 
PLoS ONE  2014;9(8):e104488.
Background and Objective
A number of studies have assessed the relationship between beta-2 adrenergic receptor (ADRB2) gene polymorphisms and asthma risk. However, the results are inconsistent. A meta-analysis that focused on the association between asthma and all ADRB2 polymorphisms with at least three case-control studies was thus performed.
Methods
A literature search of the PubMed, Embase, Web of Science, CNKI, and Wangfang databases was conducted. Odds ratios with 95% confidence intervals were used to assess the strength of associations.
Results
Arg16Gly, Gln27Glu, Thr164Ile, and Arg19Cys single nucleotide polymorphisms (SNPs) were identified in 46 case-control studies. The results showed that not all of the SNPs were associated with asthma in the overall population. Significant associations were found for the Arg16Gly polymorphism in the South American population via dominant model comparison (OR = 1.754, 95% CI = 1.179–2.609, I2 = 16.9%, studies  = 2, case  = 314, control  = 237) in an analysis stratified by ethnicity. For the Gln27Glu polymorphism, a protective association was found in children via recessive model comparison (OR = 0.566, 95% CI = 0.417–0.769, I2 = 0.0%, studies  = 11, case  = 1693, control  =  502) and homozygote genotype comparison (OR = 0.610, 95% CI = 0.434–0.856, I2 = 0.0%, studies  = 11, case  = 1693, control  = 1502), and in adults via dominant model comparison (OR = 0.864, 95% CI = 0.768–0.971, I2 = 46.9%, n = 18, case  = 3160, control  = 3433).
Conclusions
None of the ADRB2 gene polymorphisms were reproducibly associated with a risk of asthma across ethnic groups in the general population.
doi:10.1371/journal.pone.0104488
PMCID: PMC4128804  PMID: 25111792
5.  Expression of enoyl coenzyme A hydratase, short chain, 1, in colorectal cancer and its association with clinicopathological characteristics 
Molecular and Clinical Oncology  2014;2(6):1081-1084.
This study aimed to investigate the expression and clinical significance of enoyl coenzyme A hydratase, short chain, 1 (ECHS1), in patients with colorectal cancer (CRC). The ECHS1 protein expression as detected by immunohistochemistry in 148 CRC specimens was evaluated and compared by clinical pathology and prognosis; 38 specimens from proximal non-cancerous colorectal tissues were included as controls. The ECHS1 protein expression was also measured by western blot analysis in 46 fresh CRC tissue specimens and 22 normal colorectal tissue specimens. The rate of positive ECHS1 expression differed significantly between the CRC tissues (56.76%, 84/148) and the proximal non-cancerous colorectal tissues (5.26%, 2/38) (P<0.001). The ECHS1 protein expression was confirmed not to be associated with gender or age. However, the positive expression of ECHS1 tended to be positively associated with clinical TNM stage (P=0.015), lymph node metastasis (P=0.011) and histological differentiation (P=0.028). The expression of the ECHS1 protein on western blot analysis was significantly increased in CRC vs. normal tissues. In addition, the overall survival curves estimated with the Kaplan-Meier method demonstrated that CRC patients exhibiting low ECHS1 expression survived significantly longer compared to patients with high ECHS1 levels (P=0.039). Our data suggested that ECHS1 protein expression may contribute to the occurrence, progression and metastasis of CRC, is closely associated with prognosis and may provide useful information for CRC molecular-targeted therapy.
doi:10.3892/mco.2014.340
PMCID: PMC4179802  PMID: 25279201
colorectal cancer; enoyl coenzyme A hydratase; short chain; 1; metastasis; prognosis
6.  Variable Is Better Than Invariable: Sparse VSS-NLMS Algorithms with Application to Adaptive MIMO Channel Estimation 
The Scientific World Journal  2014;2014:274897.
Channel estimation problem is one of the key technical issues in sparse frequency-selective fading multiple-input multiple-output (MIMO) communication systems using orthogonal frequency division multiplexing (OFDM) scheme. To estimate sparse MIMO channels, sparse invariable step-size normalized least mean square (ISS-NLMS) algorithms were applied to adaptive sparse channel estimation (ACSE). It is well known that step-size is a critical parameter which controls three aspects: algorithm stability, estimation performance, and computational cost. However, traditional methods are vulnerable to cause estimation performance loss because ISS cannot balance the three aspects simultaneously. In this paper, we propose two stable sparse variable step-size NLMS (VSS-NLMS) algorithms to improve the accuracy of MIMO channel estimators. First, ASCE is formulated in MIMO-OFDM systems. Second, different sparse penalties are introduced to VSS-NLMS algorithm for ASCE. In addition, difference between sparse ISS-NLMS algorithms and sparse VSS-NLMS ones is explained and their lower bounds are also derived. At last, to verify the effectiveness of the proposed algorithms for ASCE, several selected simulation results are shown to prove that the proposed sparse VSS-NLMS algorithms can achieve better estimation performance than the conventional methods via mean square error (MSE) and bit error rate (BER) metrics.
doi:10.1155/2014/274897
PMCID: PMC4095674  PMID: 25089286
7.  Combined probiotic bacteria promotes intestinal epithelial barrier function in interleukin-10-gene-deficient mice 
AIM: To investigate the protective effects of combinations of probiotic (Bifico) on interleukin (IL)-10-gene-deficient (IL-10 KO) mice and Caco-2 cell monolayers.
METHODS: IL-10 KO mice were used to assess the benefits of Bifico in vivo. IL-10 KO and control mice received approximately 1.5 × 108 cfu/d of Bifico for 4 wk. Colons were then removed and analyzed for epithelial barrier function by Ussing Chamber, while an ELISA was used to evaluate proinflammatory cytokines. The colon epithelial cell line, Caco-2, was used to test the benefit of Bifico in vitro. Enteroinvasive Escherichia coli (EIEC) and the probiotic mixture Bifico, or single probiotic strains, were applied to cultured Caco-2 monolayers. Barrier function was determined by measuring transepithelial electrical resistance and tight junction protein expression.
RESULTS: Treatment of IL-10 KO mice with Bifico partially restored body weight, colon length, and epithelial barrier integrity to wild-type levels. In addition, IL-10 KO mice receiving Bifico treatment had reduced mucosal secretion of tumor necrosis factor-α and interferon-γ, and attenuated colonic disease. Moreover, treatment of Caco-2 monolayers with Bifico or single-strain probiotics in vitro inhibited EIEC invasion and reduced the secretion of proinflammatory cytokines.
CONCLUSION: Bifico reduced colon inflammation in IL-10 KO mice, and promoted and improved epithelial-barrier function, enhanced resistance to EIEC invasion, and decreased proinflammatory cytokine secretion.
doi:10.3748/wjg.v20.i16.4636
PMCID: PMC4000500  PMID: 24782616
Probiotic bacteria; Intestinal barrier function; Tight junction proteins; Interleukin-10 gene-deficient mice; Caco-2 monolayers
8.  Validation of a Novel Clinical Prediction Score for Severe Coronary Artery Diseases before Elective Coronary Angiography 
PLoS ONE  2014;9(4):e94493.
Objectives
Coronary artery disease (CAD) severity is associated with patient prognosis. However, few efficient scoring systems have been developed to screen severe CAD in patients with stable angina and suspected CAD before coronary angiography. Here, we present a novel scoring system for CAD severity before elective coronary angiography.
Methods
Five hundred fifty-one patients with stable angina who were admitted for coronary angiography were enrolled in this study. Patients were divided into training (n = 347) and validation (n = 204) cohorts. Severe CAD was defined as having a Gensini score of 20 or more. All patients underwent echocardiography (ECG) to detect ejection fraction and aortic valve calcification (AVC). Multivariable analysis was applied to determine independent risk factors and develop the scoring system.
Results
In the training cohort, age, male sex, AVC, abnormal ECG, diabetes, hyperlipidemia, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were identified as independent factors for severe CAD by multivariable analysis, and the Severe Prediction Scoring (SPS) system was developed. C-indices of receiver operating characteristic (ROC) curves for severe CAD were 0.744 and 0.710 in the training and validation groups, respectively. The SPS system also performed well during calibration, as demonstrated by Hosmer-Lemeshow analysis in the validation group. Compared with the Diamond-Forrester score, the SPS system performed better for severe CAD prediction before elective coronary angiography.
Conclusions
Severe CAD prediction was achieved by analyzing age, sex, AVC, ECG, diabetes status, and lipid levels. Angina patients who achieve high scores using this predicting system should undergo early coronary angiography.
doi:10.1371/journal.pone.0094493
PMCID: PMC3979855  PMID: 24714416
9.  Quantitative Proteomics Study of Larval Settlement in the Barnacle Balanus amphitrite 
PLoS ONE  2014;9(2):e88744.
Barnacles are major sessile components of the intertidal areas worldwide, and also one of the most dominant fouling organisms in fouling communities. Larval settlement has a crucial ecological effect not only on the distribution of the barnacle population but also intertidal community structures. However, the molecular mechanisms involved in the transition process from the larval to the juvenile stage remain largely unclear. In this study, we carried out comparative proteomic profiles of stage II nauplii, stage VI nauplii, cyprids, and juveniles of the barnacle Balanus amphitrite using label-free quantitative proteomics, followed by the measurement of the gene expression levels of candidate proteins. More than 700 proteins were identified at each stage; 80 were significantly up-regulated in cyprids and 95 in juveniles vs other stages. Specifically, proteins involved in energy and metabolism, the nervous system and signal transduction were significantly up-regulated in cyprids, whereas proteins involved in cytoskeletal remodeling, transcription and translation, cell proliferation and differentiation, and biomineralization were up-regulated in juveniles, consistent with changes associated with larval metamorphosis and tissue remodeling in juveniles. These findings provided molecular evidence for the morphological, physiological and biological changes that occur during the transition process from the larval to the juvenile stages in B. amphitrite.
doi:10.1371/journal.pone.0088744
PMCID: PMC3923807  PMID: 24551147
10.  Small cell neuroendocrine carcinoma of the ureter: A case report and literature review 
Oncology Letters  2013;7(3):728-730.
Small cell neuroendocrine carcinoma arising in the ureter is extremely rare; only a few cases have been previously reported in the literature. The current study reports the case of a 65-year-old female who presented with right-sided back pain. A mass was identified in the right ureter, and a nephroureterectomy was performed. The microscopic examination revealed that the mass was composed of a monotonous population of small cells and that the cells of the carcinoma were positive for cluster of differentiation 56, chromogranin A and synaptophysin. The tumor was diagnosed as a ureteral neuroendocrine small cell carcinoma. The patient returned 4 months later with recurrences in the retroperitoneum. Chemotherapy was administered and following 80 mg/m2 intravenous irinotecan on days 1 and 8 and 25 mg/m2 cisplatin on days 1–3, every 21 days for 4 cycles, the tumor was considerably smaller. During the regular follow-up examinations, the tumor remained stable.
doi:10.3892/ol.2013.1757
PMCID: PMC3919792  PMID: 24520292
ureter; neuroendocrine carcinoma; chemotherapy
11.  VO2 thermochromic smart window for energy savings and generation 
Scientific Reports  2013;3:3029.
The ability to achieve energy saving in architectures and optimal solar energy utilisation affects the sustainable development of the human race. Traditional smart windows and solar cells cannot be combined into one device for energy saving and electricity generation. A VO2 film can respond to the environmental temperature to intelligently regulate infrared transmittance while maintaining visible transparency, and can be applied as a thermochromic smart window. Herein, we report for the first time a novel VO2-based smart window that partially utilises light scattering to solar cells around the glass panel for electricity generation. This smart window combines energy-saving and generation in one device, and offers potential to intelligently regulate and utilise solar radiation in an efficient manner.
doi:10.1038/srep03029
PMCID: PMC3807258  PMID: 24157625
12.  Graph theoretical analysis of developmental patterns of the white matter network 
Understanding the development of human brain organization is critical for gaining insight into how the enhancement of cognitive processes is related to the fine-tuning of the brain network. However, the developmental trajectory of the large-scale white matter (WM) network is not fully understood. Here, using graph theory, we examine developmental changes in the organization of WM networks in 180 typically-developing participants. WM networks were constructed using whole brain tractography and 78 cortical regions of interest were extracted from each participant. The subjects were first divided into 5 equal sample size (n = 36) groups (early childhood: 6.0–9.7 years; late childhood: 9.8–12.7 years; adolescence: 12.9–17.5 years; young adult: 17.6–21.8 years; adult: 21.9–29.6 years). Most prominent changes in the topological properties of developing brain networks occur at late childhood and adolescence. During late childhood period, the structural brain network showed significant increase in the global efficiency but decrease in modularity, suggesting a shift of topological organization toward a more randomized configuration. However, while preserving most topological features, there was a significant increase in the local efficiency at adolescence, suggesting the dynamic process of rewiring and rebalancing brain connections at different growth stages. In addition, several pivotal hubs were identified that are vital for the global coordination of information flow over the whole brain network across all age groups. Significant increases of nodal efficiency were present in several regions such as precuneus at late childhood. Finally, a stable and functionally/anatomically related modular organization was identified throughout the development of the WM network. This study used network analysis to elucidate the topological changes in brain maturation, paving the way for developing novel methods for analyzing disrupted brain connectivity in neurodevelopmental disorders.
doi:10.3389/fnhum.2013.00716
PMCID: PMC3814848  PMID: 24198774
graph theory; neurodevelopment; anatomical connectivity; modular networks; small world network
13.  Transcriptomic Analysis of Neuropeptides and Peptide Hormones in the Barnacle Balanus amphitrite: Evidence of Roles in Larval Settlement 
PLoS ONE  2012;7(10):e46513.
The barnacle Balanus amphitrite is a globally distributed marine crustacean and has been used as a model species for intertidal ecology and biofouling studies. Its life cycle consists of seven planktonic larval stages followed by a sessile juvenile/adult stage. The transitional processes between larval stages and juveniles are crucial for barnacle development and recruitment. Although some studies have been conducted on the neuroanatomy and neuroactive substances of the barnacle, a comprehensive understanding of neuropeptides and peptide hormones remains lacking. To better characterize barnacle neuropeptidome and its potential roles in larval settlement, an in silico identification of putative transcripts encoding neuropeptides/peptide hormones was performed, based on transcriptome of the barnacle B. amphitrite that has been recently sequenced. Potential cleavage sites andstructure of mature peptides were predicted through homology search of known arthropod peptides. In total, 16 neuropeptide families/subfamilies were predicted from the barnacle transcriptome, and 14 of them were confirmed as genuine neuropeptides by Rapid Amplification of cDNA Ends. Analysis of peptide precursor structures and mature sequences showed that some neuropeptides of B. amphitrite are novel isoforms and shared similar characteristics with their homologs from insects. The expression profiling of predicted neuropeptide genes revealed that pigment dispersing hormone, SIFamide, calcitonin, and B-type allatostatin had the highest expression level in cypris stage, while tachykinin-related peptide was down regulated in both cyprids and juveniles. Furthermore, an inhibitor of proprotein convertase related to peptide maturation effectively delayed larval metamorphosis. Combination of real-time PCR results and bioassay indicated that certain neuropeptides may play an important role in cypris settlement. Overall, new insight into neuropeptides/peptide hormones characterized in this study shall provide a platform for unraveling peptidergic control of barnacle larval behavior and settlement process.
doi:10.1371/journal.pone.0046513
PMCID: PMC3462748  PMID: 23056329
14.  Identification of differential gene expressions in colorectal cancer and polyp by cDNA microarray 
AIM: To screen the differential expressed genes in colorectal cancer and polyp tissue samples.
METHODS: Tissue specimens containing 16 cases of colorectal adenocarcinoma and colorectal polyp vs normal mucosae were collected and subjected to cDNA microarray and bioinformatical analyses. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to confirm some of the cDNA microarray data.
RESULTS: The experimental data showed that eight genes were differentially expressed, most of which were upregulated in adenomatous polyp lesions. Forty-six genes expressions were altered in colorectal cancers, of which 29 were upregulated and 17 downregulated, as compared to the normal mucosae. In addition, 18 genes were similarly altered in both adenomatous polyps and colorectal cancer. qRT-PCR analyses confirmed the cDNA microarray data for four of those 18 genes: MTA1, PDCD4, TSC1 and PDGFRA.
CONCLUSION: These differentially expressed genes likely represent biomarkers for early detection of colorectal cancer and may be potential therapeutic targets after confirmed by further studies.
doi:10.3748/wjg.v18.i6.570
PMCID: PMC3280404  PMID: 22363125
Colorectal polyp; Colorectal cancer; cDNA microarray; Quantitative reverse transcription-polymerase chain reaction
15.  Expression of Calmodulin and Myosin Light Chain Kinase during Larval Settlement of the Barnacle Balanus amphitrite 
PLoS ONE  2012;7(2):e31337.
Barnacles are one of the most common organisms in intertidal areas. Their life cycle includes seven free-swimming larval stages and sessile juvenile and adult stages. The transition from the swimming to the sessile stages, referred to as larval settlement, is crucial for their survivor success and subsequent population distribution. In this study, we focused on the involvement of calmodulin (CaM) and its binding proteins in the larval settlement of the barnacle, Balanus ( = Amphibalanus) amphitrite. The full length of CaM gene was cloned from stage II nauplii of B. amphitrite (referred to as Ba-CaM), encoding 149 amino acid residues that share a high similarity with published CaMs in other organisms. Quantitative real-time PCR showed that Ba-CaM was highly expressed in cyprids, the stage at which swimming larvae are competent to attach and undergo metamorphosis. In situ hybridization revealed that the expressed Ba-CaM gene was localized in compound eyes, posterior ganglion and cement glands, all of which may have essential functions during larval settlement. Larval settlement assays showed that both the CaM inhibitor compound 48/80 and the CaM-dependent myosin light chain kinase (MLCK) inhibitor ML-7 effectively blocked barnacle larval settlement, whereas Ca2+/CaM-dependent kinase II (CaMKII) inhibitors did not show any clear effects. The subsequent real-time PCR assay showed a higher expression level of Ba-MLCK gene in larval stages than in adults, suggesting an important role of Ba-MLCK gene in larval development and competency. Overall, the results suggest that CaM and CaM-dependent MLCK function during larval settlement of B. amphitrite.
doi:10.1371/journal.pone.0031337
PMCID: PMC3278446  PMID: 22348072
16.  Toward an Understanding of the Molecular Mechanisms of Barnacle Larval Settlement: A Comparative Transcriptomic Approach 
PLoS ONE  2011;6(7):e22913.
Background
The barnacle Balanus amphitrite is a globally distributed biofouler and a model species in intertidal ecology and larval settlement studies. However, a lack of genomic information has hindered the comprehensive elucidation of the molecular mechanisms coordinating its larval settlement. The pyrosequencing-based transcriptomic approach is thought to be useful to identify key molecular changes during larval settlement.
Methodology and Principal Findings
Using 454 pyrosequencing, we collected totally 630,845 reads including 215,308 from the larval stages and 415,537 from the adults; 23,451 contigs were generated while 77,785 remained as singletons. We annotated 31,720 of the 92,322 predicted open reading frames, which matched hits in the NCBI NR database, and identified 7,954 putative genes that were differentially expressed between the larval and adult stages. Of these, several genes were further characterized with quantitative real-time PCR and in situ hybridization, revealing some key findings: 1) vitellogenin was uniquely expressed in late nauplius stage, suggesting it may be an energy source for the subsequent non-feeding cyprid stage; 2) the locations of mannose receptors suggested they may be involved in the sensory system of cyprids; 3) 20 kDa-cement protein homologues were expressed in the cyprid cement gland and probably function during attachment; and 4) receptor tyrosine kinases were expressed higher in cyprid stage and may be involved in signal perception during larval settlement.
Conclusions
Our results provide not only the basis of several new hypotheses about gene functions during larval settlement, but also the availability of this large transcriptome dataset in B. amphitrite for further exploration of larval settlement and developmental pathways in this important marine species.
doi:10.1371/journal.pone.0022913
PMCID: PMC3146488  PMID: 21829555
17.  Impaired small-world efficiency in structural cortical networks in multiple sclerosis associated with white matter lesion load 
Brain  2009;132(12):3366-3379.
White matter tracts, which play a crucial role in the coordination of information flow between different regions of grey matter, are particularly vulnerable to multiple sclerosis. Many studies have shown that the white matter lesions in multiple sclerosis are associated with focal abnormalities of grey matter, but little is known about the alterations in the coordinated patterns of cortical morphology among regions in the disease. Here, we used cortical thickness measurements from structural magnetic resonance imaging to investigate the relationship between the white matter lesion load and the topological efficiency of structural cortical networks in multiple sclerosis. Network efficiency was defined using a ‘small-world’ network model that quantifies the effectiveness of information transfer within brain networks. In this study, we first classified patients (n = 330) into six subgroups according to their total white matter lesion loads, and identified structural brain networks for each multiple sclerosis group by thresholding the corresponding inter-regional cortical thickness correlation matrix, followed by a network efficiency analysis with graph theoretical approaches. The structural cortical networks in multiple sclerosis demonstrated efficient small-world architecture regardless of the lesion load, an organization that maximizes the information processing at a relatively low wiring cost. However, we found that the overall small-world network efficiency in multiple sclerosis was significantly disrupted in a manner proportional to the extent of total white matter lesions. Moreover, regional efficiency was also significantly decreased in specific brain regions, including the insula and precentral gyrus as well as regions of prefrontal and temporal association cortices. Finally, we showed that the lesions also altered many cortical thickness correlations in the frontal, temporal and parietal lobes. Our results suggest that the white matter lesions in multiple sclerosis might be associated with aberrant neuronal connectivity among widely distributed brain regions, and provide structural (morphological) evidence for the notion of multiple sclerosis as a disconnection syndrome.
doi:10.1093/brain/awp089
PMCID: PMC2792366  PMID: 19439423
cortical thickness; connectivity; MRI; multiple sclerosis; small-world networks
18.  Age- and gender-related differences in the cortical anatomical network 
Neuroanatomical differences due to aging and gender have been well documented and these differences may be associated with differences in behaviors and cognitive performance. However, little is known about the dynamic organization of anatomical connectivity within the cerebral cortex, which may underlie population differences in brain function. In this study, we investigated age- and sex- effects on the anatomical connectivity patterns of 95 normal subjects ranging in age from 19 to 85 years. Using the connectivity probability derived from diffusion MRI tractography, we characterized the cerebral cortex as a weighted network of connected regions. This approach captures the underlying organization of anatomical connectivity for each subject at a regional level. Advanced graph theoretical analysis revealed that the resulting cortical networks exhibited “small-world” character, i.e. efficient information transfer both at local and global scale. In particular, the precuneus and posterior cingulate gyrus were consistently observed as centrally connected regions, independent of age and sex. Further analysis revealed a reduction in overall cortical connectivity with age. There were also changes in the underlying network organization that resulted in decreased local efficiency, and also a shift of regional efficiency from the parietal and occipital to frontal and temporal neocortex in older brains. In addition, women showed greater overall cortical connectivity and the underlying organization of their cortical networks was more efficient, both locally and globally. There were also distributed regional differences in efficiency between sexes. Our results provide new insights into the substrates that underlie behavioral and cognitive differences in aging and sex.
doi:10.1523/JNEUROSCI.2308-09.2009
PMCID: PMC2831804  PMID: 20016083
aging; cerebral cortex; connectivity; imaging; network; sex difference
19.  Revealing Modular Architecture of Human Brain Structural Networks by Using Cortical Thickness from MRI 
Cerebral Cortex (New York, NY)  2008;18(10):2374-2381.
Modularity, presumably shaped by evolutionary constraints, underlies the functionality of most complex networks ranged from social to biological networks. However, it remains largely unknown in human cortical networks. In a previous study, we demonstrated a network of correlations of cortical thickness among specific cortical areas and speculated that these correlations reflected an underlying structural connectivity among those brain regions. Here, we further investigated the intrinsic modular architecture of the human brain network derived from cortical thickness measurement. Modules were defined as groups of cortical regions that are connected morphologically to achieve the maximum network modularity. We show that the human cortical network is organized into 6 topological modules that closely overlap known functional domains such as auditory/language, strategic/executive, sensorimotor, visual, and mnemonic processing. The identified structure-based modular architecture may provide new insights into the functionality of cortical regions and connections between structural brain modules. This study provides the first report of modular architecture of the structural network in the human brain using cortical thickness measurements.
doi:10.1093/cercor/bhn003
PMCID: PMC2733312  PMID: 18267952
betweenness centrality; cortical thickness; modularity; morphometry; MRI; network; small world
20.  Uncovering Intrinsic Modular Organization of Spontaneous Brain Activity in Humans 
PLoS ONE  2009;4(4):e5226.
The characterization of topological architecture of complex brain networks is one of the most challenging issues in neuroscience. Slow (<0.1 Hz), spontaneous fluctuations of the blood oxygen level dependent (BOLD) signal in functional magnetic resonance imaging are thought to be potentially important for the reflection of spontaneous neuronal activity. Many studies have shown that these fluctuations are highly coherent within anatomically or functionally linked areas of the brain. However, the underlying topological mechanisms responsible for these coherent intrinsic or spontaneous fluctuations are still poorly understood. Here, we apply modern network analysis techniques to investigate how spontaneous neuronal activities in the human brain derived from the resting-state BOLD signals are topologically organized at both the temporal and spatial scales. We first show that the spontaneous brain functional networks have an intrinsically cohesive modular structure in which the connections between regions are much denser within modules than between them. These identified modules are found to be closely associated with several well known functionally interconnected subsystems such as the somatosensory/motor, auditory, attention, visual, subcortical, and the “default” system. Specifically, we demonstrate that the module-specific topological features can not be captured by means of computing the corresponding global network parameters, suggesting a unique organization within each module. Finally, we identify several pivotal network connectors and paths (predominantly associated with the association and limbic/paralimbic cortex regions) that are vital for the global coordination of information flow over the whole network, and we find that their lesions (deletions) critically affect the stability and robustness of the brain functional system. Together, our results demonstrate the highly organized modular architecture and associated topological properties in the temporal and spatial brain functional networks of the human brain that underlie spontaneous neuronal dynamics, which provides important implications for our understanding of how intrinsically coherent spontaneous brain activity has evolved into an optimal neuronal architecture to support global computation and information integration in the absence of specific stimuli or behaviors.
doi:10.1371/journal.pone.0005226
PMCID: PMC2668183  PMID: 19381298
22.  N-Benzyl-2-(2-chloro-4-methyl­phen­oxy)acetamide 
The structure determination of the title compound, C16H16ClNO2, was performed as part of a project on the inter­actions between small organic mol­ecules and proteins. In the crystal structure, the dihedral angle between the two aromatic rings is 16.14 (12)°. The molecules are connected via N—H⋯O hydrogen bonding into chains, which extend in the direction of the b axis.
doi:10.1107/S1600536808022526
PMCID: PMC2962221  PMID: 21203302
23.  Rice Dwarf Phytoreovirus Segment S6-Encoded Nonstructural Protein Has a Cell-to-Cell Movement Function 
Journal of Virology  2004;78(10):5382-5389.
Rice dwarf virus (RDV) is a member of the genus Phytoreovirus, which is composed of viruses with segmented double-stranded RNA genomes. Proteins that support the intercellular movement of these viruses in the host have not been identified. Microprojectile bombardment was used to determine which open reading frames (ORFs) support intercellular movement of a heterologous virus. A plasmid containing an infectious clone of Potato virus X (PVX) defective in cell-to-cell movement and expressing either β-glucuronidase or green fluorescent protein (GFP) was used for cobombardment with plasmids containing ORFs from RDV gene segments S1 through S12 onto leaves of Nicotiana benthamiana. Cell-to-cell movement of the movement-defective PVX was restored by cobombardment with a plasmid containing S6. In the absence of S6, no other gene segment supported movement. Identical results were obtained with Nicotiana tabacum, a host that allows fewer viruses to infect and spread within its tissue. S6 supported the cell-to-cell movement of the movement-defective PVX in sink and source leaves of N. benthamiana. A mutant S6 lacking the translation start codon did not complement the cell-to-cell movement of the movement-defective PVX. An S6 protein product (Pns6)-enhanced GFP fusion was observed near or within cell walls of epidermal cells from N. tabacum. By immunocytochemistry, unfused Pns6 was localized to plasmodesmata in rice leaves infected with RDV. S6 thus encodes a protein with characteristics identical to those of other viral proteins required for the cell-to-cell movement of their genome and therefore is likely required for the cell-to-cell movement of RDV.
doi:10.1128/JVI.78.10.5382-5389.2004
PMCID: PMC400330  PMID: 15113917
24.  112 The Development of Enterovirus 71 Vaccine 
Enterovirus 71 (EV71) is a major cause of epidemic outbreaks of hand-foot-and-mouth disease (HFMD) worldwide. The virus belongs to the family Picornaviridae, genus Enterovirus. 3 genotypes—A, B, and C and more than 10 sub-genotypes have been identified. After the initial identification of this virus in 1969, some large outbreaks of HFMD have been reported worldwide.
EV71-induced HFMD is usually characterized by the formation of maculopapular or vesicular lesions on the skin and oral mucosa, especially on the palms, soles, and mouth. There were a greater number of fatal cases with brainstem encephalitis, pulmonary edema and/or hemorrhage, and cardiopulmonary collapse.
Developing effective vaccines is considered a top choice among all control measures. We evaluated the ability of inactivated virus vaccine to elicit neutralizing antibody and to provide protection against lethal infection of EV71 in suckling mice. The purity of EV71 vaccine was up to 96.8% by HPLC identification. The purified EV71 vaccine induced high levels of neutralizing antibodies, these antibodies were shown to be protective against lethal infection when passively transferred to susceptible newborn mice. With a challenge dose of 50LD50 virus/mouse, suckling mice born to dams immunized with inactivated virus showed 100% survival. In preliminary animal trial, no side effects were detected when monkeys were immunized with purified EV71 vaccine either at normal or large doses.
The vaccine was approved of the clinical evaluation in 2009. The phase 1/2/3 clinical trail was completed in March 2013. The data suggested that the inactivated EV71 vaccine had a clinically acceptable safety profile and good immunogenicity in healthy children and infants.
Our data indicated that inactivated EV71 vaccine is the choice of vaccine preparation capable of fulfilling the demand for effective control.
doi:10.1097/01.qai.0000446692.62163.5e
PMCID: PMC4149646

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