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1.  Intersubject Variability of and Genetic Effects on the Brain's Functional Connectivity during Infancy 
The Journal of Neuroscience  2014;34(34):11288-11296.
Infancy is a period featuring a high level of intersubject variability but the brain basis for such variability and the potential genetic/environmental contributions remain largely unexplored. The assessment of the brain's functional connectivity during infancy by the resting state functional magnetic resonance imaging (rsfMRI) technique (Biswal et al., 1995) provides a unique means to probe the brain basis of intersubject variability during infancy. In this study, an unusually large typically developing human infant sample including 58 singletons, 132 dizygotic twins, and 98 monozygotic twins with rsfMRI scans during the first 2 years of life was recruited to delineate the spatial and temporal developmental patterns of both the intersubject variability of and genetic effects on the brain's functional connectivity. Through systematic voxelwise functional connectivity analyses, our results revealed that the intersubject variability at birth features lower variability in primary functional areas but higher values in association areas. Although the relative pattern remains largely consistent, the magnitude of intersubject variability undergoes an interesting U-shaped growth during the first 2 years of life. Overall, the intersubject variability patterns during infancy show both adult-like and infant-specific characteristics (Mueller et al., 2013). On the other hand, age-dependent genetic effects were observed showing significant but bidirectional relationships with intersubject variability. The temporal and spatial patterns of the intersubject variability of and genetic contributions to the brain's functional connectivity documented in this study shed light on the largely uncharted functional development of the brain during infancy.
doi:10.1523/JNEUROSCI.5072-13.2014
PMCID: PMC4138339  PMID: 25143609
early brain development; functional connectivity; genetic effects; infancy; intersubject variability; resting state
2.  An Antagonist Mutant IL-15/Fc Promotes Transplant Tolerance 
Transplantation  2006;81(1):109-116.
Background
IL-15 is a proinflammatory and antiapoptotic T-cell growth factor that plays an important role in a variety of autoimmune disorders and transplant rejection. To inhibit IL-15 function and to target IL-15 receptor (IL-15R) bearing cells, we have generated a unique lytic antagonistic mutant IL-15/Fc fusion protein (mIL-15/Fc).
Methods
In this study, we further examined the efficacy of mIL-15/Fc in preventing allograft rejection cross minor and major histocompatibility barriers.
Results
A short-course treatment with mIL-15/Fc fusion protein is sufficient to prevent cardiac allograft rejection and induce antigen-specific tolerance in minor histocompatibility complex-mismatched recipients, and permit prolonged cardiac allograft survival in fully MHC mismatched recipients. In addition, mIL-15/Fc treatment, in combination with a suboptimal dose of anti-CD154 antibody, confers permanent cardiac allograft engraftment in a fully MHC-mismatched mouse strain combination. In a murine islet allograft model, mIL-15/Fc monotherapy is capable to permit permanent allograft survival in 50% fully MHC-mismatched recipients.
Conclusion
Immunochemistry studies demonstrated that prolonged graft survival was accompanied by reduced intragraft mononuclear cell infiltration and pro-inflammatory cytokine gene expression in the mIL-15/Fc treated recipients. Moreover, parallel experiments employing a mutated nonlytic IgG2a Fc demonstrate that the Fc portion of mIL-15/Fc contributes to the overall efficacy of the molecule in vivo.
PMCID: PMC4329733  PMID: 16421485
Transplantation; Heart; Islet; Cytokines; Rejection
3.  Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study 
Rationale: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.
Objectives: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.
Methods: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than −950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.
Measurements and Main Results: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10−8) and PPT2 (rs10947233; P = 3.2 × 10−8), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase–related gene MAN2B1 (rs10411619; P = 1.1 × 10−9; minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10−10; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10−8; MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase–related gene, MAN1C1 (rs12130495; P = 9.9 × 10−6; MAF, 13.3%) was associated with percent emphysema.
Conclusions: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
doi:10.1164/rccm.201306-1061OC
PMCID: PMC3977717  PMID: 24383474
emphysema; computed tomography; multiethnic; cohort study; genetic association
4.  HIF-1α -1790G>A polymorphism significantly increases the risk of digestive tract cancer: A meta-analysis 
AIM: To investigate the association between hypoxia-inducible factor-1α (HIF-1α) polymorphisms (-1772C>T and -1790G>A) and the risk of digestive tract cancer.
METHODS: A total of 13 eligible studies were retrieved from PubMed, EMBASE, and the China National Knowledge Infrastructure database. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the associations.
RESULTS: By pooling the eligible studies, we found that the HIF-1α -1772C>T polymorphism was not associated with the risk of developing digestive tract cancer (dominant comparison, OR: 1.156; 95%CI: 0.839-1.593; Pheterogeneity = 0.007), and no significant association was found in the Asian population or the Caucasian population. However, for the -1790G>A polymorphism, carriers of the variant -1790A allele had a significantly increased risk of digestive tract cancer compared with those with the wildtype -1790G allele (dominant comparison, OR: 3.252; 95%CI: 1.661-6.368; Pheterogeneity < 0.001). Additionally, this increased risk of digestive cancer was only detected in Asians; there was no significant association in Caucasians.
CONCLUSION: This meta-analysis demonstrates that the HIF-1α -1790G>A polymorphism is associated with a significantly increased risk of digestive tract cancer, while the -1772C>T polymorphism is not.
doi:10.3748/wjg.v21.i5.1641
PMCID: PMC4316108  PMID: 25663785
Hypoxia-inducible factor-1α; Digestive tract cancer; Polymorphisms; Cancer risk; Meta-analysis
5.  Nasopharyngeal carriage and antimicrobial susceptibility of Haemophilus influenzae among children younger than 5 years of age in Beijing, China 
BMC Microbiology  2015;15:6.
Background
Haemophilus influenzae is one of the main pathogens that cause community-acquired respiratory infections in children. Our previous study showed that H. influenzae is the second most common pathogen causing pneumonia and accounts for 30–50% of bacterial meningitis among Chinese children. H. influenzae carriage in children and its resistance to commonly used antimicrobials varies widely both geographically and over time.
Results
Surveys of the nasopharyngeal carriage of H. influenzae in children younger than 5 years of age with acute respiratory tract infection (ARI) were conducted in Beijing Children’s Hospital, China in 2000, 2002, 2010, and 2012. The overall annual carriage rates of H. influenzae among children younger than 5 years of age with ARI were 35.5%, 20.6%, 14.4%, and 18.7%, and the percentages of H. influenzae isolates producing β-lactamase were 4%, 13%, 27.1%, and 31%, respectively. The percentages of susceptibility to ampicillin progressively decreased from 96% (2000) to 87% (2002) to 63% (2010) to 61% (2012). All of the ampicillin-resistant isolates were found to be beta-lactamase producers. The susceptibility to tetracycline increased from 54% (2000) to 60% (2002) to 91.5% (2010) to 94.5% (2012). No statistically significant differences were observed in the susceptibility to cefaclor, cefuroxime, sulfamethoxazole, and chloramphenicol. Amoxicillin/clavulanic acid and ceftriaxone were the most effective antimicrobials for the isolates of H. influenzae across the 10-year period.
Conclusions
This report on the H. influenzae carriage rates in children and the susceptibility of these bacteria to commonly used antibiotics showed that H. influenzae carriage decreased from 2000 to 2012. Additionally, the percentage of β-lactamase-producing isolates increased while their susceptibility to ampicillin progressively decreased during this time. These results indicate that the appropriate empirical antimicrobial therapy should be changed for pediatric patients in China.
doi:10.1186/s12866-015-0350-7
PMCID: PMC4332420  PMID: 25648185
Haemophilus influenzae; Antimicrobial susceptibility; Acute upper respiratory tract infection; Pediatrics
6.  Adjudin protects rodent cochlear hair cells against gentamicin ototoxicity via the SIRT3-ROS pathway 
Scientific Reports  2015;5:8181.
Hearing loss resulting from hair cell degeneration is a common disease that affects millions of people worldwide. Strategies to overcome the apparent irreversible hair cell loss in mammals become paramount for hearing protection. Here we reported that, by using a well-established gentamicin-induced hair cell loss model in vitro, adjudin, a multi-functional small molecule drug, protected cochlear hair cells from gentamicin damage. Immunohistochemistry, Western blotting and quantitative RT-PCR analyses revealed that adjudin exerted its otoprotective effects by up-regulating the level of Sirt3, a member of Sirtuin family protein located in mitochondria, which regulates reactive oxygen species (ROS) production in cochlear cells and inhibits the production of ROS and apoptotic cells induced by gentamicin. Sirt3 silencing experiments confirmed that Sirt3-ROS signaling axis mediated hair cell protection against gentamicin by adjudin, at least in part. Furthermore, adjudin's otoprotection effects were also observed in an in vivo gentamicin-injured animal model. Taken together, these findings identify adjudin as a novel otoprotective small molecule via elevating Sirt3 levels and Sirt3 may be of therapeutic value in hair cell protection from ototoxic insults.
doi:10.1038/srep08181
PMCID: PMC4313083  PMID: 25640330
7.  Glycomic Signatures on Serum IgGs for Prediction of Postvaccination Response 
Scientific Reports  2015;5:7648.
Millions of individuals are vaccinated worldwide each year to stimulate their adaptive immune systems to produce protective antibodies and T-cell response against pathogens. Since glycosylation of the Fc region of immunoglobulin G (IgG) can be influenced by the host's immune status, it was inferred that glycosylation profile of IgG might be altered as a result of the immune response. Therefore, subclass-specific glycosylation profiles of serum IgGs from 26 healthy adults before and after vaccination with a trivalent subunit influenza virus vaccine were comprehensively analyzed to explore glycomic signatures for vaccination. The results showed that no significant changes in the glycosylation of total IgGs took place before and after vaccination, but distinct glycosylation profiles in responders (fourfold or more increase of HI titer after vaccination) and nonresponders (less than fourfold increase of HI titer) were observed. This difference between the responders and nonresponders occurred even in the resting state. On the basis of variable importance parameters, glycosylation markers that distinguish responders from nonresponders were identified. These markers can be used as molecular signatures to predict antibody titers after vaccination. This is the first study of serum IgG glycosylation profiles in healthy adults receiving a trivalent inactivated influenza vaccine.
doi:10.1038/srep07648
PMCID: PMC4303884  PMID: 25612906
8.  Multiple mesenteric well-differentiated liposarcoma complicated by purulent inflammation: A case report 
Oncology Letters  2015;9(3):1333-1336.
Multiple mesenteric well-differentiated (WD) liposarcoma is an extremely rare entity. The present study describes a case of multiple mesenteric WD liposarcoma, complicated by purulent inflammation, in a 59-year-old male who presented with abdominal pain and pyrexia of unknown origin. A computed tomography scan of the abdomen revealed a large, non-encapsulated mass in the abdomino-pelvic cavity, which was characterized by two components, a main portion of fatty density and a non-adipose solid portion. A re-evaluated CT scan, performed eight days later, revealed an enlargement of the non-adipose mass. A laparotomy was performed, and numerous separated fatty nodules and masses of various sizes were identified within the mesentery of the small intestine. The histological findings were consistent with an adipocytic subtype of multiple mesenteric WD liposarcoma, with the largest of the tumors complicated by purulent inflammation. The multiplicity of these tumors and the concurrent purulent inflammation in the present case make it unique.
doi:10.3892/ol.2015.2847
PMCID: PMC4315053  PMID: 25663908
multiple; mesenteric; well-differentiated liposarcoma; computed tomography; purulent inflammation
9.  Development of Thalamocortical Connectivity during Infancy and Its Cognitive Correlations 
The Journal of Neuroscience  2014;34(27):9067-9075.
Although commonly viewed as a sensory information relay center, the thalamus has been increasingly recognized as an essential node in various higher-order cognitive circuits, and the underlying thalamocortical interaction mechanism has attracted increasing scientific interest. However, the development of thalamocortical connections and how such development relates to cognitive processes during the earliest stages of life remain largely unknown. Leveraging a large human pediatric sample (N = 143) with longitudinal resting-state fMRI scans and cognitive data collected during the first 2 years of life, we aimed to characterize the age-dependent development of thalamocortical connectivity patterns by examining the functional relationship between the thalamus and nine cortical functional networks and determine the correlation between thalamocortical connectivity and cognitive performance at ages 1 and 2 years. Our results revealed that the thalamus–sensorimotor and thalamus–salience connectivity networks were already present in neonates, whereas the thalamus–medial visual and thalamus–default mode network connectivity emerged later, at 1 year of age. More importantly, brain–behavior analyses based on the Mullen Early Learning Composite Score and visual–spatial working memory performance measured at 1 and 2 years of age highlighted significant correlations with the thalamus–salience network connectivity. These results provide new insights into the understudied early functional brain development process and shed light on the behavioral importance of the emerging thalamocortical connectivity during infancy.
doi:10.1523/JNEUROSCI.0796-14.2014
PMCID: PMC4078084  PMID: 24990927
development; functional connectivity; Mullen scores; resting state; thalamus; working memory
10.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
11.  NERF encodes a RING E3 ligase important for drought resistance and enhances the expression of its antisense gene NFYA5 in Arabidopsis 
Nucleic Acids Research  2014;43(1):607-617.
NFYA5 is an important drought-stress inducible transcription factor gene that is targeted by miR169 in Arabidopsis. We show here that the cis-natural antisense transcript gene of NFYA5, NFYA5 Enhancing RING FINGER (NERF), can produce siRNAs from their overlapping region (OR) and affect NFYA5 transcripts by functioning together with miR169. The NERF protein functions as an E3 ligase for ubiquitination. Overexpression of NERF or OR cDNA leads to siRNANERF accumulation, miR169 repression, and NFYA5 transcript enhancement; knock-down of NERF transcripts by an artificial miRNA enhances miR169 abundance and reduces NFYA5 transcripts. Overexpression of NFYA5 does not affect the NERF mRNA level. Deep sequencing of the small RNA library from 35S::OR plants identifies 960 sequences representing 323 unique siRNAs that originate from OR; the sequences of some siRNANERF are similar/complementary to those of miR169. Overexpression of the 195- to 280-bp OR cDNA-containing siRNAs similar/complementary to miR169 also leads to the accumulation of NFYA5 transcripts. Analysis of NERF knock-down plants and NERF overexpression lines showed that, like NFYA5, NERF is important for controlling stomatal aperture and drought resistance. This regulatory model might apply to other natural antisense transcripts with positively correlated expression patterns.
doi:10.1093/nar/gku1325
PMCID: PMC4288204  PMID: 25514924
12.  Poly(ADP-ribose) glycohydrolase silencing down-regulates TCTP and Cofilin-1 associated with metastasis in benzo(a)pyrene carcinogenesis 
Benzo(a)pyrene (BaP) is a ubiquitously distributed environmental pollutant. BaP is a known carcinogen and can induce malignant transformation of rodent and human cells. Many evidences suggest that inhibitor of poly(ADP-ribose) glycohydrolase (PARG) is potent anticancer drug candidate. However, the effect of PARG on BaP carcinogenesis remains unclear. We explored this question in a PARG-deficient human bronchial epithelial cell line (shPARG cells) treated with various concentration of BaP for 15 weeks. Soft agar assay was used to examine BaP-induced cell malignancy of human bronchial epithelial cells and shPARG cells. Mechanistic investigations were used by 2D-DIGE and mass spectrometry. Western blot analysis and Double immunofluorescence detection were used to confirm some of the results obtained from DIGE experiments. We found that PARG silencing could dramatically inhibit BaP-induced cell malignancy of human bronchial epithelial cells in soft agar assay. Altered levels of expression induced by BaP were observed within shPARG cells for numerous proteins, including proteins required for cell mobility, stress response, DNA repair and cell proliferation pathways. Among these proteins, TCTP and Cofilin-1 involved in malignancy, were validated by western blot analysis and immunofluorescence assay. PARG inhibition contributed to down-regulation of TCTP and Cofilin-1. This is the first experimental demonstration of a link between PARG silencing and reduced cell migration after BaP exposure. We propose that PARG silencing might down-regulate TCTP and Cofilin-1 associated with metastasis in BaP carcinogenesis.
PMCID: PMC4300713  PMID: 25628927
poly(ADP-ribosyl)ation; poly(ADP-ribose) glycohydrolase; benzo(a)pyrene; DNA damage; human bronchial epithelial cells (16HBE cells)
13.  Genome Sequence of the Petroleum Hydrocarbon-Degrading Bacterium Alcanivorax sp. Strain 97CO-5 
Genome Announcements  2014;2(6):e01277-14.
Alcanivorax sp. strain 97CO-5 was isolated from a crude-oil-degrading consortium, enriched from Yellow Sea sediment of China. Here, we present the draft genome of strain 97CO-5, which comprises 3,251,558 bp with a G+C content of 54.54% and contains 2,962 protein-coding genes and 42 tRNAs.
doi:10.1128/genomeA.01277-14
PMCID: PMC4263835  PMID: 25502673
14.  Anti-CTGF Single-Chain Variable Fragment Dimers Inhibit Human Airway Smooth Muscle (ASM) Cell Proliferation by Down-Regulating p-Akt and p-mTOR Levels 
PLoS ONE  2014;9(12):e113980.
Connective tissue growth factor (CTGF) contributes to airway smooth muscle (ASM) cell hyperplasia in asthma. Humanized single-chain variable fragment antibody (scFv) was well characterized as a CTGF antagonist in the differentiation of fibroblast into myofibroblast and pulmonary fibrosis in our previous studies. To further improve the bioactivity of scFv, we constructed a plasmid to express scFv-linker-matrilin-6×His fusion proteins that could self-assemble into the scFv dimers by disulfide bonds in matrilin under non-reducing conditions. An immunoreactivity assay demonstrated that the scFv dimer could highly bind to CTGF in a concentration-dependent manner. The MTT and EdU assay results revealed that CTGF (≥10 ng/mL) promoted the proliferation of ASM cells, and this effect was inhibited when the cells were treated with anti-CTGF scFv dimer. The western blot analysis results showed that increased phosphorylation of Akt and mTOR induced by CTGF could be suppressed by this scFv dimer. Based on these findings, anti-CTGF scFv dimer may be a potential agent for the prevention of airway remodeling in asthma.
doi:10.1371/journal.pone.0113980
PMCID: PMC4257608  PMID: 25478966
15.  Neurotrophic keratopathy due to dorsolateral medullary infarction (Wallenberg Syndrome): case report and literature review 
BMC Neurology  2014;14(1):231.
Background
Dorsolateral medullary infarction (Wallenberg Syndrome) is rare in clinical practice; however, the subsequent corneal lesions are more uncommon. To our knowledge, only one such case was previously reported. We report a similar case with successful treatment and recovery, and analyse both cases to address the clinical features and outcomes of such syndrome.
Case presentation
A 43-year-old male presented with neurotrophic keratopathy one month after sustaining dorsolateral medullary infarction. The patient underwent amniotic membrane transplantation twice. Two-year follow-up observation revealed changes in nerve fibers and epithelial cells of corneal by laser confocal microscopy.
Conclusion
By studying both cases, we confirm that neurotrophic keratopathy could be as a delayed-onset complication of Wallenberg syndrome. The recognition that neurotrophic keratopathy can follow dorsolateral medullary infarction could prevent the clinical misdiagnosis.
doi:10.1186/s12883-014-0231-y
PMCID: PMC4258269  PMID: 25472780
Dorsolateral medullary infarction; Neurotrophic keratopathy; Wallenberg syndrome
16.  Robust Huber-Based Iterated Divided Difference Filtering with Application to Cooperative Localization of Autonomous Underwater Vehicles 
Sensors (Basel, Switzerland)  2014;14(12):24523-24542.
A new algorithm called Huber-based iterated divided difference filtering (HIDDF) is derived and applied to cooperative localization of autonomous underwater vehicles (AUVs) supported by a single surface leader. The position states are estimated using acoustic range measurements relative to the leader, in which some disadvantages such as weak observability, large initial error and contaminated measurements with outliers are inherent. By integrating both merits of iterated divided difference filtering (IDDF) and Huber's M-estimation methodology, the new filtering method could not only achieve more accurate estimation and faster convergence contrast to standard divided difference filtering (DDF) in conditions of weak observability and large initial error, but also exhibit robustness with respect to outlier measurements, for which the standard IDDF would exhibit severe degradation in estimation accuracy. The correctness as well as validity of the algorithm is demonstrated through experiment results.
doi:10.3390/s141224523
PMCID: PMC4299124  PMID: 25536004
robustness; nonlinear state estimation; Huber-based iterated divided difference filtering; autonomous underwater vehicles; cooperative localization
17.  Instrument development and validation of the stroke pre-hospital delay behavior intention scale in a Chinese urban population 
Background
Several stroke impairment scales are currently available for stroke patients but none of them provide information regarding the pre-stroke behavioral intentions of high-risk stroke patients and their relatives. This study’s objective was to generate and validate a new written tool, the Stroke Pre-hospital Delay Behavior Intention (SPDBI) scale. It is suitable for use with high-risk stroke patients and their relatives to predict the likelihood of pre-hospital delay.
Methods
From a review of related studies, we formulated a prototype scale. We interviewed ten stroke patients in a semi-structured iterative process that included interviews with experts, high-risk patients, and their family members. Then, we pretested and filtered items. We next used a large sample size and factor analysis to determine the scale’s structure. Finally, we checked the reliability and validity of the scale.
Results
We identified five sub-domains (stroke warning signs, non-treatment justification, symptom attributions, habitual response style, and emergency system use). The SPDBI demonstrated good internal consistency and test-retest reliability (Cronbach’s α =0.808; Intraclass Correlation Coefficient [ICC] =0.797).
Conclusions
This SPDBI scale is a reliable, and valid measure of the likeliness of pre-hospital delay in high-risk stroke patients and their family members. It may provide scientific assessment for targeted health education intervention.
Electronic supplementary material
The online version of this article (doi:10.1186/s12955-014-0170-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12955-014-0170-8
PMCID: PMC4264611  PMID: 25432795
Pre-hospital delay; Behavioral intention; High-risk stroke patients
18.  Ethanol Negatively Regulates Hepatic Differentiation of hESC by Inhibition of the MAPK/ERK Signaling Pathway In Vitro 
PLoS ONE  2014;9(11):e112698.
Background
Alcohol insult triggers complex events in the liver, promoting fibrogenic/inflammatory signals and in more advanced cases, aberrant matrix deposition. It is well accepted that the regenerative capacity of the adult liver is impaired during alcohol injury. The liver progenitor/stem cells have been shown to play an important role in liver regeneration -in response to various chronic injuries; however, the effects of alcohol on stem cell differentiation in the liver are not well understood.
Methods
We employed hepatic progenitor cells derived from hESCs to study the impact of ethanol on hepatocyte differentiation by exposure of these progenitor cells to ethanol during hepatocyte differentiation.
Results
We found that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitor cells in a dose-dependent manner. There was also a moderate cell cycle arrest at G1/S checkpoint in the ethanol treated cells, which is associated with a reduced level of cyclin D1 in these cells. Ethanol treatment specifically inhibited the activation of the ERK but not JNK nor the p38 MAP signaling pathway. At the same time, the WNT signaling pathway was also reduced in the cells exposed to ethanol. Upon evaluating the effects of the inhibitors of these two signaling pathways, we determined that the Erk inhibitor replicated the effects of ethanol on the hepatocyte differentiation and attenuated the WNT/β-catenin signaling, however, inhibitors of WNT only partially replicated the effects of ethanol on the hepatocyte differentiation.
Conclusion
Our results demonstrated that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitors through inhibiting the MAPK/ERK signaling pathway, and subsequently attenuating the WNT signaling pathway. Thus, our finding provides a novel insight into the mechanism by which alcohol regulates cell fate selection of hESC-derived hepatic progenitor cells, and the identified pathways may provide therapeutic targets aimed at promoting liver repair and regeneration during alcoholic injury.
doi:10.1371/journal.pone.0112698
PMCID: PMC4231066  PMID: 25393427
19.  Benign giant-cell tumor of the common bile duct: A case report 
World Journal of Gastroenterology : WJG  2014;20(41):15448-15453.
Primary giant-cell tumors rarely arise in the common bile duct. We herein report a case of primary giant-cell tumor of the common bile duct. The patient was an 81-year-old male who was diagnosed with a well-defined 1.2-cm mass projecting into the lumen of the middle common bile duct. Excision of the gallbladder and extrahepatic bile duct and a Roux-en-Y cholangiojejunostomy were performed. Histologically, the tumor had no association with carcinomas of epithelial origin and was similar to giant-cell tumors of the bone. The tumor consisted of a mixture of mononuclear and multinucleated osteoclast-like giant cells. The mononuclear cells showed no atypical features, and their nuclei were similar to those of the multinucleated giant cells. CD68 was expressed on the mononuclear and multinucleated osteoclast-like giant cells, whereas CD163 immunoreactivity was restricted to the mononuclear cells. Six months after the operation, the patient was still alive and had no recurrence. The interest of this case lies in the rarity of this entity, the difficulty of preoperative diagnosis, and this tumor’s possible confusion with other malignant tumors.
doi:10.3748/wjg.v20.i41.15448
PMCID: PMC4223279  PMID: 25386094
Giant-cell tumor; Common bile duct; CD163; Surgical resection
20.  Toward in vivo detection of hydrogen peroxide with ultrasound molecular imaging 
Biomaterials  2013;34(35):8918-8924.
We present a new class of ultrasound molecular imaging agents that extend upon the design of micromotors that are designed to move through fluids by catalyzing hydrogen peroxide (H2O2) and propelling forward by escaping oxygen microbubbles. Micromotor converters require 62 mm of H2O2 to move – 1000-fold higher than is expected in vivo. Here, we aim to prove that ultrasound can detect the expelled microbubbles, to determine the minimum H2O2 concentration needed for microbubble detection, explore alternate designs to detect the H2O2 produced by activated neutrophils and perform preliminary in vivo testing. Oxygen microbubbles were detected by ultrasound at 2.5 mm H2O2. Best results were achieved with a 400–500 nm spherical design with alternating surface coatings of catalase and PSS over a silica core. The lowest detection limit of 10–100 µm was achieved when assays were done in plasma. Using this design, we detected the H2O2 produced by freshly isolated PMA-activated neutrophils allowing their distinction from naïve neutrophils. Finally, we were also able to show that direct injection of these nanospheres into an abscess in vivo enhanced ultrasound signal only when they contained catalase, and only when injected into an abscess, likely because of the elevated levels of H2O2 produced by inflammatory mediators.
doi:10.1016/j.biomaterials.2013.06.055
PMCID: PMC3794895  PMID: 23958028
Ultrasound; Nanotechnology; Hydrogen peroxide; Molecular imaging; Abscess
21.  Gradient Learning Algorithms for Ontology Computing 
The gradient learning model has been raising great attention in view of its promising perspectives for applications in statistics, data dimensionality reducing, and other specific fields. In this paper, we raise a new gradient learning model for ontology similarity measuring and ontology mapping in multidividing setting. The sample error in this setting is given by virtue of the hypothesis space and the trick of ontology dividing operator. Finally, two experiments presented on plant and humanoid robotics field verify the efficiency of the new computation model for ontology similarity measure and ontology mapping applications in multidividing setting.
doi:10.1155/2014/438291
PMCID: PMC4229975  PMID: 25530752
22.  Femoral Artery Occlusion Increases Muscle Pressor Reflex and Expression of Hypoxia-Inducible Factor-1α in Sensory Neurons 
Hypoxia inducible factor-1 (HIF-1) has an important contribution to pathophysiological changes of homeostasis under conditions of oxygen deprivation as well as ischemia. We examined the effects of femoral artery occlusion on HIF-1α expression in sensory dorsal root ganglion (DRG) neurons of rats. Also, we examined cardiovascular responses to static muscle contraction following femoral occlusion. We hypothesized that hindlimb vascular insufficiency increases the levels of sensory nerves’ HIF-1α and augments autonomic responses induced by activation of muscle afferent nerves. In addition, we examined if the reflex cardiovascular responses were altered as HIF-1α was increased in the DRG neurons. Our data show that HIF-1α was significantly increased in the lumbar DRG neurons 6, 24 and 72 hours after femoral artery ligation as compared with sham control. Administration of dimethyloxalylglycine (DMOG), a stabilizer of HIF-α, significantly increased HIF-1α in the lumbar DRG neurons. Furthermore, femoral occlusion enhanced the reflex pressor response to muscle contraction; however, the response was not altered by injection of DMOG. Overall, our results indicate that 1) femoral artery occlusion increases HIF-1α levels of in DRG neurons and contraction-induced pressor response; and 2) an increase in HIF-1α of DRG neurons per se may not alter the muscle pressor reflex.
PMCID: PMC4207090  PMID: 25346936
Blood pressure; HIF-1; Muscle contraction; Sensory nerve
23.  Development and Validation of the Pre-Hospital Stroke Symptoms Coping Test 
PLoS ONE  2014;9(10):e110022.
Background and Purpose
Measures of specific knowledge of coping with pre-hospital stroke symptoms can help educate high-risk patients and family caregivers. This study aimed to develop and validate the Pre-hospital Stroke Symptoms Coping Test (PSSCT).
Materials and Methods
Reliability and validity were analyzed using multiple data sources. The Delphi expert consultation method was applied to assess the test’s surface validity and content validity index. The final edition of the 19-item PSSCT contained 3 sections assessing coping with typical symptoms and symptoms associated with vomiting and twitching. Its psychometric properties were investigated in a community sample of 300 high-risk patients and family members.
Results
The PSSCT was readily accepted by participants. It demonstrated adequate surface validity and content validity, and good internal consistency (KR20 = 0.822) and test-retest reliability (0.769), with difficulty (P) and degree of differentiation (D) ranges of 0.28–0.83 and 0.15–0.66, respectively. It was also able to distinguish between individuals who had/had not experienced a stroke. Experienced individuals scored significantly higher overall and on coping with typical symptoms and twitching (P<0.01).
Conclusions
The PSSCT can practically and directly assess critical knowledge regarding coping with pre-hospital stroke symptoms and has good reliability and validity.
doi:10.1371/journal.pone.0110022
PMCID: PMC4201517  PMID: 25330453
24.  Requirement of CRTC1 coactivator for hepatitis B virus transcription 
Nucleic Acids Research  2014;42(20):12455-12468.
Transcription of hepatitis B virus (HBV) from the covalently closed circular DNA (cccDNA) template is essential for its replication. Suppressing the level and transcriptional activity of cccDNA might have anti-HBV effect. Although cellular transcription factors, such as CREB, which mediate HBV transcription, have been well described, transcriptional coactivators that facilitate this process are incompletely understood. In this study we showed that CREB-regulated transcriptional coactivator 1 (CRTC1) is required for HBV transcription and replication. The steady-state levels of CRTC1 protein were elevated in HBV-positive hepatoma cells and liver tissues. Ectopic expression of CRTC1 or its homolog CRTC2 or CRTC3 in hepatoma cells stimulated the activity of the preS2/S promoter of HBV, whereas overexpression of a dominant inactive form of CRTC1 inhibited HBV transcription. CRTC1 interacts with CREB and they are mutually required for the recruitment to the preS2/S promoter on cccDNA and for the activation of HBV transcription. Accumulation of pregenomic RNA (pgRNA) and cccDNA was observed when CRTC1 or its homologs were overexpressed, whereas the levels of pgRNA, cccDNA and secreted HBsAg were diminished when CRTC1 was compromised. In addition, HBV transactivator protein HBx stabilized CRTC1 and promoted its activity on HBV transcription. Our work reveals an essential role of CRTC1 coactivator in facilitating and supporting HBV transcription and replication.
doi:10.1093/nar/gku925
PMCID: PMC4227773  PMID: 25300488
25.  TOP2Ahigh is the phenotype of recurrence and metastasis whereas TOP2Aneg cells represent cancer stem cells in prostate cancer 
Oncotarget  2014;5(19):9498-9513.
Recurrence and metastasis are the main causes of death for prostate cancer patients and cancer stem cells (CSCs) are proposed to play important roles in cancer recurrence and metastasis. It is generally thought that genes upregulated in recurrent/metastatic disease are likely biomarkers of CSCs. Hence we analyzed multiple microarray datasets on prostate tumor tissues to identify upregulated genes associated with cancer recurrence/metastasis, and tried to explore whether those genes were true biomarkers of prostate CSCs. Our results indicated that TOP2A was the most highly upregulated gene in recurrent/metastatic prostate cancer, and its high expression was positively correlated with poor prognosis in patients. Using a promoter reporter system, we unexpectedly discovered enrichment of CSCs in TOP2Aneg cells. Compared to TOP2Ahigh cells, TOP2Aneg cells formed spheres and tumors more efficiently, and became enriched in the presence of stresses. Analysis of cell divisions by time lapse imaging indicated that more slow-cycling cells were observed in TOP2Aneg cells while the proportion of abnormal divisions was higher in TOP2Ahigh cells. Our studies demonstrate that TOP2Ahigh is the phenotype of recurrence/metastasis but TOP2Aneg cells show slow cycling and have CSCs properties in prostate cancer, which has significant implications for prostate cancer therapy.
PMCID: PMC4253449  PMID: 25237769
prostate cancer; cancer stem cells; TOP2A; recurrence; metastasis

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