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1.  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.
PMCID: PMC3729193  PMID: 22784607
adolescence; connectivity; connector hub; cortical thickness; maturation
2.  Ultrasound Image Enhancement Using Structure-Based Filtering 
Ultrasound images are prone to speckle noises. Speckles blur features which are essential for diagnosis and assessment. Thus despeckling is a necessity in ultrasound image processing. Linear filters can suppress speckles, but they smooth out features. Median filter based despeckling algorithms produce better results. However, they may produce artifact patterns in the resulted images and oversmooth nonuniform regions. This paper presents an innovative despeckle procedure for ultrasound images. In the proposed method, the diffusion tensor of intensity is computed at each pixel at first. Then the eigensystem of the diffusion tensor is calculated and employed to detect and classify the underlying structure. Based on the classification result, a feasible filter is selected to suppress speckles and enhance features. Test results show that the proposed despeckle method reduces speckles in uniform areas and enhances tissue boundaries and spots.
PMCID: PMC4089207  PMID: 25110515
3.  Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer 
Oncotarget  2014;5(12):4269-4282.
A cancer phenotype is driven by several proteins and targeting a cluster of functionally interdependent molecules should be more effective for therapeutic intervention. This is specifically important for Ras-dependent cancer, as mutated (MT) Ras is non-druggable and targeting its interaction with effectors may be essential for therapeutic intervention. Here, we report that a protein-complex activated by the Ras effector p38γ MAPK is a novel therapeutic target for K-Ras-dependent colon cancer. Unbiased proteomic screening and immune-precipitation analyses identified p38γ interaction with heat shock protein 90 (Hsp90) and K-Ras in K-Ras MT, but not wild-type (WT), colon cancer cells, indicating a role of this complex in Ras-dependent growth. Further experiments showed that this complex requires p38γ and Hsp90 activity to maintain MT, but not WT, K-Ras protein expression. Additional studies demonstrated that this complex is activated by p38γ-induced Hsp90 phosphorylation at S595, which is important for MT K-Ras stability and for K-Ras dependent growth. Of most important, pharmacologically inhibition of Hsp90 or p38γ activity disrupts the complex, decreases K-Ras expression, and selectively inhibits the growth of K-Ras MT colon cancer in vitro and in vivo. These results demonstrated that the p38γ-activated ternary complex is a novel therapeutic target for K-Ras-dependent colon cancer.
PMCID: PMC4147322  PMID: 24962213
p38γ MAPK; Hsp90; K-Ras; ternary complex; therapeutic target; and colon cancer
4.  Circulating MicroRNAs in gynecological malignancies: from detection to prediction 
MicroRNAs (miRNAs) have been demonstrated to play critical roles in many physiological and pathophysiological processes. The presence of altered miRNA profiles in human body fluids has been reported for a number of diseases including gynecological malignancies. In this review, we summarized the current progresses of circulating miRNAs associated with malignancies in gynecology, with an emphasizing on the circulating miRNAs as diagnostic and prognostic biomarkers in ovarian cancer, endometrial carcinoma and cervical cancer.
PMCID: PMC4047546  PMID: 24910811
5.  Terrestrial Origin of Viviparity in Mesozoic Marine Reptiles Indicated by Early Triassic Embryonic Fossils 
PLoS ONE  2014;9(2):e88640.
Viviparity in Mesozoic marine reptiles has traditionally been considered an aquatic adaptation. We report a new fossil specimen that strongly contradicts this traditional interpretation. The new specimen contains the oldest fossil embryos of Mesozoic marine reptile that are about 10 million years older than previous such records. The fossil belongs to Chaohusaurus (Reptilia, Ichthyopterygia), which is the oldest of Mesozoic marine reptiles (ca. 248 million years ago, Early Triassic). This exceptional specimen captures an articulated embryo in birth position, with its skull just emerged from the maternal pelvis. Its headfirst birth posture, which is unlikely to be a breech condition, strongly indicates a terrestrial origin of viviparity, in contrast to the traditional view. The tail-first birth posture in derived ichthyopterygians, convergent with the conditions in whales and sea cows, therefore is a secondary feature. The unequivocally marine origin of viviparity is so far not known among amniotes, a subset of vertebrate animals comprising mammals and reptiles, including birds. Therefore, obligate marine amniotes appear to have evolved almost exclusively from viviparous land ancestors. Viviparous land reptiles most likely appeared much earlier than currently thought, at least as early as the recovery phase from the end-Permian mass extinction.
PMCID: PMC3922983  PMID: 24533127
6.  In Vivo Analysis of Trapeziometacarpal Joint Kinematics during Pinch Tasks 
BioMed Research International  2014;2014:157295.
This study investigated how the posture of the thumb while performing common pinch movements and the levels of pinch force applied by the thumb affect the arthrokinematics of the trapeziometacarpal joint in vivo. Fifteen subjects performed the pinch tasks at the distal phalange (DP), proximal interphalangeal (PIP) joint, and metacarpophalangeal (MP) joint of the index finger with 0%, 50%, and 80% of maximal pinch forces by a single-axis load cell. 3D images of the thumb were obtained using the computed tomography. The results show that the reference points moved from the central region to the dorsal-radial region when changing from pinching the DP to the MP joint without pinching force being applied. Pinching with 80% of the maximum pinching force resulted in reference points being the closest to the volar-ulnar direction. Significant differences were seen between 0% and 50% of maximum pinch force, as well as between 0% and 80%, when pinching the MP joint in the distal-proximal direction. The effects of posture of the thumb and applied pinch force on the arthrokinematics of the joint were investigated with a 3D model of the trapeziometacarpal joint. Pinching with more than 50% of maximum pinch force might subject this joint to extreme displacement.
PMCID: PMC3934769  PMID: 24683540
7.  The Role of the High-Sensitivity C-Reactive Protein in Patients with Stable Non-Cystic Fibrosis Bronchiectasis 
Pulmonary Medicine  2013;2013:795140.
Study Objectives. The aim of this study is to investigate the correlation between serum high-sensitivity C-reactive protein (hs-CRP) and other clinical tools including high-resolution computed tomography (HRCT) in patients with stable non-CF bronchiectasis. Design. A within-subject correlational study of a group of patients with stable non-CF bronchiectasis, who were recruited from our outpatient clinic, was done over a two-year period. Measurements. Sixty-nine stable non-CF bronchiectasis patients were evaluated in terms of hs-CRP, 6-minute walk test, pulmonary function tests, and HRCT. Results. Circulating hs-CRP levels were significantly correlated with HRCT scores (n = 69, r = 0.473, P < 0.001) and resting oxygenation saturation (r = −0.269, P = 0.025). HRCT severity scores significantly increased in patients with hs-CRP level of 4.26 mg/L or higher (mean ± SD 28.1 ± 13.1) compared to those with hs-CRP level less than 4.26 mg/L (31.7 ± 9.8, P = 0.004). Oxygenation saturation at rest was lower in those with hs-CRP level of 4.26 mg/L or higher (93.5 ± 4.4%) compared to those with hs-CRP level less than 4.26 mg/L (96.4 ± 1.6%, P = 0.001). Conclusion. There was a good correlation between serum hs-CRP and HRCT scores in the patients with stable non-CF bronchiectasis.
PMCID: PMC3870862  PMID: 24381758
8.  Neuropathic pain in hereditary coproporphyria 
Acute porphyrias are rare diseases with varying incidences worldwide. These diseases are disorders of heme biosynthesis characterized by acute attacks of neurological symptoms. Acute porphyria should be considered in patients with unexplained abdominal pain or neurological damage. Clinical manifestations of acute porphyria are nonspecific and are associated with multiple organ systems. This report examines a rare case of an uncommon type of acute porphyria in a patient with an initial presentation of abdominal pain and progressive polyneuropathy.
PMCID: PMC3809238  PMID: 24353603
Hereditary coproporphyria; Polyneuropathy; Neuropathic pain; Photosensitivity
9.  Metabolomic Analysis of Complex Chinese Remedies: Examples of Induced Nephrotoxicity in the Mouse from a Series of Remedies Containing Aristolochic Acid 
Aristolochic acid nephropathy is caused by aristolochic acid (AA) and AA-containing herbs. In traditional Chinese medicine, a principle called “Jun-Chen-Zou-Shi” may be utilized to construct a remedial herbal formula that attempts to mitigate the toxicity of the main ingredient. This study used Bu-Fei-A-Jiao-Tang (BFAJT) to test if the compound remedy based on a principle of “Jun-Chen-Zou-Shi” can decrease the toxicity of AA-containing herbs. We compared the three toxicities of AA standard, Madouling (an Aristolochia herb), and a herbal formula BFAJT. AA standard was given for BALB/c mice at a dose of 5 mg/kg bw/day or 7.5 mg/kg bw/day for 10 days. Madouling and BFAJT were given at an equivalence of AA 0.5 mg/kg bw/day for 21 days. Nephrotoxicity was evaluated by metabolomics and histopathology. The urinary metabolomics profiles were characterized by 1H NMR spectroscopy. The spectral data was analyzed with partial least squares discriminant analysis, and the significant differential metabolites between groups were identified. The result showed different degrees of acute renal tubular injuries, and metabolomics analysis found that the kidney injuries were focused in proximal renal tubules. Both metabolomics and pathological studies revealed that AA standard, Madouling, and BFAJT were all nephrotoxicants. The compositions of the compound remedy did not diminish the nephrotoxicity caused by AA.
PMCID: PMC3626396  PMID: 23606874
10.  Novel Application of a Multiscale Entropy Index as a Sensitive Tool for Detecting Subtle Vascular Abnormalities in the Aged and Diabetic 
Although previous studies have shown the successful use of pressure-induced reactive hyperemia as a tool for the assessment of endothelial function, its sensitivity remains questionable. This study aims to investigate the feasibility and sensitivity of a novel multiscale entropy index (MEI) in detecting subtle vascular abnormalities in healthy and diabetic subjects. Basic anthropometric and hemodynamic parameters, serum lipid profiles, and glycosylated hemoglobin levels were recorded. Arterial pulse wave signals were acquired from the wrist with an air pressure sensing system (APSS), followed by MEI and dilatation index (DI) analyses. MEI succeeded in detecting significant differences among the four groups of subjects: healthy young individuals, healthy middle-aged or elderly individuals, well-controlled diabetic individuals, and poorly controlled diabetic individuals. A reduction in multiscale entropy reflected age- and diabetes-related vascular changes and may serve as a more sensitive indicator of subtle vascular abnormalities compared with DI in the setting of diabetes.
PMCID: PMC3590579  PMID: 23509600
11.  Defective Antiviral Responses of Induced Pluripotent Stem Cells to Baculoviral Vector Transduction 
Journal of Virology  2012;86(15):8041-8049.
Genetic engineering of induced pluripotent stem cells (iPSCs) is important for their clinical applications, and baculovirus (BV) holds promise as a gene delivery vector. To explore the feasibility of using BV for iPSCs transduction, in this study we first examined how iPSCs responded to BV. We determined that BV transduced iPSCs efficiently, without inducing appreciable negative effects on cell proliferation, apoptosis, pluripotency, and differentiation. BV transduction slightly perturbed the transcription of 12 genes involved in the Toll-like receptor (TLR) signaling pathway, but at the protein level BV elicited no well-known cytokines (e.g., interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-α], and beta interferon [IFN-β]) except for IP-10. Molecular analyses revealed that iPSCs expressed no TLR1, -6, -8, or -9 and expressed merely low levels of TLR2, -3, and -4. In spite of evident expression of such RNA/DNA sensors as RIG-I and AIM2, iPSCs barely expressed MDA5 and DAI (DNA-dependent activator of IFN regulatory factor [IRF]). Importantly, BV transduction of iPSCs stimulated none of the aforementioned sensors or their downstream signaling mediators (IRF3 and NF-κB). These data together confirmed that iPSCs responded poorly to BV due to the impaired sensing and signaling system, thereby justifying the transduction of iPSCs with the baculoviral vector.
PMCID: PMC3421682  PMID: 22623765
12.  Hyoscine-N-Butyl-Bromide-Induced Hypotension and Myocardial Ischemia 
Case Reports in Critical Care  2013;2013:414856.
Hyoscine N-butyl bromide, also known as scopolamine, is a type of antimuscarinic agent. This drug is associated with numerous common side effects, including abdominal fullness, constipation, urinary retention, blurred vision, skin flushing, tachycardia, decreased sweating, and salivation. The most unfavorable side effect is hemodynamic instability. In the present case, hypotension and acute myocardial infarction developed after intravenous hyoscine injection as a premedication therapy for colonoscopy. It was difficult to differentiate the cause-effect relationship between myocardial infarction and hypotension. Because both conditions were present under drug effects, we considered 2 possible diagnoses. One was coronary spasm with cardiogenic shock, and the other was myocardial ischemic sequela due to shock status. The latter diagnosis was confirmed after a series of examinations.
PMCID: PMC4010047  PMID: 24829823
13.  Ethylene response pathway is essential for ARABIDOPSIS A-FIFTEEN function in floral induction and leaf senescence 
Plant Signaling & Behavior  2012;7(4):457-460.
ARABIDOPSIS A-FIFTEEN (AAF) encodes a plastid protein and was originally identified as a SENESCENCE-ASSOCIATED GENE. Previously, we found that overexpression of AAF (AAF-OX) in Arabidopsis led to accumulated reactive oxygen species and promoted leaf senescence induced by oxidative stress, which was suppressed by a null mutant, ein2-5, in ethylene response pathway. Whether AAF function is involved in ethylene biosynthesis and/or the response pathway remained unknown. Here we show that neither overexpression (AAF-OX) nor a null mutant (aaf-KO) of AAF generates a higher level of ethylene than the wild type and display a typical triple-response phenotype in etiolated seedlings treated with 1-aminocyclopropane-1-carboxylic acid (ACC). Nevertheless, ein2-5 suppresses the phenotypes of early flowering and age-dependent leaf senescence in AAF-OX plants. We reveal that a functional ethylene response is essential for AAF function in leaf senescence and floral induction, but AAF is unlikely a regulatory component integral to the ethylene pathway.
PMCID: PMC3419032  PMID: 22499170
Arabidopsis; leaf senescence; oxidative stress; ethylene; EIN2; reactive oxygen species
14.  MK2 Regulates Ras Oncogenesis through Stimulating ROS Production 
Genes & Cancer  2012;3(7-8):521-530.
Ras signals through both mitogenic and stress pathways and studies of Ras regulatory effects of stress pathways hold great promise to control Ras-dependent malignancies. Our previous work showed Ras activation of a stress kinase (MAPK-activated protein kinase 2 [MK2]), and here, we examine regulatory effects of MK2 on Ras oncogenesis. MK2 knockout was shown to increase Ras transformation in mouse embryonic fibroblasts (MEFs) in vitro and to enhance the resultant tumor growth in mice, indicating a tumor suppressor activity. In Ras-dependent and -independent human colon cancer, however, MK2-forced expression increases and MK2 depletion decreases the malignant growth, suggesting its oncogenic activity. The oncogenic activity of MK2 couples with its activation by both stress and mitogenic signals through extracellular signal–regulated kinase and p38α pathways, whereas its tumor-suppressing effect links to its stimulation only by stress downstream of p38α. Of interest, MK2 was shown to decrease intracellular levels of reactive oxygen species (ROS) in MEFs but increase its production in human colon cancer cells, and experiments with antioxidants revealed that ROS is required for Ras oncogenesis in both systems. These results indicate that MK2 can increase or decrease Ras oncogenesis dependent of its ROS regulatory activities.
PMCID: PMC3527985  PMID: 23264852
MK2; Ras; Ros
15.  Synthesis and Biological Evaluation of Phenanthrenes as Cytotoxic Agents with Pharmacophore Modeling and ChemGPS-NP Prediction as Topo II Inhibitors 
PLoS ONE  2012;7(5):e37897.
In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC50 0.08–1.66 µg/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a–b and for the carbonyl group of 5-OCOCH3 in 7a–b, important for their cytotoxic properties. The SAR for moderately active 5a–b (5-OCH3), and highly active 6a–b and 7a–b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a–b as topoisomerase II inhibitors.
PMCID: PMC3362575  PMID: 22666407
16.  Traffic-Related Air Pollution and DNA Damage: A Longitudinal Study in Taiwanese Traffic Conductors 
PLoS ONE  2012;7(5):e37412.
There is accumulating epidemiologic evidence that exposure to traffic-related air pollutants, including particulate matter (PM) and polyaromatic hydro carbons (PAHs), plays a role in etiology and prognosis of a large scale of illnesses, although the role of specific causal agents and underlying mechanisms for different health outcomes remains unknown.
Our general objective was to assess the relations between personal exposure to traffic exhausts, in particular ambient PM2.5 and PAHs, and the occurrence of DNA strand breaks by applying personal monitoring of PM and biomarkers of exposure (urinary 1-hydroxypyrene-glucuronide, 1-OHPG) and effect (urinary 8-hydroxydeoxyguanosine, 8-OHdG and DNA strand breaks).
We recruited 91 traffic conductors and 53 indoor office workers between May 2009 and June 2011 in Taipei City, Taiwan. We used PM2.5 personal samplers to collect breathing-zone particulate PAHs samples. Spot urine and blood samples after work shift of 2 consecutive days were analyzed for 1-OHPG, 8-OHdG and DNA strand breaks, respectively. Statistical methods included linear regression and mixed models.
Urinary 8-OHdG levels and the occurrence of DNA strand breaks in traffic conductors significantly exceeded those in indoor office workers in mixed models. Particulate PAHs levels showed a positive association with urinary 1-OHPG in the regression model (β = 0.056, p = 0.01). Urinary 1-OHPG levels were significantly associated with urinary 8-OHdG levels in the mixed model (β = 0.101, p = 0.023). Our results provide evidence that exposure to fine particulates causes DNA damage. Further, particulate PAHs could be biologically active constituents of PM2.5 with reference to the induction of oxidative DNA damages.
PMCID: PMC3357412  PMID: 22629390
17.  PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization 
Oncogene  2010;30(14):1706-1715.
Tyrosine phosphorylation is tightly regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), and plays a critical role in malignant transformation and progression. While PTKs have a well-established role in regulating breast cancer growth, contribution of PTPs remains mostly unknown. Here, we report that the tyrosine phosphatase PTPH1 stimulates breast cancer growth through regulating vitamin D receptor (VDR) expression. PTPH1 was shown to be over-expressed in 49% of primary breast cancer and levels of its protein expression positively correlate with the clinic metastasis, suggesting its oncogenic activity. Indeed, PTPH1 promotes breast cancer growth by a mechanism independent of its phosphatase activity but dependent of its stimulatory effect on the nuclear receptor VDR protein expression and depletion of induced VDR abolishes the PTPH1 oncogenic activity. Additional analyses showed that PTPH1 binds VDR and increases its cytoplasmic accumulation leading to their mutual stabilization and stable expression of a nuclear localization deficient VDR abolishes the growth-inhibitory activity of the receptor independent of 1, 25-dihydroxyvitamin D3 (vitamin D3). These results reveal a new paradigm in which a protein tyrosine phosphatase may stimulate breast cancer growth through increasing cytoplasmic translocation of a nuclear receptor leading to their mutual stabilization.
PMCID: PMC3072445  PMID: 21119599
PTPH1; VDR; VDR cytoplasmic translocation; mutual stabilization; breast cancer
18.  Role of ARABIDOPSIS A-FIFTEEN in regulating leaf senescence involves response to reactive oxygen species and is dependent on ETHYLENE INSENSITIVE2 
Journal of Experimental Botany  2011;63(1):275-292.
Leaf senescence is a highly regulated developmental process that is coordinated by several factors. Many senescence-associated genes (SAGs) have been identified, but their roles during senescence remain unclear. A sweet potato (Ipomoea batatas) SAG, named SPA15, whose function was unknown, was identified previously. To understand the role of SPA15 in leaf senescence further, the orthologue of SPA15 in Arabidopsis thaliana was identified and characterized, and it was named ARABIDOPSIS A-FIFTEEN (AAF). AAF was expressed in early senescent leaves and in tissues with highly proliferative activities. AAF was localized to the chloroplasts by transient expression in Arabidopsis mesophyll protoplasts. Overexpression of AAF (AAF-OX) in Arabidopsis promoted, but the T-DNA insertion mutant (aaf-KO), delayed age-dependent leaf senescence. Furthermore, stress-induced leaf senescence caused by continuous darkness was enhanced in AAF-OX but suppressed in aaf-KO. Transcriptome analysis of expression profiles revealed up-regulated genes related to pathogen defence, senescence, and oxidative stress in 3-week-old AAF-OX plants. Indeed, elevated levels of reactive oxygen species (ROS) and enhanced sensitivity to oxidative and dark stress were apparent in AAF-OX but reduced in aaf-KO. ETHYLENE INSENSITIVE2 (EIN2) was required for the dark- and ROS-induced senescence phenotypes in AAF-OX and the induction of AAF expression by treatment with the immediate precursor of ethylene, 1-aminocyclopropane-1-carboxylic acid. The results indicate the functional role of AAF is an involvement in redox homeostasis to regulate leaf senescence mediated by age and stress factors during Arabidopsis development.
PMCID: PMC3245469  PMID: 21940719
Arabidopsis thaliana; chloroplast; ethylene; leaf senescence; oxidative stress; reactive oxygen species; senescence-associated gene (SAG)
19.  PTPH1 dephosphorylates and cooperates with p38γ MAPK to increase Ras oncogenesis through PDZ-mediated interaction 
Cancer research  2010;70(7):2901-2910.
Protein phosphatases are believed to coordinate with kinases to execute biological functions and examples of such integrated activities however are still missing. In this report, we have identified PTPH1 (protein tyrosine phosphatase H1) as a specific phosphatase for p38γ MAPK (mitogen-activated protein kinase) and demonstrated their cooperative oncogenic activity through direct binding. p38γ, a Ras effector known to act independent of its phosphorylation, was first shown to require its unique PDZ-binding motif to increase Ras transformation. Yeast two-hybrid screening and in vitro and in vivo analysis further identified PTPH1 as a specific p38γ phosphatase through PDZ-mediated binding. Additional experiments showed that PTPH1 itself plays a role in Ras-dependent malignant growth in vitro and/or in mice by mechanism depending on its p38γ-binding activity. Moreover, Ras increases both p38γ and PTPH1 protein expression and there is a coupling of increased p38γ and PTPH1 protein expression in primary colon cancer tissues. These results reveal a coordinative oncogenic activity of a MAPK with its specific phosphatase and suggest that PDZ-mediated p38γ/PTPH1 complex may be a novel target for Ras-dependent malignancies.
PMCID: PMC2848905  PMID: 20332238
20.  4-Bromo-2-[1-(4-eth­oxy­phen­yl)-1-methyl­eth­yl]-1-methyl­benzene 
In title compound, C18H21BrO, the dihedral angle between two rings is 85.72°. No classical hydrogen bonds are found and only van der Waals forces stabilize the crystal packing.
PMCID: PMC3050309  PMID: 21522710
21.  Baculovirus Transduction of Mesenchymal Stem Cells Triggers the Toll-Like Receptor 3 Pathway ▿ †  
Journal of Virology  2009;83(20):10548-10556.
Human mesenchymal stem cells (hMSCs) can be genetically modified with viral vectors and hold promise as a cell source for regenerative medicine, yet how hMSCs respond to viral vector transduction remains poorly understood, leaving the safety concerns unaddressed. Here, we explored the responses of hMSCs against an emerging DNA viral vector, baculovirus (BV), and discovered that BV transduction perturbed the transcription of 816 genes associated with five signaling pathways. Surprisingly, Toll-like receptor-3 (TLR3), a receptor that generally recognizes double-stranded RNA, was apparently upregulated by BV transduction, as confirmed by microarray, PCR array, flow cytometry, and confocal microscopy. Cytokine array data showed that BV transduction triggered robust secretion of interleukin-6 (IL-6) and IL-8 but not of other inflammatory cytokines and beta interferon (IFN-β). BV transduction activated the signaling molecules (e.g., Toll/interleukin-1 receptor domain-containing adaptor-inducing IFN-β, NF-κB, and IFN regulatory factor 3) downstream of TLR3, while silencing the TLR3 gene with small interfering RNA considerably abolished cytokine expression and promoted cell migration. These data demonstrate, for the first time, that a DNA viral vector can activate the TLR3 pathway in hMSCs and lead to a cytokine expression profile distinct from that in immune cells. These findings underscore the importance of evaluating whether the TLR3 signaling cascade plays roles in the immune response provoked by other DNA vectors (e.g., adenovirus). Nonetheless, BV transduction barely disturbed surface marker expression and induced only transient and mild cytokine responses, thereby easing the safety concerns of using BV for hMSCs engineering.
PMCID: PMC2753105  PMID: 19656899
22.  In Utero and Postnatal Exposure to Arsenic Alters Pulmonary Structure and Function 
Toxicology and applied pharmacology  2008;235(1):105-113.
In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airway reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 μm in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.
PMCID: PMC2669654  PMID: 19095001
arsenic; lung development; pulmonary function; airway smooth muscle; extracellular matrix
23.  The DNA sequence of the human X chromosome 
Ross, Mark T. | Grafham, Darren V. | Coffey, Alison J. | Scherer, Steven | McLay, Kirsten | Muzny, Donna | Platzer, Matthias | Howell, Gareth R. | Burrows, Christine | Bird, Christine P. | Frankish, Adam | Lovell, Frances L. | Howe, Kevin L. | Ashurst, Jennifer L. | Fulton, Robert S. | Sudbrak, Ralf | Wen, Gaiping | Jones, Matthew C. | Hurles, Matthew E. | Andrews, T. Daniel | Scott, Carol E. | Searle, Stephen | Ramser, Juliane | Whittaker, Adam | Deadman, Rebecca | Carter, Nigel P. | Hunt, Sarah E. | Chen, Rui | Cree, Andrew | Gunaratne, Preethi | Havlak, Paul | Hodgson, Anne | Metzker, Michael L. | Richards, Stephen | Scott, Graham | Steffen, David | Sodergren, Erica | Wheeler, David A. | Worley, Kim C. | Ainscough, Rachael | Ambrose, Kerrie D. | Ansari-Lari, M. Ali | Aradhya, Swaroop | Ashwell, Robert I. S. | Babbage, Anne K. | Bagguley, Claire L. | Ballabio, Andrea | Banerjee, Ruby | Barker, Gary E. | Barlow, Karen F. | Barrett, Ian P. | Bates, Karen N. | Beare, David M. | Beasley, Helen | Beasley, Oliver | Beck, Alfred | Bethel, Graeme | Blechschmidt, Karin | Brady, Nicola | Bray-Allen, Sarah | Bridgeman, Anne M. | Brown, Andrew J. | Brown, Mary J. | Bonnin, David | Bruford, Elspeth A. | Buhay, Christian | Burch, Paula | Burford, Deborah | Burgess, Joanne | Burrill, Wayne | Burton, John | Bye, Jackie M. | Carder, Carol | Carrel, Laura | Chako, Joseph | Chapman, Joanne C. | Chavez, Dean | Chen, Ellson | Chen, Guan | Chen, Yuan | Chen, Zhijian | Chinault, Craig | Ciccodicola, Alfredo | Clark, Sue Y. | Clarke, Graham | Clee, Chris M. | Clegg, Sheila | Clerc-Blankenburg, Kerstin | Clifford, Karen | Cobley, Vicky | Cole, Charlotte G. | Conquer, Jen S. | Corby, Nicole | Connor, Richard E. | David, Robert | Davies, Joy | Davis, Clay | Davis, John | Delgado, Oliver | DeShazo, Denise | Dhami, Pawandeep | Ding, Yan | Dinh, Huyen | Dodsworth, Steve | Draper, Heather | Dugan-Rocha, Shannon | Dunham, Andrew | Dunn, Matthew | Durbin, K. James | Dutta, Ireena | Eades, Tamsin | Ellwood, Matthew | Emery-Cohen, Alexandra | Errington, Helen | Evans, Kathryn L. | Faulkner, Louisa | Francis, Fiona | Frankland, John | Fraser, Audrey E. | Galgoczy, Petra | Gilbert, James | Gill, Rachel | Glöckner, Gernot | Gregory, Simon G. | Gribble, Susan | Griffiths, Coline | Grocock, Russell | Gu, Yanghong | Gwilliam, Rhian | Hamilton, Cerissa | Hart, Elizabeth A. | Hawes, Alicia | Heath, Paul D. | Heitmann, Katja | Hennig, Steffen | Hernandez, Judith | Hinzmann, Bernd | Ho, Sarah | Hoffs, Michael | Howden, Phillip J. | Huckle, Elizabeth J. | Hume, Jennifer | Hunt, Paul J. | Hunt, Adrienne R. | Isherwood, Judith | Jacob, Leni | Johnson, David | Jones, Sally | de Jong, Pieter J. | Joseph, Shirin S. | Keenan, Stephen | Kelly, Susan | Kershaw, Joanne K. | Khan, Ziad | Kioschis, Petra | Klages, Sven | Knights, Andrew J. | Kosiura, Anna | Kovar-Smith, Christie | Laird, Gavin K. | Langford, Cordelia | Lawlor, Stephanie | Leversha, Margaret | Lewis, Lora | Liu, Wen | Lloyd, Christine | Lloyd, David M. | Loulseged, Hermela | Loveland, Jane E. | Lovell, Jamieson D. | Lozado, Ryan | Lu, Jing | Lyne, Rachael | Ma, Jie | Maheshwari, Manjula | Matthews, Lucy H. | McDowall, Jennifer | McLaren, Stuart | McMurray, Amanda | Meidl, Patrick | Meitinger, Thomas | Milne, Sarah | Miner, George | Mistry, Shailesh L. | Morgan, Margaret | Morris, Sidney | Müller, Ines | Mullikin, James C. | Nguyen, Ngoc | Nordsiek, Gabriele | Nyakatura, Gerald | O’Dell, Christopher N. | Okwuonu, Geoffery | Palmer, Sophie | Pandian, Richard | Parker, David | Parrish, Julia | Pasternak, Shiran | Patel, Dina | Pearce, Alex V. | Pearson, Danita M. | Pelan, Sarah E. | Perez, Lesette | Porter, Keith M. | Ramsey, Yvonne | Reichwald, Kathrin | Rhodes, Susan | Ridler, Kerry A. | Schlessinger, David | Schueler, Mary G. | Sehra, Harminder K. | Shaw-Smith, Charles | Shen, Hua | Sheridan, Elizabeth M. | Shownkeen, Ratna | Skuce, Carl D. | Smith, Michelle L. | Sotheran, Elizabeth C. | Steingruber, Helen E. | Steward, Charles A. | Storey, Roy | Swann, R. Mark | Swarbreck, David | Tabor, Paul E. | Taudien, Stefan | Taylor, Tineace | Teague, Brian | Thomas, Karen | Thorpe, Andrea | Timms, Kirsten | Tracey, Alan | Trevanion, Steve | Tromans, Anthony C. | d’Urso, Michele | Verduzco, Daniel | Villasana, Donna | Waldron, Lenee | Wall, Melanie | Wang, Qiaoyan | Warren, James | Warry, Georgina L. | Wei, Xuehong | West, Anthony | Whitehead, Siobhan L. | Whiteley, Mathew N. | Wilkinson, Jane E. | Willey, David L. | Williams, Gabrielle | Williams, Leanne | Williamson, Angela | Williamson, Helen | Wilming, Laurens | Woodmansey, Rebecca L. | Wray, Paul W. | Yen, Jennifer | Zhang, Jingkun | Zhou, Jianling | Zoghbi, Huda | Zorilla, Sara | Buck, David | Reinhardt, Richard | Poustka, Annemarie | Rosenthal, André | Lehrach, Hans | Meindl, Alfons | Minx, Patrick J. | Hillier, LaDeana W. | Willard, Huntington F. | Wilson, Richard K. | Waterston, Robert H. | Rice, Catherine M. | Vaudin, Mark | Coulson, Alan | Nelson, David L. | Weinstock, George | Sulston, John E. | Durbin, Richard | Hubbard, Tim | Gibbs, Richard A. | Beck, Stephan | Rogers, Jane | Bentley, David R.
Nature  2005;434(7031):325-337.
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
PMCID: PMC2665286  PMID: 15772651
24.  9-Ethyl-3-(imidazo[1,2-a]pyrimidin-3-yl)-9H-carbazole 
The title compound, C20H16N4, is a precursor for the production of electron-transporting and -emitting materials. The bond lengths and angles in this compound are normal. In the crystal structure, there are no significant hydrogen-bonding inter­actions or π–π stacking inter­actions between mol­ecules.
PMCID: PMC2959935  PMID: 21581376
25.  Large scale variation in Enterococcus faecalis illustrated by the genome analysis of strain OG1RF 
Genome Biology  2008;9(7):R110.
A comparison of two strains of the hospital pathogen Enterococcus faecalis suggests that mediators of virulence differ between strains and that virulence does not depend on mobile gene elements
Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies.
The 2,739,625 base pair chromosome of OG1RF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OG1RF. The 64 areas of divergence were classified into three categories. First, OG1RF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence specific to V583 was substituted by a sequence specific to OG1RF. For example, the iol operon of OG1RF replaces a possible prophage and the vanB transposon in V583. Finally, we found 16 regions that were present in V583 but missing from OG1RF, including the proposed pathogenicity island, several probable prophages, and the cpsCDEFGHIJK capsular polysaccharide operon. OG1RF was more rapidly but less frequently lethal than V583 in the mouse peritonitis model and considerably outcompeted V583 in a murine model of urinary tract infections.
E. faecalis OG1RF carries a number of unique loci compared to V583, but the almost complete lack of mobile genetic elements demonstrates that this is not a defining feature of the species. Additionally, OG1RF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements.
PMCID: PMC2530867  PMID: 18611278

Results 1-25 (29)