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Now showing items 1 - 16 of 23

  • SAHA-induced loss of the Pten gene promotes thyroid carcinogenesis in a model

    Zhu, Xuguang   Kim, Dong-Wook   Zhao, Li   Willingham, Mark   Cheng, Sheue-yann  

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  • MapReduce optimisation information query method for file management system

    Zhu, XuGuang   Shen, Yuzhi  

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    Provided are a continuous casting system for an amorphous alloy and a continuous casting method using the system. The system comprises a material-melting device (2), a water cooling crystallizer (4), a traction rod (5), a traction rod sealing sleeve (6) and a traction device (8), wherein the material-melting device is arranged inside a vacuum chamber; an outlet of the material-melting device is connected to the water cooling crystallizer, and the traction rod is arranged in a channel for an amorphous alloy melt, with a flow guide end thereof being connected to the outlet of the material-melting device; the traction rod sealing sleeve is arranged outside a traction end of the traction rod, and the traction end of the traction rod is connected to the traction device; and the traction rod, the traction rod sealing sleeve and the water cooling crystallizer form a closed cavity (7), and the water cooling crystallizer is provided with a vacuum control valve (404) for controlling the degree of vacuum of the closed cavity. The continuous casting system is a continuous casting system for amorphous alloy materials with a single vacuum chamber, and can effectively prevent the surface of amorphous alloy materials from being oxidized during casting; furthermore, the system has a simple structure, is low in cost and is suitable for large-scale use.
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  • New insights into regulation of lipid metabolism by thyroid hormone

    Zhu, Xuguang   Cheng, Sheue-yann  

    Purpose of review Thyroid hormone (3,3',5-triiodo-L-thyronine) plays an important role in thermogenesis and maintenance of lipid homeostasis. The present article reviews the evidence that 3,3',5-triiodo-L-thyronine regulates lipid metabolism via thyroid hormone receptors, focusing particularly on in-vivo findings using genetically engineered mice. Recent findings That lipid metabolism is regulated via thyroid hormone receptor isoforms in a tissue-dependent manner was recently uncovered by using knockin mutant mice harboring an identical mutation in the Thra gene (Thra1(PV) mouse) or the Thrb gene (Thrb(PV) mouse). The mutation in the Thra gene dramatically decreases the mass of both white adipose tissue and liver. In contrast, the mutation in the Thrb gene markedly increases the mass of liver with an excess depot of lipids, but no significant abnormality is observed in white adipose tissue. Molecular studies show that the expression of lipogenic genes is decreased in white adipose tissue of Thra1(PV) mice, but not in Thrb(PV) mice. Markedly increased lipogenic enzyme expression, and decreased fatty acid beta-oxidation activity contribute to the adipogenic steatosis and lipid accumulation in the liver of Thrb(PV) mice. In contrast, reduced expression of genes critical for lipogenesis mediates decreased liver mass with lipid scarcity in Thra1(PV) mice. Summary Studies using Thra1(PV) and Thrb(PV) mice indicate that apo-thyroid hormone receptor-beta and apo-thyroid hormone receptor-alpha-1 mediate distinct deleterious effects on lipid metabolism. Thus, both thyroid hormone receptor isoforms contribute to the pathogenesis of lipid abnormalities in hypothyroidism, but in a target tissue-dependent manner. These studies suggest that thyroid hormone receptor isoform-specific ligands could be designed as therapeutic targets for lipid abnormalities.
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    A continuous casting system for an amorphous master alloy ingot, comprising a material-melting device (2), a water cooling crystallizer (4), a traction rod (8) and a traction device (9), wherein the material-melting device is arranged inside a vacuum chamber (1), and an outlet of the material-melting device is connected to the water cooling crystallizer; and the traction rod is arranged in a channel for an amorphous alloy melt, with a flow guide end thereof being connected to the outlet of the material-melting device and a traction end thereof being connected to the traction device. The channel for the amorphous alloy melt is in a perpendicular direction; and the water cooling crystallizer is provided with a sealing portion, wherein a medium in the sealing portion is in direct contact with the traction rod, and a sealing ring (603) is arranged at the connection between the sealing portion and the traction rod. In the continuous casting system, the amorphous master alloy ingot output direction is the perpendicular direction; by means of the structural design, external air can be effectively prevented from entering a melting chamber, thus preventing defects, such as surface cracks, segregation knobs and throwing chatter marks, generated due to oxidization, of the amorphous master alloy ingot.
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  • Near-Net Forming Complex Shaped Zr-Based Bulk Metallic Glasses by High Pressure Die Casting

    Liu, Lehua   Zhang, Tao   Liu, Zhiyuan   Yu, Chunyan   Dong, Xixi   He, Liangju   Gao, Kuan   Zhu, Xuguang   Li, Wenhao   Wang, Chengyong   Li, Peijie   Zhang, Laichang   Li, Lugee  

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  • Synergistic Signaling of KRAS and Thyroid Hormone Receptor β Mutants Promotes Undifferentiated Thyroid Cancer through MYC Up-Regulation

    Zhu, Xuguang   Zhao, Li   Park, Jeong Won   Willingham, Mark C.   Cheng, Sheue-yann  

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  • Near-Net Forming Complex Shaped Zr-Based Bulk Metallic Glasses by High Pressure Die Casting

    Liu, Lehua   Zhang, Tao   Liu, Zhiyuan   Yu, Chunyan   Dong, Xixi   He, Liangju   Gao, Kuan   Zhu, Xuguang   Li, Wenhao   Wang, Chengyong   Li, Peijie   Zhang, Laichang   Li, Lugee  

    Forming complex geometries using the casting process is a big challenge for bulk metallic glasses (BMGs), because of a lack of time of the window for shaping under the required high cooling rate. In this work, we open an approach named the "entire process vacuum high pressure die casting" (EPV-HPDC), which delivers the ability to fill die with molten metal in milliseconds, and create solidification under high pressure. Based on this process, various Zr-based BMGs were prepared by using industrial grade raw material. The results indicate that the EPV-HPDC process is feasible to produce a glassy structure for most Zr-based BMGs, with a size of 3 mm x 10 mm and with a high strength. In addition, it has been found that EPV-HPDC process allows complex industrial BMG parts, some of which are hard to be formed by any other metal processes, to be net shaped precisely. The BMG components prepared by the EVP-HPDC process possess the advantages of dimensional accuracy, efficiency, and cost compared with the ones formed by other methods. The EVP-HPDC process paves the way for the large-scale application of BMGs.
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  • Modulation of thyroid hormone action by mutant thyroid hormone receptors, c-erbA-alpha-2 and peroxisome proliferator-activated receptor: Evidence for different mechanisms of inhibition

    Meier-Heusler, Sibylle C.   Zhu, Xuguang   Juge-Aubry, Cristiana   Pernin, Agnes   Burger, Albert G.   Cheng, Sheue-Yann   Meier, Christoph A.  

    Thyroid hormone action is not only determined by hormone availability, but also by target organ sensitivity. A dominant negative interaction is known to occur between thyroid hormone receptors (TRs) and the non-ligand binding splicing variant c-erbA-alpha-2 as well as mutant TR-beta-1 from kindreds with resistance to thyroid hormone. We compared the inhibitory effect of naturally occurring mutant hTR-beta-1, artificially created hTR-alpha-1 mutants, c-erbA-alpha-2 and the human peroxisome proliferator-activated receptor (hPPAR) on three prototypic T3-response elements (TREs), TRE-PAL, DR+4 and TRE-LAP. The inhibitory effect of mutant hTR-alpha-1 and beta-1 occurred only on TRE-LAP and to a minor degree on DR+4 when equimolar ratios of mutant/wildtype receptor were present. In contrast, the cerbA-alpha-2 splicing variant and the hPPAR inhibited TR action on all three TREs. Gel mobility shift experiments in the presence of T3 showed increased binding of mutant hTR-alpha-1 and beta-1 only to TRE-LAP compared to the binding of wildtype hTRs, thereby explaining their TRE-selective dominant negative potency. Contrarily, equal amounts of c-erbA-alpha-2 or hPPAR protein did not bind to either of the three response elements even in the presence of RXR. Since the TR:RXR heterodimers were only partially displaced from DNA in the presence of excess amounts of c-erbA-alpha-2, it is likely that the TRE-unspecific dominant negative action of c-erbA-alpha-2 is due in part to competition for DNA-binding and for TR-auxiliary proteins. In contrast, equimolar amounts of hPPAR completely inhibited the DNA-binding of hTR-beta-1:RXR heterodimers, but not of TR:TR homodimers, suggesting that hPPAR has a higher RXR-binding affinity and is therefore a potent competitor for intranuclear RXR. Since thyroid hormones and peroxisome proliferators regulate in part a similar subset of target genes involved in fatty acid metabolism, these results suggest the possibility of cross-talk among the thyroid hormone and peroxisome proliferator signalling pathways. In summary, the results suggest that thyroid hormone action can be modulated by at least three different mechanisms: (i) increased binding of mutant hTRs to specific TREs; (ii) efficient competition for limiting amounts of RXR through the preferential formation of hPPAR:RXR, rather than TR:RXR heterodimers; and (iii) competition for binding to DNA and to auxiliary proteins other than RXR in the case of c-erbA-alpha-2.
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  • Reactivation of the Silenced Thyroid Hormone Receptor beta Gene Expression Delays Thyroid Tumor Progression

    Kim, Won Gu   Zhu, Xuguang   Kim, Dong Wook   Zhang, Lisa   Kebebew, Electron  

    That a knock-in mouse harboring a dominant-negative thyroid hormone receptor (TR)-beta (Thrb) mutation develops metastatic thyroid cancer strongly suggests the involvement of TR beta in carcinogenesis. Epigenetic silencing of the THRB gene is common in human cancers. The aim of the present study was to determine how DNA methylation affected the expression of the THRB gene in differentiated thyroid cancer (DTC) and how reexpression of the THRB gene attenuated the cancer phenotypes. We used methylation-specific PCR to examine the expression and promoter methylation of the THRB gene in DTC tissues. Thyroid cancer cells with hypermethylated THRB were treated with the demethylating agents 5'-aza-2'-deoxycytidine (5'-aza-CdR) and zebularine to evaluate their impact on the cancer cell phenotypes. THRB mRNA expression in DTC was 90% lower than in normal controls, and this decrease was associated with a higher tumor/lymph node staging. The promoter methylation level of the THRB gene had a significant negative correlation with the expression level of the THRB gene. Treatment of FTC-236 cells with 5'-aza-CdR or zebularine induced reexpression of the THRB gene and inhibited cell proliferation and migration. FTC-236 cells stably expressing TR beta exhibited lower cell proliferation and migration through inhibition of beta-catenin signaling pathways compared with FTC-236 without TR beta. 5'-Aza-CdR also led to suppression of tumor growth in an in vivo xenograft model using FTC-236 cells consistent with the cell-based studies. These finding indicate that TR beta is a tumor suppressor and could be tested as a potential therapeutic target. (Endocrinology 154: 25-35, 2013)
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  • Thyroid hormone receptor alpha mutation causes a severe and thyroxine-resistant skeletal dysplasia in female mice.

    Bassett, J H Duncan   Boyde, Alan   Zikmund, Tomas   Evans, Holly   Croucher, Peter I   Zhu, Xuguang   Park, Jeong Won   Cheng, Sheue-yann   Williams, Graham R  

    A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor alpha1 (TRalpha1). Affected children have a high serum T3:T4 ratio and variable degrees of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are receiving varying doses and durations of T4 treatment, but responses have been inconsistent so far. Thra1(PV/+) mice express a similar potent dominant-negative mutant TRalpha1 to affected individuals, and thus represent an excellent disease model. We hypothesized that Thra1(PV/+) mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult female Thra1(PV/+) mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth, or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TRalpha1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T4 treatment, which depend on the severity of the causative mutation. =20
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  • Investigation on chip deformation behaviors of Zr-based bulk metallic glass during machining

    Ding, Feng   Wang, Chengyong   Zhang, Tao   Zheng, Lijuan   Zhu, Xuguang   Li, Weirong   Li, Lugee  

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  • Fine mapping of calcineurin (PPP3CA) gene reveals novel alternative splicing patterns, association of 5'UTR trinucleotide repeat with addiction vulnerability, and differential isoform expression in Alzheimer's disease.

    Chiocco, Matthew J   Zhu, Xuguang   Walther, Donna   Pletnikova, Olga   Troncoso, Juan C   Uhl, George R   Liu, Qing-Rong  

    Fine mapping of calcineurin (PPP3CA) gene identified single nucleotide polymorphisms (SNPs) and simple sequence repeat polymorphisms that are associated with addiction vulnerability. A trinucleotide repeat marker, located in the 5'untranslated region (5'UTR) of the PPP3CA mRNA, exhibited significantly different genotype and allele frequencies between abusers and controls in the NIDA African-American sample. The polymorphism showed allelic-specific expression in mRNA extracted from postmortem brain specimens. Novel alternatively spliced isoforms of PPP3CA were identified and their expressions were found altered in brain regions of postmortem Alzheimer's disease patients. These data underscore the importance of calcineurin gene in the molecular mechanism of addiction and Alzheimer's diseases.
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  • Three-dimensional telomere dynamics in follicular thyroid cancer.

    Wark, Landon   Danescu, Adrian   Natarajan, Suchitra   Zhu, Xuguang   Cheng, Sheue-yann   Hombach-Klonisch, Sabine   Mai, Sabine   Klonisch, Thomas  

    BACKGROUND: Over the last decade, annual incidence rates for thyroid cancer have been among the highest of all cancers in the Western world. However, the genomic mechanisms impacting thyroid carcinogenesis remain elusive.; METHODS: We employed an established mouse model of follicular thyroid cancer (FTC) with a homozygous proline to valine mutation (Thrb(PV/PV)) in the thyroid receptor beta1 (TRbeta1) and applied quantitative three-dimensional (3D) telomere analysis to determine 3D telomeric profiles in Thrb(PV)(/PV), Thrb(PV/)(+), and Thrb(+/+) mouse thyrocytes before and after histological presentation of FTC.; RESULTS: Using quantitative fluorescent in situ hybridization (Q-FISH) and TeloView image analysis, we found altered telomeric signatures specifically in mutant mouse thyrocytes. As early as 1 month of age, Thrb(PV/PV) mouse thyrocytes showed more telomeres than normal and heterozygous age-matched counterparts. Importantly, at the very early age of 1 month, 3D telomeric profiles of Thrb(PV/PV) thyrocyte nuclei reveal genetic heterogeneity with several nuclei populations exhibiting different telomere numbers, suggestive of various degrees of aneuploidy within the same animal. This was detected exclusively in Thrb(PV/PV) mice well before the presentation of histological signs of thyroid carcinoma.; CONCLUSIONS: We identified quantitative 3D telomere analysis as a novel tool for early detection and monitoring of thyrocyte chromosomal (in)stability. This technique has the potential to identify human patients at risk for developing thyroid carcinoma.=20
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  • Regeneration of thyroid follicles from primordial cells in a murine thyroidectomized model

    Lee, Junguee   Yi, Shinae   Chang, Joon Young   Kang, Yea Eun   Kim, Hyun Jung   Park, Ki Cheol   Yang, Keum-Jin   Sul, Hae Joung   Kim, Jong Ok   Yi, Hyon-Seung   Zhu, Xuguang   Cheng, Sheue-yann   Shong, Minho  

    The functional unit of the thyroid gland, the thyroid follicle, dynamically responds to various stimuli to maintain thyroid hormone homeostasis. However, thyroid follicles in the adult human thyroid gland have a very limited regenerative capacity following partial resection of the thyroid gland. To gain insight into follicle regeneration in the adult thyroid gland, we observed the regeneration processes of murine thyroid follicles after partial resection of the lower third of the thyroid gland in 10-week-old male C57BL/6 mice. Based on sequential observation of the partially resected thyroid lobe, we found primitive follicles forming in the area corresponding to the central zone of the intact lateral thyroid lobe. The primitive thyroid follicles were multiciliated and had coarsely vacuolated cytoplasm and large vesicular nuclei. Consistently, these primitive follicular cells did not express the differentiation markers paired box gene-8 and thyroid transcription factor-1 (clone SPT24), but were positive for forkhead box protein A2 and leucine-rich repeat-containing G-protein-coupled receptor 4/GPR48. Follicles newly generated from the primitive follicles had clear or vacuolar cytoplasm with dense, darkly stained nuclei. At day 21 after partial thyroidectomy, the tall cuboidal follicular epithelial cells had clear or vacuolar cytoplasm, and the intraluminal colloid displayed pale staining. Smaller activated follicles were found in the central zone of the lateral lobe, whereas larger mature follicles were located in the peripheral zone. Based on these observations, we propose that the follicle regeneration process in the partially resected adult murine thyroid gland associated with the appearance of primitive follicular cells may be a platform for the budding of differentiated follicles in mice.
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  • Tumor Suppressor Action of Liganded Thyroid Hormone Receptor beta by Direct Repression of beta-Catenin Gene Expression

    Guigon, Celine J.   Kim, Dong Wook   Zhu, Xuguang   Zhao, Li   Cheng, Sheue-Yann  

    The abundance of beta-catenin, which plays a critical role in oncogenesis, is tightly controlled by proteasomal pathways. Its aberrant accumulation is associated with the overactivation of its oncogenic signaling and tumorigenesis in cancers, including thyroid cancer. Our previous studies have suggested that beta-catenin abundance could also be regulated at the transcriptional level by thyroid hormone (T(3)) and thyroid hormone receptor beta (TR beta). By using hypothyroid mice supplemented or not with T(3), we showed that T(3) significantly repressed Ctnnb1 expression in vivo in the thyroid. By using two human cell lines, i.e., the thyroid HTori and the cervical cancer HeLa cell lines, each stably expressing TR beta, we observed that T(3) induced the down-regulation of CTNNB1 transcript levels. Luciferase reporter assays with various constructs harboring 5' deletion of the CTNNB1 promoter or with mutated thyroid hormone response element (TRE) binding sites, and EMSAs showed that this transrepression was mediated through an interaction between TR beta-retinoid X receptor beta complexes and TREs located in the human CTNNB1 promoter between -807 and -772 and consisting of two hexamers separated by 14 nucleotides. The direct regulation of CTNNB1 expression by TR beta was further confirmed by chromatin immunoprecipitation assays showing TR beta recruitment to the CTNNB1 promoter in thyroid cells. This is the first report demonstrating a direct repression of the beta-catenin gene by liganded TR beta through interaction with negative TREs located in CTNNB1 promoter. Importantly, this study uncovers a new molecular mechanism whereby liganded TR beta acts as a tumor suppressor via inhibition of the expression of a potent tumor promoter, the CTNNB1 gene. (Endocrinology 151: 5528-5536, 2010)
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