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  • 1
    Publication Date: 2018-01-03
    Description: Hepatitis B virus (HBV) infection is a prevalent infectious disease with serious outcomes like chronic and acute hepatitis, cirrhosis, and hepatocellular carcinoma. However, the metabolic alteration by HBV is rarely taken into consideration. With the high prevalence of alcohol consumption and chronic HBV infection, their overlap is assumed to be an increasing latent hazard; although the extent has not been calculated. Moreover, the impact of chronic alcohol consumption combined with HBV on cholesterol metabolism is unknown. Six-week-old male FVB/Ncrl mice were hydrodynamically injected with a pGEM-4Z-1.3HBV vector and then fed an ethanol diet for 6 weeks. Serum biomarkers and liver histology, liver cholesterol levels, and cholesterol metabolism-related molecules were measured. In vitro assays with HBx, hepatitis B surface (HBs), or hepatitis B core (HBc) protein expression in HepG2 cells costimulated with ethanol were conducted to assess the cholesterol metabolism. HBV expression synergistically increased cholesterol deposition in the setting of alcoholic fatty liver. The increase of intrahepatic cholesterol was due to metabolic alteration in cholesterol metabolism, including increased cholesterol synthesis, decreased cholesterol degradation, and impaired cholesterol uptake. Overexpression of HBV component HBc, but not HBs or HBx, selectively promoted the hepatocellular cholesterol level.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 2
    Publication Date: 2018-11-08
    Description: Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1 , CCM2 , and CCM3 , have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration–approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 3
    Keywords: POPULATION ; RISK ; MELANOMA ; BRCA1 MUTATION CARRIERS ; CONSORTIUM ; TUMOR SUBTYPES
    Abstract: Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P 1 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR 1.16; P 1.1 10(8)) but showed a weaker association with overall breast cancer (OR 1.08, P 1.3 10(6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR 1.01, P 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR 1.12; P 1.1 10(9)), and with both ER-positive (OR 1.09; P 1.5 10(5)) and ER-negative (OR 1.16, P 2.5 10(7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
    Type of Publication: Journal article published
    PubMed ID: 22976474
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  • 4
    Publication Date: 2018-01-03
    Description: A genomic variant in the human ADTRP [androgen-dependent tissue factor (TF) pathway inhibitor (TFPI) regulating protein] gene increases the risk of coronary artery disease, the leading cause of death worldwide. TFPI is the TF pathway inhibitor that is involved in coagulation. Here, we report that adtrp and tfpi form a regulatory axis that specifies primitive myelopoiesis and definitive hematopoiesis, but not primitive erythropoiesis or vasculogenesis. In zebrafish, there are 2 paralogues for adtrp ( i.e. , adtrp1 and adtrp2 ). Knockdown of adtrp1 expression inhibits the specification of hemangioblasts, as shown by decreased expression of the hemangioblast markers, etsrp , fli1a , and scl ; blocks primitive hematopoiesis, as shown by decreased expression of pu.1 , mpo , and l-plastin ; and disrupts the specification of hematopoietic stem cells (definitive hematopoiesis), as shown by decreased expression of runx1 and c-myb . However, adtrp1 knockdown does not affect erythropoiesis during primitive hematopoiesis (no effect on gata1 or h-bae1 ) or vasculogenesis (no effect on kdrl , ephb2a, notch3 , dab2 , or flt4 ). Knockdown of adtrp2 expression does not have apparent effects on all markers tested. Knockdown of adtrp1 reduced the expression of tfpi , and hematopoietic defects in adtrp1 morphants were rescued by tfpi overexpression. These data suggest that the regulation of tfpi expression is one potential mechanism by which adtrp1 regulates primitive myelopoiesis and definitive hematopoiesis.—Wang, L., Wang, X., Wang, L., Yousaf, M., Li, J., Zuo, M., Yang, Z., Gou, D., Bao, B., Li, L., Xiang, N., Jia, H., Xu, C., Chen, Q., Wang, Q. K. Identification of a new adtrp1-tfpi regulatory axis for the specification of primitive myelopoiesis and definitive hematopoiesis.
    Print ISSN: 0892-6638
    Electronic ISSN: 1530-6860
    Topics: Biology
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  • 5
    Publication Date: 2018-08-01
    Description: Late embryogenesis abundant (LEA) proteins play key roles in plant drought tolerance. In this study, 157, 85 and 89 candidate LEA2 proteins were identified in G. hirsutum , G. arboreum and G. raimondii respectively. LEA2 genes were classified into 6 groups, designated as group 1 to 6. Phylogenetic tree analysis revealed orthologous gene pairs within the cotton genome. The cotton specific LEA2 motifs identified were E, R and D in addition to Y, K and S motifs. The genes were distributed on all chromosomes. LEA2s were found to be highly enriched in non-polar, aliphatic amino acid residues, with leucine being the highest, 9.1% in proportion. The miRNA, ghr-miR827a/b/c/d and ghr-miR164 targeted many genes are known to be drought stress responsive. Various stress-responsive regulatory elements, ABA-responsive element (ABRE), Drought-responsive Element (DRE/CRT), MYBS and low-temperature-responsive element (LTRE) were detected. Most genes were highly expressed in leaves and roots, being the primary organs greatly affected by water deficit. The expression levels were much higher in G. tomentosum as opposed to G. hirsutum . The tolerant genotype had higher capacity to induce more of LEA2 genes. Over expression of the transformed gene Cot_AD24498 showed that the LEA2 genes are involved in promoting root growth and in turn confers drought stress tolerance. We therefore infer that Cot_AD24498 , CotAD_20020 , CotAD_21924 and CotAD_59405 could be the candidate genes with profound functions under drought stress in upland cotton among the LEA2 genes. The transformed Arabidopsis plants showed higher tolerance levels to drought stress compared to the wild types. There was significant increase in antioxidants, catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) accumulation, increased root length and significant reduction in oxidants, Hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) concentrations in the leaves of transformed lines under drought stress condition. This study provides comprehensive analysis of LEA2 proteins in cotton thus forms primary foundation for breeders to utilize these genes in developing drought tolerant genotypes.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 6
    Publication Date: 2018-06-28
    Description: A method developed based on the capillary effect and capillary condensation theory was used to synthesize an innovative Fe/C/Pd composite in this study. This composite (Fe@CNTs@Pd) consists of carbon nanotubes (CNTs) with nanoscale zerovalent iron (NZVI) on the inner surface and palladium nanoparticles supported on the outer surface of CNTs. This structure successfully addresses the problems of high iron corrosion rate and lower utilization rate of hydrogen in the application of bimetal nanoparticles for trichloroethylene (TCE) removal. TCE degradation experiments and electrochemical tests were conducted to investigate the material properties and reaction mechanisms of the composite. It is found that the prepared composite material contribute a high level of TCE dechlorination rate and substantially reduced hydrogen production during iron corrosion in water compared with the conventional CNTs-supported bimetal materials (Fe/Pd@CNTs). Hydrogen spillover effect helps the reactivity of Fe@CNTs@Pd for TCE degradation and suppressed the galvanic cell effect, which results in a stronger resistance to corrosion. Although the K obs of Fe@CNTs@Pd was 16.87% lower than that of Fe/Pd@CNTs, the hydrogen production rate of Fe@CNTs@Pd was 10 times slower than that of Fe/Pd@CNTs. Therefore, Fe@CNTs@Pd shows a significant reduction in the corrosion rate at a cost of slightly slower degradation of TCE. In sum, the prepared composites demonstrate important characteristics, including alleviating NZVI agglomeration, maintaining high TCE removal efficiency and reducing the corrosion of NZVI.
    Keywords: nanotechnology, environmental chemistry, environmental science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 7
    Publication Date: 2018-05-31
    Description: Glioblastoma (GBM) is the most lethal primary brain tumor and is highly resistant to current treatments. GBM harbors glioma stem cells (GSCs) that not only initiate and maintain malignant growth but also promote therapeutic resistance including radioresistance. Thus, targeting GSCs is critical for overcoming the resistance to improve GBM treatment. Because the bone marrow and X-linked (BMX) nonreceptor tyrosine kinase is preferentially up-regulated in GSCs relative to nonstem tumor cells and the BMX-mediated activation of the signal transducer and activator of transcription 3 (STAT3) is required for maintaining GSC self-renewal and tumorigenic potential, pharmacological inhibition of BMX may suppress GBM growth and reduce therapeutic resistance. We demonstrate that BMX inhibition by ibrutinib potently disrupts GSCs, suppresses GBM malignant growth, and effectively combines with radiotherapy. Ibrutinib markedly disrupts the BMX-mediated STAT3 activation in GSCs but shows minimal effect on neural progenitor cells (NPCs) lacking BMX expression. Mechanistically, BMX bypasses the suppressor of cytokine signaling 3 (SOCS3)–mediated inhibition of Janus kinase 2 (JAK2), whereas NPCs dampen the JAK2-mediated STAT3 activation via the negative regulation by SOCS3, providing a molecular basis for targeting BMX by ibrutinib to specifically eliminate GSCs while preserving NPCs. Our preclinical data suggest that repurposing ibrutinib for targeting GSCs could effectively control GBM tumor growth both as monotherapy and as adjuvant with conventional therapies.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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  • 8
    Publication Date: 2018-06-02
    Description: Background: Increasing studies suggest that long noncoding RNAs (lncRNAs) are involved in carcinogenesis of human cancers and might be used as diagnostic biomarkers for cancers. Methods: A total of 301 participants were recruited in the first part of the study, including a hepatocellular carcinoma (HCC) group ( n = 60), liver cirrhosis (LC) group ( n = 85), chronic hepatitis B (CHB) group ( n = 96), and healthy subjects ( n = 60). In the second part, we collected 55 HCC patients, 60 CHB patients, and 60 healthy subjects as an independent cohort to validate the ability of the experiential lncRNAs for identifying HCC from CHB. A commercial kit was used to isolate serum exosomes and total RNA. The relative levels of lnRNAs and GAPDH mRNA were measured with TaqMan PCR. Results: The results showed that the levels of ENSG00000258332.1 and LINC00635 in the HCC group were significantly higher than those in the other groups (all P 〈 0.05). A high ENSG00000258332.1 level in HCC was associated with portal vein tumor emboli, lymph node metastasis, TNM stage, and overall survival (OS; all P 〈 0.05), and a high LINC00635 level was related to lymph node metastasis, TNM stage, and OS (all P 〈 0.05). ENSG00000258332.1 discriminated HCC from CHB, gaining an area under the ROC curve (AUC) of 0.719 (cutoff value of 1.345); LINC00635 gained an AUC of 0.750 (cutoff value of 1.690). Furthermore, the AUC for the combination of the 2 lncRNAs and serum AFP (cutoff value of 20 μg/L) was 0.894. The abilities of the 2 lncRNAs for identifying HCC from CHB were validated by an independent cohort. Conclusions: The results suggested that the combination of serum exosomal ENSG00000258332.1 , LINC00635 , and AFP may be a valuable assay in diagnosis and prognosis of HCC. Impact: Our data will shed light on exosomal lncRNAs as biomarkers for HCC. Cancer Epidemiol Biomarkers Prev; 27(6); 710–6. ©2018 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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  • 9
    Publication Date: 2018-02-10
    Description: The neonatal Fc receptor (FcRn) is involved in IgG metabolism and transport in placental mammals. However, whether FcRn is responsible for IgG transfer from maternal serum to colostrum/milk is controversial. Interestingly, large domestic animals, such as cows, pigs, sheep, and horses, in which passive IgG transfer is exclusively completed via colostrum/milk, all express an FcRn α-chain that is shorter in the cytoplasmic tail (CYT) than its counterparts in humans and rodents. To address whether the length variation has any functional significance, we performed in vitro experiments using the Transwell system with the MDCK cell line stably transfected with various FcRn constructs; these clearly suggested that truncation of the CYT tail caused a polar change in IgG transfer. However, we observed no evidence supporting functional changes in IgG in vivo using mice in which the FcRn CYT was precisely truncated. These data suggest that the length variation in FcRn is not functionally associated with passive IgG transfer routes in mammals.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 10
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    American Association for the Advancement of Science (AAAS)
    In: Science
    Publication Date: 2018-08-10
    Description: The high density of heat generated in power electronics and optoelectronic devices is a critical bottleneck in their application. New materials with high thermal conductivity are needed to effectively dissipate heat and thereby enable enhanced performance of power controls, solid-state lighting, communication, and security systems. We report the experimental discovery of high thermal conductivity at room temperature in cubic boron arsenide (BAs) grown through a modified chemical vapor transport technique. The thermal conductivity of BAs, 1000 ± 90 watts per meter per kelvin meter-kelvin, is higher than that of silicon carbide by a factor of 3 and is surpassed only by diamond and the basal-plane value of graphite. This work shows that BAs represents a class of ultrahigh–thermal conductivity materials predicted by a recent theory, and that it may constitute a useful thermal management material for high–power density electronic devices.
    Keywords: Physics, Applied, Materials Science
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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