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1.
  • Klionsky, Daniel J., et al. (author)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Research review (peer-reviewed)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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2.
  • Ma, Tao, et al. (author)
  • Genomic insights into salt adaptation in a desert poplar
  • 2013
  • In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 4, s. 2797-
  • Journal article (peer-reviewed)abstract
    • Despite the high economic and ecological importance of forests, our knowledge of the genomic evolution of trees under salt stress remains very limited. Here we report the genome sequence of the desert poplar, Populus euphratica, which exhibits high tolerance to salt stress. Its genome is very similar and collinear to that of the closely related mesophytic congener, P. trichocarpa. However, we find that several gene families likely to be involved in tolerance to salt stress contain significantly more gene copies within the P. euphratica lineage. Furthermore, genes showing evidence of positive selection are significantly enriched in functional categories related to salt stress. Some of these genes, and others within the same categories, are significantly upregulated under salt stress relative to their expression in another salt-sensitive poplar. Our results provide an important background for understanding tree adaptation to salt stress and facilitating the genetic improvement of cultivated poplars for saline soils.
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3.
  • Zhang, Guojie, et al. (author)
  • Comparative genomics reveals insights into avian genome evolution and adaptation
  • 2014
  • In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6215, s. 1311-1320
  • Journal article (peer-reviewed)abstract
    • Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
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4.
  • Wang, Zhaoming, et al. (author)
  • Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
  • 2014
  • In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
  • Journal article (peer-reviewed)abstract
    • Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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5.
  • An, Junghwa, et al. (author)
  • Permanent Genetic Resources added to Molecular Ecology Resources Database 1 October 2009-30 November 2009
  • 2010
  • In: Molecular Ecology Resources. - : Wiley. - 1755-098X .- 1755-0998. ; 10:2, s. 404-408
  • Journal article (peer-reviewed)abstract
    • This article documents the addition of 411 microsatellite marker loci and 15 pairs of Single Nucleotide Polymorphism (SNP) sequencing primers to the Molecular Ecology Resources Database. Loci were developed for the following species: Acanthopagrus schlegeli, Anopheles lesteri, Aspergillus clavatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus oryzae, Aspergillus terreus, Branchiostoma japonicum, Branchiostoma belcheri, Colias behrii, Coryphopterus personatus, Cynogolssus semilaevis, Cynoglossus semilaevis, Dendrobium officinale, Dendrobium officinale, Dysoxylum malabaricum, Metrioptera roeselii, Myrmeciza exsul, Ochotona thibetana, Neosartorya fischeri, Nothofagus pumilio, Onychodactylus fischeri, Phoenicopterus roseus, Salvia officinalis L., Scylla paramamosain, Silene latifo, Sula sula, and Vulpes vulpes. These loci were cross-tested on the following species: Aspergillus giganteus, Colias pelidne, Colias interior, Colias meadii, Colias eurytheme, Coryphopterus lipernes, Coryphopterus glaucofrenum, Coryphopterus eidolon, Gnatholepis thompsoni, Elacatinus evelynae, Dendrobium loddigesii Dendrobium devonianum, Dysoxylum binectariferum, Nothofagus antarctica, Nothofagus dombeyii, Nothofagus nervosa, Nothofagus obliqua, Sula nebouxii, and Sula variegata. This article also documents the addition of 39 sequencing primer pairs and 15 allele specific primers or probes for Paralithodes camtschaticus.
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6.
  • Bettegowda, Chetan, et al. (author)
  • Detection of circulating tumor DNA in early- and late-stage human malignancies
  • 2014
  • In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:224, s. 224ra24-
  • Journal article (peer-reviewed)abstract
    • The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
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7.
  • Du, Jian, et al. (author)
  • Antiproliferative effect of alpinetin in BxPC-3 pancreatic cancer cells
  • 2012
  • In: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 29:4, s. 607-612
  • Journal article (peer-reviewed)abstract
    • Alpinetin is a novel plant flavonoid derived from Alpinia katsumadai Hayata, found to possess strong anticancer effects. However, the antitumor effect of alpinetin on pancreatic cancer cells and the detailed mechanism remain unclear. The aim of this study was to investigate alpinetin's beneficial effect on pancreatic cancer and the possible molecular mechanism involved. Pancreatic cancer cell lines were treated with alpinetin at various doses and for different times, and the effect of alpinetin on cell growth inhibition, apoptosis and the cell cycle was determined. The expression of Bcl-2, Bcl-xL, XIAP and Bax, the activity of caspases and the levels of cytochrome c released were measured. The results showed that alpinetin inhibited the viability of three pancreatic cancer cell lines and induced apoptosis of BxPC-3 cells in a dose- and time-dependent manner. This was accompanied by regulation of the expression of Bcl-2, Bcl-xL, Bax and XIAP. Furthermore, alpinetin treatment led to the release of cytochrome c and activation of caspases-3, -8 and -9 proteins. Taken together, our studies indicate that alpinetin inhibited the proliferation of pancreatic cancer cells possibly through the regulation of the Bcl-2 family and XIAP expression, release of cytochrome c and the activation of caspases. Alpinetin may serve as a potential agent for the development of pancreatic cancer cell therapies.
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8.
  • Tang, Bo, et al. (author)
  • Alpinetin suppresses proliferation of human hepatoma cells by the activation of MKK7 and elevates sensitization to cis-diammined dichloridoplatium
  • 2012
  • In: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 27:4, s. 1090-1096
  • Journal article (peer-reviewed)abstract
    • Alpinetin is a type of novel plant flavonoid derived from Alpinia katsumadai Hayata, found to possess strong antihepatoma effects. However, the detailed antitumor mechanism of Alpinetin remains unclear. Mitogen-activated protein kinase kinase-7 (MKK7) can regulate cellular growth, differentiation and apoptosis. The aim of this study was to investigate the role of MKK7 in the anti-hepatoma effect mediated by Alpinetin. HepG2 cells were treated with Alpinetin at various doses and for different times, and the levels of phosphorylated MKK7 (p-MKK7) and total MKK7 were tested by RT-PCR and Western blotting. Following transient transfection with RNA interference, cell viability and cell cycle stage were determined using methyl thiazolyl tetrazolium assay and flow cytometry, in order to assess the antitumor action of Alpinetin. In addition, chemosensitization to cis-diammined dichloridoplatium (CDDP) by Alpinetin was assessed by cell counting array and the cell growth inhibitory rate was calculated. The results showed that Alpinetin suppressed HepG2 cell proliferation and arrested cells in the G0/G1 phase by up-regulating the expression levels of p-MKK7. On the contrary, inhibiting the expression of MKK7 reversed the antitumor effect of Alpinetin. Moreover, Alpinetin enhanced the sensitivity of HepG2 hepatoma cells to the chemotherapeutic agent CDDP. Taken together, our studies indicate that activation of MKK7 mediates the anti-hepatoma effect of Alpinetin. MKK7 may be a putative target for molecular therapy against hepatoma and Alpinetin could serve as a potential agent for the development of hepatoma therapy.
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9.
  • Brownstein, Catherine A., et al. (author)
  • An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
  • 2014
  • In: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
  • Journal article (peer-reviewed)abstract
    • Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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10.
  • Cerhan, James R., et al. (author)
  • Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma
  • 2014
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:11, s. 1233-1238
  • Journal article (peer-reviewed)abstract
    • Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 x 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 x 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 x 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 x 10(-13) and 3.63 x 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
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11.
  • Figueroa, Jonine D., et al. (author)
  • Genome-wide association study identifies multiple loci associated with bladder cancer risk
  • 2014
  • In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 23:5, s. 1387-1398
  • Journal article (peer-reviewed)abstract
    • andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
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12.
  • Gu, Jian, et al. (author)
  • TGF-beta-Induced CD4(+) Foxp3(+) T Cells Attenuate Acute Graft-versus-Host Disease by Suppressing Expansion and Killing of Effector CD8(+) Cells
  • 2014
  • In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 193:7, s. 3388-3397
  • Journal article (peer-reviewed)abstract
    • The use of TGF-beta-induced CD4(+) Foxp3(+) T cells (induced regulatory T cells [iTregs]) is an important prevention and treatment strategy in autoimmune diseases and other disorders. However, the potential use of iTregs as a treatment modality for acute graft-versus-host disease (aGVHD) has not been realized because they may be unstable and less suppressive in this disease. We restudied the ability of iTregs to prevent and treat aGVHD in two mouse models. Our results showed that, as long as an appropriate iTreg-generation protocol is used, these iTregs consistently displayed a potent ability to control aGVHD development and reduce mortality in the aGVHD animal models. iTreg infusion markedly suppressed the engraftment of donor CD8(+) cells and CD4(+) cells, the expression of granzyme A and B, the cytotoxic effect of donor CD8(+) cells, and the production of T cell cytokines in aGVHD. Therefore, we conclude that as long as the correct methods for generating iTregs are used, they can prevent and even treat aGVHD.
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13.
  • Jarvis, Erich D., et al. (author)
  • Whole-genome analyses resolve early branches in the tree of life of modern birds
  • 2014
  • In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6215, s. 1320-1331
  • Journal article (peer-reviewed)abstract
    • To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago.
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14.
  • Li, Cai, et al. (author)
  • Two Antarctic penguin genomes reveal insights into their evolutionary history and molecular changes related to the Antarctic environment
  • 2014
  • In: GigaScience. - 2047-217X. ; 3
  • Journal article (peer-reviewed)abstract
    • Background: Penguins are flightless aquatic birds widely distributed in the Southern Hemisphere. The distinctive morphological and physiological features of penguins allow them to live an aquatic life, and some of them have successfully adapted to the hostile environments in Antarctica. To study the phylogenetic and population history of penguins and the molecular basis of their adaptations to Antarctica, we sequenced the genomes of the two Antarctic dwelling penguin species, the Adelie penguin [Pygoscelis adeliae] and emperor penguin [Aptenodytes forsteri]. Results: Phylogenetic dating suggests that early penguins arose similar to 60 million years ago, coinciding with a period of global warming. Analysis of effective population sizes reveals that the two penguin species experienced population expansions from similar to 1 million years ago to similar to 100 thousand years ago, but responded differently to the climatic cooling of the last glacial period. Comparative genomic analyses with other available avian genomes identified molecular changes in genes related to epidermal structure, phototransduction, lipid metabolism, and forelimb morphology. Conclusions: Our sequencing and initial analyses of the first two penguin genomes provide insights into the timing of penguin origin, fluctuations in effective population sizes of the two penguin species over the past 10 million years, and the potential associations between these biological patterns and global climate change. The molecular changes compared with other avian genomes reflect both shared and diverse adaptations of the two penguin species to the Antarctic environment.
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15.
  • Li, Yadi, et al. (author)
  • Virtual and In vitro bioassay screening of phytochemical inhibitors from flavonoids and isoflavones against Xanthine oxidase and Cyclooxygenase-2 for gout treatment
  • 2013
  • In: Chemical Biology and Drug Design. - : John Wiley & Sons. - 1747-0277 .- 1747-0285. ; 81:4, s. 537-544
  • Journal article (peer-reviewed)abstract
    • Synthetic drugs such as allopurinol and benzbroarone are commonly used to treat the complex pathogenesis of gout, a metabolic disease that results from an inflammation of the joints caused by precipitation of uric acid. We seek to discover novel phytochemicals that could treat gout, by targeting the xanthine oxidase (XO) and cyclooxygenase 2 (COX-2) enzymes. In this study, we report the screening of 9 compounds of flavonoids from the ZINC and PubChem databases (containing 2,092 flavonoids) using the iGEMDOCK software tool against the XO and COX-2 3D protein structures. Each compound was also evaluated by an in vitro bioassay testing the inhibition of XO and COX-2. Myricetin and luteolin were found to be the potential dual inhibitors of XO and COX-2 as demonstrated by IC50: 62.7 and 3.29μg/mL (XO) / 70.8 and 16.38μg/mL (COX-2), respectively. In addition, structure activity relationships and other important factors of the flavonoids binding to the active site of XO and COX-2 were discussed, which is expected for further rational drug design.
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16.
  • Skibola, Christine F, et al. (author)
  • Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region.
  • 2014
  • In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 95:4, s. 462-471
  • Journal article (peer-reviewed)abstract
    • Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.
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17.
  • Wang, Baosheng, 1983-, et al. (author)
  • Colonization of the Tibetan Plateau by the homoploid hybrid pine Pinus densata
  • 2011
  • In: Molecular Ecology. - Leicester : Blackwell Scientific Publications. - 0962-1083 .- 1365-294X. ; 20:18, s. 3796-3811
  • Journal article (peer-reviewed)abstract
    • Pinus densata is an intriguingly successful homoploid hybrid species that occupies vast areas of the southeastern Tibetan Plateau in which neither of its parental species are present, but the colonization processes involved are poorly understood. To shed light on how this species colonized and became established on the plateau, we surveyed paternally inherited chloroplast (cp) and maternally inherited mitochondrial (mt) DNA variation within and among 54 populations of P. densata and its putative parental species throughout their respective ranges. Strong spatial genetic structure of both cp and mtDNA were detected in P. densata populations. Mitotypes specific to P. densata were likely generated by complex recombination events. A putative ancestral hybrid zone in the northeastern periphery of P. densata was identified, and we propose that the species then colonized the plateau by migrating westwards. Along the colonization route, consecutive bottlenecks and surfing of rare alleles caused a significant reduction in genetic diversity and strong population differentiation. The direction and intensity of introgression from parental species varied among geographic regions. In western parts of its range, the species seems to have been isolated from seed and pollen flow from its parent species for a long time. The observed spatial distribution of genetic diversity in P. densata also appears to reflect the persistence of this species on the plateau during the last glaciation. Our results indicate that both ancient and contemporary population dynamics have contributed to the spatial distribution of genetic diversity in P. densata, which accordingly reflects its evolutionary history.
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18.
  • Wang, Baosheng, 1983-, et al. (author)
  • Impact of Geography and Climate on the Genetic Differentiation of the Subtropical Pine Pinus yunnanensis
  • 2013
  • In: PLOS ONE. - : plosone. - 1932-6203. ; 8:6, s. e67345-
  • Journal article (peer-reviewed)abstract
    • Southwest China is a biodiversity hotspot characterized by complex topography, heterogeneous regional climates and rich flora. The processes and driving factors underlying this hotspot remain to be explicitly tested across taxa to gain a general understanding of the evolution of biodiversity and speciation in the region. In this study, we examined the role played by historically neutral processes, geography and environment in producing the current genetic diversity of the subtropical pine Pinus yunnanensis. We used genetic and ecological methods to investigate the patterns of genetic differentiation and ecological niche divergence across the distribution range of this species. We found both continuous genetic differentiation over the majority of its range, and discrete isolated local clusters. The discrete differentiation between two genetic groups in the west and east peripheries is consistent with niche divergence and geographical isolation of these groups. In the central area of the species' range, population structure was shaped mainly by neutral processes and geography rather than by ecological selection. These results show that geographical and environmental factors together created stronger and more discrete genetic differentiation than isolation by distance alone, and illustrate the importance of ecological factors in forming or maintaining genetic divergence across a complex landscape. Our findings differ from other phylogenetic studies that identified the historical drainage system in the region as the primary factor shaping population structure, and highlight the heterogeneous contributions that geography and environment have made to genetic diversity among taxa in southwest China.
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19.
  • Wang, Chunlin, et al. (author)
  • High throughput sequencing reveals a complex pattern of dynamic interrelationships among human T cell subsets
  • 2010
  • In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:4, s. 1518-1523
  • Journal article (peer-reviewed)abstract
    • Developing T cells face a series of cell fate choices in the thymus and in the periphery. The role of the individual T cell receptor (TCR) in determining decisions of cell fate remains unresolved. The stochastic/selection model postulates that the initial fate of the cell is independent of TCR specificity, with survival dependent on additional TCR/coreceptor "rescue" signals. The "instructive" model holds that cell fate is initiated by the interaction of the TCR with a cognate peptide-MHC complex. T cells are then segregated on the basis of TCR specificity with the aid of critical coreceptors and signal modulators [Chan S, Correia-Neves M, Benoist C, Mathis (1998) Immunol Rev 165: 195-207]. The former would predict a random representation of individual TCR across divergent T cell lineages whereas the latter would predict minimal overlap between divergent T cell subsets. To address this issue, we have used high-throughput sequencing to evaluate the TCR distribution among key T cell developmental and effector subsets from a single donor. We found numerous examples of individual subsets sharing identical TCR sequence, supporting a model of a stochastic process of cell fate determination coupled with dynamic patterns of clonal expansion of T cells bearing the same TCR sequence among both CD4(+) and CD8+ populations.
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20.
  • Wang, Dandan, et al. (author)
  • Ultrafast carrier dynamics of near-band-edge emission in single-crystal ZnO nanorods
  • 2011
  • In: Materials research bulletin. - : Elsevier Science B.V., Amsterdam.. - 0025-5408 .- 1873-4227. ; 46:6, s. 937-940
  • Journal article (peer-reviewed)abstract
    • We report on rational synthesis and optical characteristics of highly crystallined ZnO nanorods which were grown by a facile chemical vapor transport method. Temperature-dependent photoluminescence spectra of as-fabricated ZnO nanorods are dominated by near-band-edge emission with a characteristic fine structure due to high crystallinity. Furthermore, the recombination emission involving carrier dynamics of near-band-edge emission in ZnO nanorods was systematically investigated by temperature-dependent time-resolved photoluminescence spectroscopy. Recombination peaks pertaining to the exciton emissions are monitored and resolved in both temporal and spatial regimes.
  •  
21.
  • Wang, Yutao, et al. (author)
  • Implementing stricter environmental regulation to enhance eco-efficiency and sustainability: a case study of Shandong Province's pulp and paper industry, China
  • 2011
  • In: Journal of Cleaner Production. - : Elsevier BV. - 0959-6526. ; 19:4, s. 303-310
  • Journal article (peer-reviewed)abstract
    • There has been much debate on the topic of whether stricter environmental regulations can promote environmental performance and economic performance at the same time. Different researchers have used different indicators to measure environmental performance and economic performance in their empirical studies. However, it is a surprise that few studies have checked the relationship between environmental regulation and eco-efficiency, as the latter is widely regarded as a quite powerful tool of considering ecology and economy together. In this study the background is the implementation in 2003 of the Stricter Discharge Standard (SDS) in Shandong Province's Pulp and Paper Industry (SPPI), compared to the national standards of China. The stricter regulations were intended to promote corporate change from passive management to active control and from end-of-pipe treatment to cleaner production. This study investigated the eco-efficiency trends of SPPI from 2001 to 2008 in three fields: water efficiency, energy efficiency and environment efficiency. A "de-linking" and "re-linking" tool was used to attain a further evaluation. The study showed that with the implementation of stricter regulation most of the efficiency indicators (except CO2 emission and energy consumption) had achieved significant improvements, and the overall environmental performance trends of SPPI showed it to be more sustainable. However, the study also found that it was not enough to address a single indicator in the environmental regulation of the pulp and paper industry. More holistic eco-efficiency indicators need to be further considered and introduced to the industry as the next step to create true sustainable development. (C) 2010 Elsevier Ltd. All rights reserved,
  •  
22.
  • Wang, Yufei, et al. (author)
  • Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer
  • 2014
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:7, s. 736-741
  • Journal article (peer-reviewed)abstract
    • We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 x 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 x 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 x 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.
  •  
23.
  • Wang, Yutao, et al. (author)
  • Strategic assessment of fuel taxation in energy conservation and CO2 reduction for road transportation: a case study from China
  • 2013
  • In: Stochastic Environmental Research and Risk Assessment. - : Springer Science and Business Media LLC. - 1436-3240 .- 1436-3259. ; 27:5, s. 1231-1238
  • Journal article (peer-reviewed)abstract
    • Road transportation has attracted extensive attention throughout the world because of its high energy demands and numerous externalities. Sustainable road transportation has thus become a great challenge for politicians and decision-makers all over the world. There have been a series of studies indicating that appropriate pricing of fuel can be both effective and efficient for reducing overconsumption of transport fuel. However, relatively little research has been done on fuel price approaches in developing country contexts. For a country like China, where road traffic today is growing more than in other countries, there is a strategic interest to do more economic analyses of fair and efficient pricing of fuel. In this study, we present a strategic assessment of fuel pricing in energy conservation and CO2 reduction from road transportation in China, both in a retrospective and a prospective perspective. First of all, the correlation between fuel price and road transport gasoline demand, based upon data from 1995 to 2007, was examined with an econometric model. Secondly, on basis of the elasticity model, the potential reductions with respect to fuel demand and Green House Gas (GHG) emissions as a consequence of a strategic fuel tax implementation in China were examined up to 2030. The results indicate that such strategic fuel taxation can play a considerable role in steering the growth of road transport gasoline demand, and thus also Chinese GHG emissions.
  •  
24.
  • Yu, Weifang, et al. (author)
  • Cystatin C Deficiency Promotes Epidermal Dysplasia in K14-HPV16 Transgenic Mice
  • 2010
  • In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:11
  • Journal article (peer-reviewed)abstract
    • Background: Cysteine protease cathepsins are important in extracellular matrix protein degradation, cell apoptosis, and angiogenesis. Mice lacking cathepsins are protected from tumor progression in several animal models, suggesting that the regulation of cathepsin activities controls the growth of various malignant tumors. Methods and Results: We tested the role of cathepsins using a mouse model of multistage epithelial carcinogenesis, in which the human keratin-14 promoter/enhancer drove the expression of human papillomavirus type 16 (HPV16) early region E6/E7 transgenes. During the progression of premalignant dysplasia, we observed increased expression of cysteine protease cathepsin S, but concomitantly reduced expression of cathepsin endogenous inhibitor cystatin C in the skin tissue extract. Absence of cystatin C in these transgenic mice resulted in more progression of dysplasia to carcinoma in situ on the face, ear, chest, and tail. Chest and ear skin extract real time PCR and immunoblot analysis, mouse serum sample ELISA, tissue immunohistological analysis, and tissue extract-mediated in vitro elastinolysis and collagenolysis assays demonstrated that cystatin C deficiency significantly increased cathepsin expression and activity. In skin from both the chest and ear, we found that the absence of cystatin C reduced epithelial cell apoptosis but increased proliferation. From the same tissue preparations, we detected significantly higher levels of pro-angiogenic laminin 5-derived c2 peptides and concurrently increased neovascularization in cystatin C-deficient mice, compared to those from wild-type control mice. Conclusion: Enhanced cathepsin expression and activity in cystatin C-deficient mice contributed to the progression of dysplasia by altering premalignant tissue epithelial proliferation, apoptosis, and neovascularization.
  •  
25.
  • Zhao, Wei, et al. (author)
  • Weak Crossability Barrier but Strong Juvenile Selection Supports Ecological Speciation of the Hybrid Pine Pinus Densata on the Tibetan Plateau
  • 2014
  • In: Evolution. - : John Wiley & Sons. - 0014-3820 .- 1558-5646. ; 68:11, s. 3120-3133
  • Journal article (peer-reviewed)abstract
    • Determining how a new hybrid lineage can achieve reproductive isolation is a key to understanding the process and mechanisms of homoploid hybrid speciation. Here, we evaluated the degree and nature of reproductive isolation between the ecologically successful hybrid species Pinus densata and its parental species P. tabuliformis and P. yunnanensis. We performed interspecific crosses among the three species to assess their crossability. We then conducted reciprocal transplantation experiments to evaluate their fitness differentiation, and to examine how natural populations representing different directions of introgression differ in adaptation. The crossing experiments revealed weak genetic barriers among the species. The transplantation trials showed manifest evidence of local adaptation as the three species all performed best in their native habitats. Pinus densata populations from the western edge of its distribution have evolved a strong local adaptation to the specific habitat in that range; populations representing different directions of introgressants with the two parental species all showed fitness disadvantages in this P. densata habitat. These observations illustrate that premating isolation through selection against immigrants from other habitat types or postzygotic isolation through selection against backcrosses between the three species is strong. Thus, ecological selection in combination with endogenous components and geographic isolation has likely played a significant role in the speciation of P. densata.
  •  
26.
  • Berndt, Sonja I., et al. (author)
  • Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
  • 2013
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
  • Journal article (peer-reviewed)abstract
    • Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
  •  
27.
  • Chen, Mingming, et al. (author)
  • Carbon anode in direct carbon fuel cell
  • 2010
  • In: International journal of hydrogen energy. - : Elsevier BV. - 0360-3199 .- 1879-3487. ; 35:7, s. 2732-2736
  • Journal article (peer-reviewed)abstract
    • Direct carbon fuel cell (DCFC) is a kind of high temperature fuel cell using carbon materials directly as anode. Electrochemical reactivity and surface property of carbon were taken into account in this paper. Four representative carbon samples were selected. The most suitable ratio of the ternary eutectic mixture Li2CO3-K2CO3-Al2O3 was determined at 1.05:1.2:1(mass ration). Conceptual analysis for electrochemical reactivity of carbon anode shows the importance of (1) reactive characteristics including lattice disorder, edge-carbon ratio and the number of short alkyl side chain of carbon material, which builds the prime foundation of the anodic half-cell reaction; (2) surface wetting ability, which assures the efficient contact of anode surface with electrolyte. It indicates that anode reaction rate and DCFC output can be notably improved if carbon are pre-dispersed into electrolyte before acting as anode, due to the straightway shift from cathode to anode for CO32- provided by electrolyte soaked in carbon material.
  •  
28.
  • Chen, Qiuyang, et al. (author)
  • Effect of bi-layer interconnector design on mass transfer performance in porous anode of solid oxide fuel cells
  • 2011
  • In: International Journal of Heat and Mass Transfer. - : Elsevier BV. - 0017-9310. ; 54:9-10, s. 1994-2003
  • Journal article (peer-reviewed)abstract
    • We propose a novel interconnector design, termed bi-layer interconnector, for solid oxide fuel cells (SOFCs). It can disturb the fuel gas and air on the planes normal to the SOFC three-phase-boundary (TPB) layer. In this paper, a two-dimensional half-cell model is developed to study the concentration overpotentials in the fuel side of the SOFC stack with conventional and novel bi-layer interconnectors. The numerical results show that the novel bi-layer interconnector can increase the velocity of the fuel gas in the porous anode. The results of mole fraction distribution illustrate that the novel bi-layer interconnector can effectively disturb the fuel flow. The average H-2 mole fraction in the porous anode of SOFC with bi-layer interconnector is about 4.7% higher than that of conventional SOFC. The average H-2 mole fraction at TPB interface is about 9.2% higher. The concentration overpotential of the novel SOFC design is lower than that of the conventional SOFC design by 5%. It can enhance the mass transfer in porous electrode and improve the performance of SOFC. (C) 2011 Elsevier Ltd. All rights reserved.
  •  
29.
  • Cho, Yoon Shin, et al. (author)
  • Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.
  • 2012
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:1
  • Journal article (peer-reviewed)abstract
    • We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.
  •  
30.
  • Dai, Daoxin, et al. (author)
  • Silicon Multimode Photonic Integrated Devices For On-Chip Mode-Division-Multiplexed Optical Interconnects
  • 2013
  • In: Progress In Electromagnetics Research. - 1070-4698 .- 1559-8985. ; 143, s. 773-819
  • Journal article (peer-reviewed)abstract
    • Multimode spatial-division multiplexing (SDM) technology has attracted much attention for its potential to enhance the capacity of an optical-interconnect link with a single wavelength carrier. For a mode-multiplexed optical-interconnect link, the functional elements are quite different from the conventional ones as multiple modes are involved. In this paper we give a review and discussion on multimode photonic integrated devices for mode-multiplexed optical-interconnects. Light propagation and mode conversion in tapered waveguides as well as bent waveguides are discussed first. Recent progress on mode converter-(de)multiplexers is then reviewed. The demands of some functional devices used for mode-multiplexed optical-interconnects are also discussed. In particular, the fabrication tolerance is analyzed in detail for our hybrid demultiplexer, which enables mode-/polarization-division-(de)multiplexing simultaneously.
  •  
31.
  • Ding, Bao-Jian, et al. (author)
  • A plant factory for moth pheromone production
  • 2014
  • In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 1-3353
  • Journal article (peer-reviewed)abstract
    • Moths depend on pheromone communication for mate finding and synthetic pheromones are used for monitoring or disruption of pheromone communication in pest insects. Here we produce moth sex pheromone, using Nicotiana benthamiana as a plant factory, by transient expression of up to four genes coding for consecutive biosynthetic steps. We specifically produce multicomponent sex pheromones for two species. The fatty alcohol fractions from the genetically modified plants are acetylated to mimic the respective sex pheromones of the small ermine moths Yponomeuta evonymella and Y. padella. These mixtures are very efficient and specific for trapping of male moths, matching the activity of conventionally produced pheromones. Our long-term vision is to design tailor-made production of any moth pheromone component in genetically modified plants. Such semisynthetic preparation of sex pheromones is a novel and cost-effective way of producing moderate to large quantities of pheromones with high purity and a minimum of hazardous waste.
  •  
32.
  • Ding, Bao-Jian, et al. (author)
  • Terminal fatty-acyl-CoA desaturase involved in sex pheromone biosynthesis in the Winter Moth (Operophtera brumata)
  • 2011
  • In: Insect Biochemistry and Molecular Biology. - : Elsevier BV. - 1879-0240 .- 0965-1748. ; 41, s. 715-722
  • Journal article (peer-reviewed)abstract
    • The Winter Moth (Operophtera brumata L., Lepidoptera: Geometridae) utilizes a single hydrocarbon, 1,Z3,Z6,Z9-nonadecatetraene, as its sex pheromone. We tested the hypothesis that a fatty acid precursor, Z11,Z14,Z17,19-nonadecanoic acid, is biosynthesized from α-linolenic acid, through chain elongation by one 2-carbon unit, and subsequent methyl-terminus desaturation. Our results show that labeled α-linolenic acid is indeed incorporated into the pheromone component in vivo. A fatty-acyl-CoA desaturase gene that we found to be expressed in the abdominal epidermal tissue, the presumed site of biosynthesis for type II pheromones, was characterized and expressed heterologously in a yeast system. The transgenic yeast expressing this insect derived gene could convert Z11,Z14,Z17-eicosatrienoic acid into Z11,Z14,Z17,19-eicosatetraenoic acid. These results provide evidence that a terminal desaturation step is involved in the winter moth pheromone biosynthesis, prior to the decarboxylation.
  •  
33.
  • Feng, Cun-Feng, et al. (author)
  • Effects of average degree of network on an order-disorder transition in opinion dynamics
  • 2010
  • In: Chinese Physics B. - : IOPScience. - 1674-1056. ; 19:6, s. 060203-
  • Journal article (peer-reviewed)abstract
    • We have investigated the influence of the average degree (k) of network on the location of an order-disorder transition in opinion dynamics. For this purpose, a variant of majority rule (VMR) model is applied to Watts–Strogatz (WS) small-world networks and Barabási–Albert (BA) scale-free networks which may describe some non-trivial properties of social systems. Using Monte Carlo simulations, we find that the order–disorder transition point of the VMR model is greatly affected by the average degree (k) of the networks; a larger value of (k) results in a more ordered state of the system. Comparing WS networks with BA networks, we find WS networks have better orderliness than BA networks when the average degree (k) is small. With the increase of (k), BA networks have a more ordered state. By implementing finite-size scaling analysis, we also obtain critical exponents β/ν, γ/ν and 1/ν for several values of average degree (k). Our results may be helpful to understand structural effects on order–disorder phase transition in the context of the majority rule model.
  •  
34.
  • Figueroa, Jonine D., et al. (author)
  • Genome-wide interaction study of smoking and bladder cancer risk
  • 2014
  • In: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 35:8, s. 1737-1744
  • Journal article (peer-reviewed)abstract
    • Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 x 10(-5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 x 10(-7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 x 10-7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.
  •  
35.
  • Fu, Yi-Ping, et al. (author)
  • The 19q12 Bladder Cancer GWAS Signal : Association with Cyclin E Function and Aggressive Disease
  • 2014
  • In: Cancer Research. - 0008-5472 .- 1538-7445. ; 74:20, s. 5808-5818
  • Journal article (peer-reviewed)abstract
    • A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) >= 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 x 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P-trend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
  •  
36.
  • Guan, Jian-Yue, et al. (author)
  • Cooperation influenced by the correlation degree of two-layered complex networks in evolutionary prisoner's dilemma games
  • 2010
  • In: Chinese Physics B. - : Institute of Physics (IOP). - 1674-1056. ; 19:2
  • Journal article (peer-reviewed)abstract
    • An evolutionary prisoner's dilemma game is investigated on two-layered complex networks respectively representing interaction and learning networks in one and two dimensions. A parameter q is introduced to denote the correlation degree between the two-layered networks. Using Monte Carlo simulations we studied the effects of the correlation degree on cooperative behaviour and found that the cooperator density nontrivially changes with q for different payoff parameter values depending on the detailed strategy updating and network dimension. An explanation for the obtained results is provided.
  •  
37.
  • Hempel, Antje, et al. (author)
  • The Ser/Thr protein kinase AfsK regulates polar growth and hyphal branching in the filamentous bacteria Streptomyces.
  • 2012
  • In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 109:35, s. 2371-2379
  • Journal article (peer-reviewed)abstract
    • In cells that exhibit apical growth, mechanisms that regulate cell polarity are crucial for determination of cellular shape and for the adaptation of growth to intrinsic and extrinsic cues. Broadly conserved pathways control cell polarity in eukaryotes, but less is known about polarly growing prokaryotes. An evolutionarily ancient form of apical growth is found in the filamentous bacteria Streptomyces, and is directed by a polarisome-like complex involving the essential protein DivIVA. We report here that this bacterial polarization machinery is regulated by a eukaryotic-type Ser/Thr protein kinase, AfsK, which localizes to hyphal tips and phosphorylates DivIVA. During normal growth, AfsK regulates hyphal branching by modulating branch-site selection and some aspect of the underlying polarisome-splitting mechanism that controls branching of Streptomyces hyphae. Further, AfsK is activated by signals generated by the arrest of cell wall synthesis and directly communicates this to the polarisome by hyperphosphorylating DivIVA. Induction of high levels of DivIVA phosphorylation by using a constitutively active mutant AfsK causes disassembly of apical polarisomes, followed by establishment of multiple hyphal branches elsewhere in the cell, revealing a profound impact of this kinase on growth polarity. The function of AfsK is reminiscent of the phoshorylation of polarity proteins and polarisome components by Ser/Thr protein kinases in eukaryotes.
  •  
38.
  • Jacobs, Kevin B, et al. (author)
  • Detectable clonal mosaicism and its relationship to aging and cancer.
  • 2012
  • In: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
  • Journal article (peer-reviewed)abstract
    • In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
  •  
39.
  • Ji, Hong, et al. (author)
  • TNFR1 mediates TNF-alpha-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling
  • 2014
  • In: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 5:4944
  • Journal article (peer-reviewed)abstract
    • Inflammation and lymphangiogenesis are two cohesively coupled processes that promote tumour growth and invasion. Here we report that TNF-alpha markedly promotes tumour lymphangiogenesis and lymphatic metastasis. The TNF-alpha-TNFR1 signalling pathway directly stimulates lymphatic endothelial cell activity through a VEGFR3-independent mechanism. However, VEGFR3-induced lymphatic endothelial cell tips are a prerequisite for lymphatic vessel growth in vivo, and a VEGFR3 blockade completely ablates TNF-alpha-induced lymphangiogenesis. Moreover, TNF-alpha-TNFR1-activated inflammatory macrophages produce high levels of VEGF-C to coordinately activate VEGFR3. Genetic deletion of TNFR1 (Tnfr1(-/-)) in mice or depletion of tumour-associated macrophages (TAMs) virtually eliminates TNF-alpha-induced lymphangiogenesis and lymphatic metastasis. Gain-of-function experiments show that reconstitution of Tnfr1(+/+) macrophages in Tnfr1(+/+) mice largely restores tumour lymphangiogenesis and lymphatic metastasis. These findings shed mechanistic light on the intimate interplay between inflammation and lymphangiogenesis in cancer metastasis, and propose therapeutic intervention of lymphatic metastasis by targeting the TNF-alpha-TNFR1 pathway.
  •  
40.
  • Jin, Zhichao, et al. (author)
  • A retrospective survey of research design and statistical analyses in selected Chinese medical journals in 1998 and 2008
  • 2010
  • In: PLOS ONE. - : PLOS. - 1932-6203. ; 5:5
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: High quality clinical research not only requires advanced professional knowledge, but also needs sound study design and correct statistical analyses. The number of clinical research articles published in Chinese medical journals has increased immensely in the past decade, but study design quality and statistical analyses have remained suboptimal. The aim of this investigation was to gather evidence on the quality of study design and statistical analyses in clinical researches conducted in China for the first decade of the new millennium.METHODOLOGY/PRINCIPAL FINDINGS: Ten (10) leading Chinese medical journals were selected and all original articles published in 1998 (N = 1,335) and 2008 (N = 1,578) were thoroughly categorized and reviewed. A well-defined and validated checklist on study design, statistical analyses, results presentation, and interpretation was used for review and evaluation. Main outcomes were the frequencies of different types of study design, error/defect proportion in design and statistical analyses, and implementation of CONSORT in randomized clinical trials. From 1998 to 2008: The error/defect proportion in statistical analyses decreased significantly ( = 12.03, p<0.001), 59.8% (545/1,335) in 1998 compared to 52.2% (664/1,578) in 2008. The overall error/defect proportion of study design also decreased ( = 21.22, p<0.001), 50.9% (680/1,335) compared to 42.40% (669/1,578). In 2008, design with randomized clinical trials remained low in single digit (3.8%, 60/1,578) with two-third showed poor results reporting (defects in 44 papers, 73.3%). Nearly half of the published studies were retrospective in nature, 49.3% (658/1,335) in 1998 compared to 48.2% (761/1,578) in 2008. Decreases in defect proportions were observed in both results presentation ( = 93.26, p<0.001), 92.7% (945/1,019) compared to 78.2% (1023/1,309) and interpretation ( = 27.26, p<0.001), 9.7% (99/1,019) compared to 4.3% (56/1,309), some serious ones persisted.CONCLUSIONS/SIGNIFICANCE: Chinese medical research seems to have made significant progress regarding statistical analyses, but there remains ample room for improvement regarding study designs. Retrospective clinical studies are the most often used design, whereas randomized clinical trials are rare and often show methodological weaknesses. Urgent implementation of the CONSORT statement is imperative.
  •  
41.
  • Karlsson, Andréas, et al. (author)
  • ePUMA : A unique memory access based parallel DSP processor for SDR and CR
  • 2013
  • In: Global Conference on Signal and Information Processing (GlobalSIP), 2013 IEEE. - : IEEE. - 9781479902484 ; , s. 1234-1237
  • Conference paper (peer-reviewed)abstract
    • This paper presents ePUMA, a master-slave heterogeneous DSP processor for communications and multimedia. We introduce the ePUMA VPE, a vector processing slave-core designed for heavy DSP workloads and demonstrate how its features can used to implement DSP kernels that efficiently overlap computing, data access and control to achieve maximum datapath utilization. The efficiency is evaluated by implementing a basic set of kernels commonly used in SDR. The experiments show that all kernels asymptotically reach above 90% effective datapath utilization. while many approach 100%, thus the design effectively overlaps computing, data access and control. Compared to popular VLIW solutions, the need for a large register file with many ports is eliminated, thus saving power and chip area. When compared to a commercial VLIW solution, our solution also achieves code size reductions of up to 30 times and a significantly simplified kernel implementation.
  •  
42.
  • Keunen, Olivier, et al. (author)
  • Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma
  • 2011
  • In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:9, s. 3749-3754
  • Journal article (peer-reviewed)abstract
    • Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.
  •  
43.
  • Li, Jian, et al. (author)
  • Array Comparative Genomic Hybridization of Keratoacanthomas and Squamous Cell Carcinomas: Different Patterns of Genetic Aberrations Suggest Two Distinct Entities
  • 2012
  • In: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 132:8, s. 2060-2066
  • Journal article (peer-reviewed)abstract
    • Keratoacanthoma (KA) is a benign keratinocytic neoplasm that spontaneously regresses after 3-6 months and shares features with squamous cell carcinomas (SCCs). Furthermore, there are reports of KAs that have metastasized, invoking the question of whether KA is a variant of SCC (Hodak et al., 1993). To date, no reported criteria are sensitive enough to discriminate reliably between KA and SCC, and consequently there is a clinical need for discriminating markers. Our previous study analyzed 132 KAs and 29 SCCs and revealed significantly different regions of genomic aberrations using chromosomal comparative genomic hybridization (CGH). In the present study, we applied array CGH to investigate 98 KAs and 22 SCCs from the above samples. The result shows that all KAs and SCCs have some degree of genetic aberrations. The distribution of numbers of aberrant clones per sample differed significantly between KAs and SCCs (P<0.02), which also demonstrated recurrent aberrations that differed significantly (P<0.001), as illustrated by unsupervised cluster analysis. Classifiers for clinicopathological parameters of KAs were established based on t-test statistics and permutation tests. Tumor size, fibrosis, and inflammation, which are related to the developmental stages of KAs, showed significant (t-test, permutation test) associations with aberrations of selected genomic regions. This suggests chromosomal instability during the whole life cycle of KAs.
  •  
44.
  • Li-Juan, Zhang, et al. (author)
  • A novel water layer structure inside nanobubbles at room temperature
  • 2014
  • In: NUCL SCI TECH. - 1001-8042. ; 25:6, s. 060503-
  • Journal article (peer-reviewed)abstract
    • Molecularly thin water layer, with a hydrogen bonding network different from those in bulk water and ice, has unique properties and is generally involved in many important processes such as wetting, erosion, atmosphere chemical reaction, protein folding and biomolecular interaction. Here, we report a new water layer structure at room temperature, which is found inside nanobubbles by using synchrotron based scanning transmission soft X-ray microscopy (STXM). The three peaks 535.0, 536.8 and 540.9 eV at O K edge inside the nanobubbles show a novel characteristics of very thin water layers, which has never been observed before.
  •  
45.
  • Lin, Li-Li, et al. (author)
  • Determination of the Configuration of a Single Molecule Junction by Inelastic Electron Tunneling Spectroscopy
  • 2010
  • In: The Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 114:11, s. 5199-5202
  • Journal article (peer-reviewed)abstract
    • First-principles calculations for inelastic electron tunneling spectroscopy (IETS) of a single 1,3-propanedithiol molecule covalently bound to gold electrodes are presented. Inelastic electron tunneling spectra of the single molecule junction with different contact geometries and molecular orientations at the interface are simulated. It is demonstrated that the delicate variation in the configuration of the single molecule junction caused by separating the two electrodes call result in significant changes in the inelastic electron tunneling spectral profile of the junction. The two Most probable configurations of the molecular junction formed in the experiment (Nano Lett. 2008, 8, 1673) are theoretically identified, and the experimental IET spectra are correctly assigned.
  •  
46.
  • Lin, Zhaowei, et al. (author)
  • Effects of BMP2 and VEGF165 on the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells.
  • 2014
  • In: Experimental and Therapeutic Medicine. - : Spandidos Publications. - 1792-1015 .- 1792-0981. ; 7:3, s. 625-629
  • Journal article (peer-reviewed)abstract
    • Bone marrow-derived mesenchymal stem cells (MSCs) are dominant seed cell sources for bone regeneration. Bone morphogenetic proteins (BMPs) initiate cartilage and bone formation in a sequential cascade. Vascular endothelial growth factor (VEGF) is an essential coordinator of extracellular matrix remodeling, angiogenesis and bone formation. In the present study, the effects of the vascular endothelial growth factor 165 (VEGF165) and bone morphogenetic protein 2 (BMP2) genes on bone regeneration were investigated by the lentivirus-mediated cotransfection of the two genes into rat bone marrow-derived MSCs. The successful co-expression of the two genes in the MSCs was confirmed using quantitative polymerase chain reaction (qPCR) and western blot analysis. The results of alizarin red and alkaline phosphatase (ALP) staining at 14 days subsequent to transfection showed that the area of staining in cells transfected with BMP2 alone was higher than that in cells transfected with BMP2 and VEGF165 or untransfected control cells, while the BMP2 + VEGF165 group showed significantly more staining than the untransfected control. This indicated that BMP2 alone exhibited a stronger effect in bone regeneration than BMP2 in combination with VEGF165. Similarly, in inducing culture medium, the ALP activity of the BMP2 + VEGF165 group was notably suppressed compared with that of the BMP2 group. The overexpression of VEGF165 inhibited BMP2-induced MSC differentiation and osteogenesis in vitro. Whether or not local VEGF gene therapy is likely to affect bone regeneration in vivo requires further investigation.
  •  
47.
  • Liu, Dake, et al. (author)
  • ePUMA embedded parallel DSP processor with Unique Memory Access
  • 2011
  • In: Information, Communications and Signal Processing (ICICS), 2011. - : IEEE. - 9781457700293 ; , s. 1-5
  • Conference paper (peer-reviewed)abstract
    • Computing unto 100GOPS without cooling is essential for high-end embedded systems and much required by markets. A novel master-slave multi-SIMD architecture and its kernel (template) based parallel programming flow is thus introduced as a parallel signal processing platform, ePUMA, embedded Parallel DSP processor with Unique Memory Access. It is an on chip multi-DSP-processor (CMP) targeting to predictable signal processing for communications and multimedia. The essential technologies are to separate the processing of control stream from parallel computing, and to separate parallel data access from parallel arithmetic computing kernels. By separations, the computation and data access can be orthogonal both in hardware and in programs. Orthogonal operations can therefore be executed in parallel and the run time cost of data access can be minimized. Benchmark shows that the computing performance therefore reaches about 80% of the hardware limit. Less than 40% of the hardware limit can be reached by normal processors. The unique SIMD memory subsystem architecture offers programmable conflict free parallel data accesses. Programming flow and tools are also developed to support coding on the unique hardware architecture. A prototype on FPGA shows especially high performance over silicon cost.
  •  
48.
  • Liu, Dake, et al. (author)
  • Parallel Programming and its architectures Based on data access separated algorithm Kernels
  • 2010
  • In: International Journal of Embedded and Real-Time Communication Systems. - : IGI Global. - 1947-3176 .- 1947-3184. ; 1:1, s. 65-85
  • Journal article (peer-reviewed)abstract
    • A novel master-multi-SIMD architecture and its kernel (template) based parallel programming flow is introduced as a parallel signal processing platform. The name of the platform is ePUMA (embedded Parallel DSP processor architecture with Unique Memory Access). The essential technology is to separate data accessing kernels from arithmetic computing kernels so that the run-time cost of data access can be minimized by running it in parallel with algorithm computing. The SIMD memory subsystem architecture based on the proposed flow dramatically improves the total computing performance. The hardware system and programming flow introduced in this article will primarily aim at low-power high-performance embedded parallel computing with low silicon cost for communications and similar real-time signal processing. Copyright © 2010, IGI Global.
  •  
49.
  • Liu, Jian, et al. (author)
  • Printable highly conductive conjugated polymer sensitized ZnO NCs as cathode interfacial layer for efficient polymer solar cells
  • 2014
  • In: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 6:11, s. 8237-8245
  • Journal article (peer-reviewed)abstract
    • We report a facile way to produce printable highly conductive cathode interfacial layer (CIL) for efficient polymer solar cells (PSCs) by sensitizing ZnO nanocrystals (NCs) with a blue fluorescent conjugated polymer, poly(9, 9-bis-(6-diethoxylphosphorylhexyl) fluorene) (PFEP). Herein, PFEP plays dual distinctive roles in the composite. Firstly, PFEP chains can effectively block the aggregation of ZnO NCs, leading to uniform and smooth film during solution processing via assembly on ZnO NC surfaces through their pending phosphonate groups. Secondly, PFEP can greatly improve the conductivity of ZnO NCs by charge transfer doping, that is the charge transfer from the sensitizer driven by electron-chemical potential equilibrium, which could be even more pronounced under light illumination because of light excitation of PFEP sensitizer. The increased conductivity in ZnO-PFEP layer renders more efficient electron transport and extraction compared to pristine ZnO layer. This ZnO-PFEP CIL was successfully applied to PSCs based on three polymer donor systems with different band-gaps, and efficiency enhancements from 44 to 70% were observed compared to those PSCs with pristine ZnO CIL. The highest efficiency of 7.56% was achieved in P(IID-DTC):PC70BM-based PSCs by using ZnO-PFEP film as CIL. Moreover, the enhanced conductivity due to the charge-transfer doping effect allows thick ZnO-PFEP film to be used as CIL in high-performance PSCs. Both the high conductivity and good film-forming properties of ZnO-PFEP CIL are favorable for large-scale printable PSCs, which is also verified by high-efficiency PSCs with ZnO-PFEP CIL fabricated using doctor-blading, a large-scale processing technique. The work provides an efficient printable cathode interfacial material for efficient PSCs.
  •  
50.
  • Liu, Ning, et al. (author)
  • Transcriptional regulation mechanisms of hypoxia-induced neuroglobin gene expression.
  • 2012
  • In: The Biochemical journal. - 1470-8728 .- 0264-6021. ; 443:1, s. 153-164
  • Journal article (peer-reviewed)abstract
    • Ngb (neuroglobin) has been identified as a novel endogenous neuroprotectant. However, little is known about the regulatory mechanisms of Ngb expression, especially under conditions of hypoxia. In the present study, we located the core proximal promoter of the mouse Ngb gene to a 554bp segment, which harbours putative conserved NF-κB (nuclear factor κB)- and Egr1 (early growth-response factor 1) -binding sites. Overexpression and knockdown of transcription factors p65, p50, Egr1 or Sp1 (specificity protein 1) increased and decreased Ngb expression respectively. Experimental assessments with transfections of mutational Ngb gene promoter constructs, as well as EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation) assays, demonstrated that NF-κB family members (p65, p50 and cRel), Egr1 and Sp1 bound in vitro and in vivo to the proximal promoter region of the Ngb gene. Moreover, a κB3 site was found as a pivotal cis-element responsible for hypoxia-induced Ngb promoter activity. NF-κB (p65) and Sp1 were also responsible for hypoxia-induced up-regulation of Ngb expression. Although there are no conserved HREs (hypoxia-response elements) in the promoter of the mouse Ngb gene, the results of the present study suggest that HIF-1α (hypoxia-inducible factor-1α) is also involved in hypoxia-induced Ngb up-regulation. In conclusion, we have identified that NF-κB, Egr1 and Sp1 played important roles in the regulation of basal Ngb expression via specific interactions with the mouse Ngb promoter. NF-κB, Sp1 and HIF-1α contributed to the up-regulation of mouse Ngb gene expression under hypoxic conditions.
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