3,422 research outputs found

    Genomic structure, alternative splicing and tissue expression of rFrp/sFRP-4, the rat frizzled related protein gene

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    Secreted frizzled related proteins (sFRP) are regulators of Wnt signaling pathways that play central roles in developmental processes and oncogenesis. Various sFRP genes have been cloned from different tissues and implicated in diverse biological activities. rFrp, the rat homologue of sFRP-4, was initially identified as being upregulated in mutant p53-induced cellular transformation. Here, we report on the isolation of five novel splice variants, rFrp/sFRP-4 II, II, III, IVa and IVb. The complete rFrp/sFRP-4 genomic structure spans over 31 kb covering 9 exons. Except for the variant IVb, which was derived from IVa by alternative polyadenylation signal, variants I to IVa were alternatively spliced to different exons in the 3'end of mRNA and resulted in transcripts with truncated open reading frame. The deduced proteins of the variants had truncated C-termini, however, the two key functional protein domains, the cysteine-rich domain and the netrin-like domain of the isoforms, were not altered. In addition, different transcriptional initiation sites were found with variants II and IV, implying that these variants may be regulated differently from the rFrp/sFRP-4. RT-PCR analysis showed that these splice variants displayed different patterns of tissue-specific expression. Northern blot analysis revealed that the rFrp/sFRP-4 is most abundant in the ovary. Taken together, our findings suggest that alternative splicing of rFrp/sFRP-4 plays a role in regulating tissue-specific expression. The truncated C terminals of rFrp/sFRP-4 variants may confer structural specificity and hence exert different biological functions in different tissues. Characterization of these novel splice variants should help to elucidate the function of the sFRP family gene. © 2005 Elsevier B.V. All rights reserved.postprin

    The School Finance Redesign Project: A Synthesis of Project Work to Date

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    Highlights the School Finance Redesign Project's early findings on the funding needed for all students to meet academic standards, promising ideas for focusing funding on promoting learning and rewarding educators, and the current system's constraints

    Epigenetic regulation of the secreted frizzled-related protein family in human glioblastoma multiforme

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    Glioblastoma multiforme (GBM) are intracranial tumors of the central nervous system and the most lethal among solid tumors. Current therapy is palliative and is limited to surgical resection followed by radiation therapy and temozolomide treatment. Aberrant WNT pathway activation mediates not only cancer cell proliferation but also promotes radiation and chemotherapeutic resistance. WNT antagonists such as the secreted frizzled-related protein (sFRP) family have an ability to sensitize glioma cells to chemotherapeutics, decrease proliferation rate and induce apoptosis. During tumor development, sFRP genes (1–5) are frequently hypermethylated, causing transcriptional silencing. We investigated a possible involvement of methylation-mediated silencing of the sFRP gene family in human GBM using four human glioblastoma cell lines (U87, U138, A172 and LN18). To induce demethylation of the DNA, we inhibited DNA methyltransferases through treatment with 5-azacytidine. Genomic DNA, RNA and total protein were isolated from GBM cells before and after treatment. We utilized bisulfite modification of genomic DNA to examine the methylation status of the respective sFRP promoter regions. Pharmacological demethylation of the GBM cell lines demonstrated a loss of methylation in sFRP promoter regions, as well as an increase in sFRP gene-specific mRNA abundance. Western blot analysis demonstrated an increased protein expression of sFRP-4 and increased levels of phosphorylated-ß-catenin. These data indicate an important role of methylation-induced gene silencing of the sFRP gene family in human GBM

    Frizzled Proteins are bona fide G Protein-Coupled Receptors

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    Receptors of the Frizzled family initiate Wnt ligand-dependent signaling controlling
multiple steps in organism development and highly conserved in evolution.
Misactivation of the Wnt/Frizzled signaling is cancerogenic. Frizzled receptors
launch several signaling cascades: the canonical pathway regulating beta-catenin-dependent transcription; the planar cell polarity pathway polarizing the
cytoskeleton within the epithelial plane; and the calcium pathway. Frizzled
receptors possess seven transmembrane domains and their signaling depends on
trimeric G proteins in various organisms. However, Frizzleds constitute a
distinct group within the G protein-coupled receptors (GPCR) superfamily, and
Frizzled signaling can be G protein-independent in some experimental setups, which led to concerns about the GPCR nature of Frizzled. Here we demonstrate
that human Frizzled receptors can directly bind the trimeric Go protein in a
pertussis toxin-sensitive manner. Furthermore, addition of Wnt ligands elicits
Frizzled-dependent guanine nucleotide exchange on Go. An excess of secreted
Frizzled-related protein (a Wnt antagonist) prevents Go activation, as does
pretreatment of Go with pertussis toxin. These experiments provide a biochemical
proof of the GPCR activities of Frizzled receptors and establish an in vitro assay to
monitor Frizzled activation by Wnt ligands, applicable for the high-throughput
agonist/antagonist screening

    Gravitational wave quasinormal mode from Population III massive black hole binaries in various models of population synthesis

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    Focusing on the remnant black holes after merging binary black holes, we show that ringdown gravitational waves of Population III binary black holes mergers can be detected with the rate of 5.9500 events yr1 (SFRp/(102.5 M yr1 Mpc3))([fb/(1+fb)]/0.33)5.9-500~{\rm events~yr^{-1}}~({\rm SFR_p}/ (10^{-2.5}~M_\odot~{\rm yr^{-1}~Mpc^{-3}})) \cdot ({\rm [f_b/(1+f_b)]/0.33}) for various parameters and functions. This rate is estimated for the events with SNR>8>8 for the second generation gravitational wave detectors such as KAGRA. Here, SFRp{\rm SFR_p} and fb{\rm f_b} are the peak value of the Population III star formation rate and the fraction of binaries, respectively. When we consider only the events with SNR>35>35, the event rate becomes 0.0464.21 events yr1 (SFRp/(102.5 M yr1 Mpc3))([fb/(1+fb)]/0.33)0.046-4.21~{\rm events~yr^{-1}}~({\rm SFR_p}/ (10^{-2.5}~M_\odot~{\rm yr^{-1}~Mpc^{-3}})) \cdot ({\rm [f_b/(1+f_b)]/0.33}). This suggest that for remnant black hole's spin qf>0.95q_f>0.95 we have the event rate with SNR>35>35 less than 0.037 events yr1 (SFRp/(102.5 M yr1 Mpc3))([fb/(1+fb)]/0.33)0.037~{\rm events~yr^{-1}}~({\rm SFR_p}/ (10^{-2.5}~M_\odot~{\rm yr^{-1}~Mpc^{-3}})) \cdot ({\rm [f_b/(1+f_b)]/0.33}), while it is 330 events yr1 (SFRp/(102.5 M yr1 Mpc3))([fb/(1+fb)]/0.33)3-30~{\rm events~yr^{-1}}~({\rm SFR_p}/ (10^{-2.5}~M_\odot~{\rm yr^{-1}~Mpc^{-3}})) \cdot ({\rm [f_b/(1+f_b)]/0.33}) for the third generation detectors such as Einstein Telescope. If we detect many Population III binary black holes merger, it may be possible to constrain the Population III binary evolution paths not only by the mass distribution but also by the spin distribution.Comment: Submitted to PTEP. comments welcom

    A Leap of Faith: Redesigning Teacher Compensation

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    Summarizes three reports: Teacher Attitudes About Compensation Reform, Returns to Skill and Teacher Wage Premiums, and Teacher Labor Markets and the Perils of Using Hedonics to Estimate Compensating Differentials in the Public Sector

    Possible confirmation of the existence of ergoregion by the Kerr quasinormal mode in gravitational waves from Pop III massive black hole binary

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    The existence of the ergoregion of the Kerr space-time has not been confirmed observationally yet. We show that the confirmation would be possible by observing the quasinormal mode in gravitational waves. As an example, using the recent population synthesis results of Pop III binary black holes, we find that the peak of the final merger mass (MfM_f) is about 50 M50~\rm M_{\odot}, while the fraction of the final spin qf=af/Mf>0.7q_f = a_f/M_f > 0.7 needed for the confirmation of a part of ergoregion is 77%\sim 77\%. To confirm the frequency of the quasinormal mode, SNR>35{\rm SNR} > 35 is needed. The standard model of Pop III population synthesis tells us that the event rate for the confirmation of more than 50%50\% of the ergoregion by the second generation gravitational wave detectors is 2.3\sim 2.3 events yr1 (SFRp/(102.5 Myr1 Mpc3))([fb/(1+fb)]/0.33){\rm events\ yr^{-1}\ (SFR_p/(10^{-2.5}\ M_\odot yr^{-1}\ Mpc^{-3}))} \cdot (\rm [f_b/(1+f_b)]/0.33) where SFRp{\rm SFR_p} and fb{\rm f_b} are the peak value of the Pop III star formation rate and the fraction of binaries, respectively.Comment: Accepted for publication in PTEP. Comments welcom
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