Sample records for factor 1a ptf1a

  1. Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression.

    PubMed

    Pascual, Marta; Abasolo, Ibane; Mingorance-Le Meur, Ana; Martínez, Albert; Del Rio, José A; Wright, Christopher V E; Real, Francisco X; Soriano, Eduardo

    2007-03-20

    We report in this study that, in the cerebellum, the pancreatic transcription factor Ptf1a is required for the specific generation of Purkinje cells (PCs) and interneurons. Moreover, granule cell progenitors in the external GCL (EGL) appear to be unaffected by deletion of Ptf1a. Cell lineage analysis in Ptf1a(Cre/Cre) mice was used to establish that, in the absence of Ptf1a expression, ventricular zone progenitors, normally fated to produce PCs and interneurons, aberrantly migrate to the EGL and express typical markers of these cells, such as Math1, Reelin, and Zic1/2. Furthermore, these cells have a fine structure typical of EGL progenitors, indicating that they adopt an EGL-like cell phenotype. These findings indicate that Ptf1a is necessary for the specification and normal production of PCs and cerebellar interneurons. Moreover, our results suggest that Ptf1a is also required for the suppression of the granule cell specification program in cerebellar ventricular zone precursors.

  2. Pdx-1 and Ptf1a concurrently determine fate specification of pancreatic multipotent progenitor cells

    PubMed Central

    Burlison, Jared S.; Long, Qiaoming; Fujitani, Yoshio; Wright, Christopher V.E.; Magnuson, Mark A.

    2008-01-01

    The pancreas is derived from a pool of multipotent progenitor cells (MPCs) that co-express Pdx-1 and Ptf1a. To more precisely define how the individual and combined loss of Pdx-1 and Ptf1a affects pancreatic MPC specification and differentiation we derived and studied mice bearing a novel Ptf1aYFP allele. While the expression of Pdx-1 and Ptf1a in pancreatic MPCs coincides between E9.5–12.5 the developmental phenotypes of Pdx-1 null and Pdx-1; Ptf1a double null mice are indistinguishable, and an early pancreatic bud is formed in both cases. This finding indicates that Pdx-1 is required in the foregut endoderm prior to Ptf1a for pancreatic MPC specification. We also found that Ptf1a is neither required for specification of Ngn3-positive endocrine progenitors nor differentiation of mature β-cells. In the absence of Pdx-1 Ngn3-positive cells were not observed after E9.5. Thus, in contrast to the deletion of Ptf1a, the loss of Pdx-1 precludes the sustained Ngn3-based derivation of endocrine progenitors from pancreatic MPCs. Taken together, these studies indicate that Pdx-1 and Ptf1a have distinct but interdependent functions during pancreatic MPC specification. PMID:18294628

  3. Pdx-1 and Ptf1a concurrently determine fate specification of pancreatic multipotent progenitor cells.

    PubMed

    Burlison, Jared S; Long, Qiaoming; Fujitani, Yoshio; Wright, Christopher V E; Magnuson, Mark A

    2008-04-01

    The pancreas is derived from a pool of multipotent progenitor cells (MPCs) that co-express Pdx-1 and Ptf1a. To more precisely define how the individual and combined loss of Pdx-1 and Ptf1a affects pancreatic MPC specification and differentiation we derived and studied mice bearing a novel Ptf1a(YFP) allele. While the expression of Pdx-1 and Ptf1a in pancreatic MPCs coincides between E9.5 and 12.5 the developmental phenotypes of Pdx-1 null and Pdx-1; Ptf1a double null mice are indistinguishable, and an early pancreatic bud is formed in both cases. This finding indicates that Pdx-1 is required in the foregut endoderm prior to Ptf1a for pancreatic MPC specification. We also found that Ptf1a is neither required for specification of Ngn3-positive endocrine progenitors nor differentiation of mature beta-cells. In the absence of Pdx-1 Ngn3-positive cells were not observed after E9.5. Thus, in contrast to the deletion of Ptf1a, the loss of Pdx-1 precludes the sustained Ngn3-based derivation of endocrine progenitors from pancreatic MPCs. Taken together, these studies indicate that Pdx-1 and Ptf1a have distinct but interdependent functions during pancreatic MPC specification.

  4. Ptf1a determines horizontal and amacrine cell fates during mouse retinal development.

    PubMed

    Fujitani, Yoshio; Fujitani, Shuko; Luo, Huijun; Qiu, Feng; Burlison, Jared; Long, Qiaoming; Kawaguchi, Yoshiya; Edlund, Helena; MacDonald, Raymond J; Furukawa, Takahisa; Fujikado, Takashi; Magnuson, Mark A; Xiang, Mengqing; Wright, Christopher V E

    2006-11-01

    The vertebrate neural retina comprises six classes of neurons and one class of glial cells, all derived from a population of multipotent progenitors. There is little information on the molecular mechanisms governing the specification of cell type identity from multipotent progenitors in the developing retina. We report that Ptf1a, a basic-helix-loop-helix (bHLH) transcription factor, is transiently expressed by post-mitotic precursors in the developing mouse retina. Recombination-based lineage tracing analysis in vivo revealed that Ptf1a expression marks retinal precursors with competence to exclusively produce horizontal and amacrine neurons. Inactivation of Ptf1a leads to a fate-switch in these precursors that causes them to adopt a ganglion cell fate. This mis-specification of neurons results in a complete loss of horizontal cells, a profound decrease of amacrine cells and an increase in ganglion cells. Furthermore, we identify Ptf1a as a primary downstream target for Foxn4, a forkhead transcription factor involved in the genesis of horizontal and amacrine neurons. These data, together with the previous findings on Foxn4, provide a model in which the Foxn4-Ptf1a pathway plays a central role in directing the differentiation of retinal progenitors towards horizontal and amacrine cell fates.

  5. Regulating the dorsal neural tube expression of Ptf1a through a distal 3' enhancer.

    PubMed

    Mona, Bishakha; Avila, John M; Meredith, David M; Kollipara, Rahul K; Johnson, Jane E

    2016-10-01

    Generating the correct balance of inhibitory and excitatory neurons in a neural network is essential for normal functioning of a nervous system. The neural network in the dorsal spinal cord functions in somatosensation where it modulates and relays sensory information from the periphery. PTF1A is a key transcriptional regulator present in a specific subset of neural progenitor cells in the dorsal spinal cord, cerebellum and retina that functions to specify an inhibitory neuronal fate while suppressing excitatory neuronal fates. Thus, the regulation of Ptf1a expression is critical for determining mechanisms controlling neuronal diversity in these regions of the nervous system. Here we identify a sequence conserved, tissue-specific enhancer located 10.8kb 3' of the Ptf1a coding region that is sufficient to direct expression to dorsal neural tube progenitors that give rise to neurons in the dorsal spinal cord in chick and mouse. DNA binding motifs for Paired homeodomain (Pd-HD) and zinc finger (ZF) transcription factors are required for enhancer activity. Mutations in these sequences implicate the Pd-HD motif for activator function and the ZF motif for repressor function. Although no repressor transcription factor was identified, both PAX6 and SOX3 can increase enhancer activity in reporter assays. Thus, Ptf1a is regulated by active and repressive inputs integrated through multiple sequence elements within a highly conserved sequence downstream of the Ptf1a gene. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons.

    PubMed

    Yamada, Mayumi; Seto, Yusuke; Taya, Shinichiro; Owa, Tomoo; Inoue, Yukiko U; Inoue, Takayoshi; Kawaguchi, Yoshiya; Nabeshima, Yo-Ichi; Hoshino, Mikio

    2014-04-02

    In the cerebellum, the bHLH transcription factors Ptf1a and Atoh1 are expressed in distinct neuroepithelial regions, the ventricular zone (VZ) and the rhombic lip (RL), and are required for producing GABAergic and glutamatergic neurons, respectively. However, it is unclear whether Ptf1a or Atoh1 is sufficient for specifying GABAergic or glutamatergic neuronal fates. To test this, we generated two novel knock-in mouse lines, Ptf1a(Atoh1) and Atoh1(Ptf1a), that are designed to express Atoh1 and Ptf1a ectopically in the VZ and RL, respectively. In Ptf1a(Atoh1) embryos, ectopically Atoh1-expressing VZ cells produced glutamatergic neurons, including granule cells and deep cerebellar nuclei neurons. Correspondingly, in Atoh1(Ptf1a) animals, ectopically Ptf1a-expressing RL cells produced GABAergic populations, such as Purkinje cells and GABAergic interneurons. Consistent results were also obtained from in utero electroporation of Ptf1a or Atoh1 into embryonic cerebella, suggesting that Ptf1a and Atoh1 are essential and sufficient for GABAergic versus glutamatergic specification in the neuroepithelium. Furthermore, birthdating analyses with BrdU in the knock-in mice or with electroporation studies showed that ectopically produced fate-changed neuronal types were generated at temporal schedules closely simulating those of the wild-type RL and VZ, suggesting that the VZ and RL share common temporal information. Observations of knock-in brains as well as electroporated brains revealed that Ptf1a and Atoh1 mutually negatively regulate their expression, probably contributing to formation of non-overlapping neuroepithelial domains. These findings suggest that Ptf1a and Atoh1 specify spatial identities of cerebellar neuron progenitors in the neuroepithelium, leading to appropriate production of GABAergic and glutamatergic neurons, respectively.

  7. Program Specificity for Ptf1a in Pancreas versus Neural Tube Development Correlates with Distinct Collaborating Cofactors and Chromatin Accessibility

    PubMed Central

    Meredith, David M.; Borromeo, Mark D.; Deering, Tye G.; Casey, Bradford H.; Savage, Trisha K.; Mayer, Paul R.; Hoang, Chinh; Tung, Kuang-Chi; Kumar, Manonmani; Shen, Chengcheng; Swift, Galvin H.

    2013-01-01

    The lineage-specific basic helix-loop-helix transcription factor Ptf1a is a critical driver for development of both the pancreas and nervous system. How one transcription factor controls diverse programs of gene expression is a fundamental question in developmental biology. To uncover molecular strategies for the program-specific functions of Ptf1a, we identified bound genomic regions in vivo during development of both tissues. Most regions bound by Ptf1a are specific to each tissue, lie near genes needed for proper formation of each tissue, and coincide with regions of open chromatin. The specificity of Ptf1a binding is encoded in the DNA surrounding the Ptf1a-bound sites, because these regions are sufficient to direct tissue-restricted reporter expression in transgenic mice. Fox and Sox factors were identified as potential lineage-specific modifiers of Ptf1a binding, since binding motifs for these factors are enriched in Ptf1a-bound regions in pancreas and neural tube, respectively. Of the Fox factors expressed during pancreatic development, Foxa2 plays a major role. Indeed, Ptf1a and Foxa2 colocalize in embryonic pancreatic chromatin and can act synergistically in cell transfection assays. Together, these findings indicate that lineage-specific chromatin landscapes likely constrain the DNA binding of Ptf1a, and they identify Fox and Sox gene families as part of this process. PMID:23754747

  8. A novel subset of enteric neurons revealed by ptf1a:GFP in the developing zebrafish enteric nervous system.

    PubMed

    Uribe, Rosa A; Gu, Tiffany; Bronner, Marianne E

    2016-03-01

    The enteric nervous system, the largest division of the peripheral nervous system, is derived from vagal neural crest cells that invade and populate the entire length of the gut to form diverse neuronal subtypes. Here, we identify a novel population of neurons within the enteric nervous system of zebrafish larvae that express the transgenic marker ptf1a:GFP within the midgut. Genetic lineage analysis reveals that enteric ptf1a:GFP(+) cells are derived from the neural crest and that most ptf1a:GFP(+) neurons express the neurotransmitter 5HT, demonstrating that they are serotonergic. This transgenic line, Tg(ptf1a:GFP), provides a novel neuronal marker for a subpopulation of neurons within the enteric nervous system, and highlights the possibility that Ptf1a may act as an important transcription factor for enteric neuron development. © 2016 Wiley Periodicals, Inc.

  9. The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

    PubMed Central

    Krah, Nathan M; De La O, Jean-Paul; Swift, Galvin H; Hoang, Chinh Q; Willet, Spencer G; Chen Pan, Fong; Cash, Gabriela M; Bronner, Mary P; Wright, Christopher VE; MacDonald, Raymond J; Murtaugh, L Charles

    2015-01-01

    Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas. DOI: http://dx.doi.org/10.7554/eLife.07125.001 PMID:26151762

  10. Pancreatic Agenesis due to Compound Heterozygosity for a Novel Enhancer and Truncating Mutation in the PTF1A Gene.

    PubMed

    Gabbay, Monica; Ellard, Sian; De Franco, Elisa; Moisés, Regina S

    2017-09-01

    Neonatal diabetes, defined as the onset of diabetes within the first six months of life, is very rarely caused by pancreatic agenesis. Homozygous truncating mutations in the PTF1A gene, which encodes a transcriptional factor, have been reported in patients with pancreatic and cerebellar agenesis, whilst mutations located in a distal pancreatic-specific enhancer cause isolated pancreatic agenesis. We report an infant, born to healthy non-consanguineous parents, with neonatal diabetes due to pancreatic agenesis. Initial genetic investigation included sequencing of KCNJ11, ABCC8 and INS genes, but no mutations were found. Following this, 22 neonatal diabetes associated genes were analyzed by a next generation sequencing assay. We found compound heterozygous mutations in the PTF1A gene: A frameshift mutation in exon 1 (c.437_462 del, p.Ala146Glyfs*116) and a mutation affecting a highly conserved nucleotide within the distal pancreatic enhancer (g.23508442A>G). Both mutations were confirmed by Sanger sequencing. Isolated pancreatic agenesis resulting from compound heterozygosity for truncating and enhancer mutations in the PTF1A gene has not been previously reported. This report broadens the spectrum of mutations causing pancreatic agenesis.

  11. Pancreatic Agenesis due to Compound Heterozygosity for a Novel Enhancer and Truncating Mutation in the PTF1A Gene

    PubMed Central

    Gabbay, Monica; Ellard, Sian; De Franco, Elisa; Moisés, Regina S.

    2017-01-01

    Neonatal diabetes, defined as the onset of diabetes within the first six months of life, is very rarely caused by pancreatic agenesis. Homozygous truncating mutations in the PTF1A gene, which encodes a transcriptional factor, have been reported in patients with pancreatic and cerebellar agenesis, whilst mutations located in a distal pancreatic-specific enhancer cause isolated pancreatic agenesis. We report an infant, born to healthy non-consanguineous parents, with neonatal diabetes due to pancreatic agenesis. Initial genetic investigation included sequencing of KCNJ11, ABCC8 and INS genes, but no mutations were found. Following this, 22 neonatal diabetes associated genes were analyzed by a next generation sequencing assay. We found compound heterozygous mutations in the PTF1A gene: A frameshift mutation in exon 1 (c.437_462 del, p.Ala146Glyfs*116) and a mutation affecting a highly conserved nucleotide within the distal pancreatic enhancer (g.23508442A>G). Both mutations were confirmed by Sanger sequencing. Isolated pancreatic agenesis resulting from compound heterozygosity for truncating and enhancer mutations in the PTF1A gene has not been previously reported. This report broadens the spectrum of mutations causing pancreatic agenesis. PMID:28663161

  12. Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment.

    PubMed

    Jakubison, Brad L; Schweickert, Patrick G; Moser, Sarah E; Yang, Yi; Gao, Hongyu; Scully, Kathleen; Itkin-Ansari, Pamela; Liu, Yunlong; Konieczny, Stephen F

    2018-05-02

    Pancreatic acinar cells synthesize, package, and secrete digestive enzymes into the duodenum to aid in nutrient absorption and meet metabolic demands. When exposed to cellular stresses and insults, acinar cells undergo a dedifferentiation process termed acinar-ductal metaplasia (ADM). ADM lesions with oncogenic mutations eventually give rise to pancreatic ductal adenocarcinoma (PDAC). In healthy pancreata, the basic helix-loop-helix (bHLH) factors MIST1 and PTF1a coordinate an acinar-specific transcription network that maintains the highly developed differentiation status of the cells, protecting the pancreas from undergoing a transformative process. However, when MIST1 and PTF1a gene expression is silenced, cells are more prone to progress to PDAC. In this study, we tested whether induced MIST1 or PTF1a expression in PDAC cells could (i) re-establish the transcriptional program of differentiated acinar cells and (ii) simultaneously reduce tumor cell properties. As predicted, PTF1a induced gene expression of digestive enzymes and acinar-specific transcription factors, while MIST1 induced gene expression of vesicle trafficking molecules as well as activation of unfolded protein response components, all of which are essential to handle the high protein production load that is characteristic of acinar cells. Importantly, induction of PTF1a in PDAC also influenced cancer-associated properties, leading to a decrease in cell proliferation, cancer stem cell numbers, and repression of key ATP-binding cassette efflux transporters resulting in heightened sensitivity to gemcitabine. Thus, activation of pancreatic bHLH transcription factors rescues the acinar gene program and decreases tumorigenic properties in pancreatic cancer cells, offering unique opportunities to develop novel therapeutic intervention strategies for this deadly disease. © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  13. Ascl1 as a Novel Player in the Ptf1a Transcriptional Network for GABAergic Cell Specification in the Retina

    PubMed Central

    Parlier, Damien; Pretto, Silvia; Hamdache, Johanna; Vernier, Philippe; Locker, Morgane; Bellefroid, Eric; Perron, Muriel

    2014-01-01

    In contrast with the wealth of data involving bHLH and homeodomain transcription factors in retinal cell type determination, the molecular bases underlying neurotransmitter subtype specification is far less understood. Using both gain and loss of function analyses in Xenopus, we investigated the putative implication of the bHLH factor Ascl1 in this process. We found that in addition to its previously characterized proneural function, Ascl1 also contributes to the specification of the GABAergic phenotype. We showed that it is necessary for retinal GABAergic cell genesis and sufficient in overexpression experiments to bias a subset of retinal precursor cells towards a GABAergic fate. We also analysed the relationships between Ascl1 and a set of other bHLH factors using an in vivo ectopic neurogenic assay. We demonstrated that Ascl1 has unique features as a GABAergic inducer and is epistatic over factors endowed with glutamatergic potentialities such as Neurog2, NeuroD1 or Atoh7. This functional specificity is conferred by the basic DNA binding domain of Ascl1 and involves a specific genetic network, distinct from that underlying its previously demonstrated effects on catecholaminergic differentiation. Our data show that GABAergic inducing activity of Ascl1 requires the direct transcriptional regulation of Ptf1a, providing therefore a new piece of the network governing neurotransmitter subtype specification during retinogenesis. PMID:24643195

  14. LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function.

    PubMed

    Holmstrom, Sam R; Deering, Tye; Swift, Galvin H; Poelwijk, Frank J; Mangelsdorf, David J; Kliewer, Steven A; MacDonald, Raymond J

    2011-08-15

    We have determined the cistrome and transcriptome for the nuclear receptor liver receptor homolog-1 (LRH-1) in exocrine pancreas. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq analyses reveal that LRH-1 directly induces expression of genes encoding digestive enzymes and secretory and mitochondrial proteins. LRH-1 cooperates with the pancreas transcription factor 1-L complex (PTF1-L) in regulating exocrine pancreas-specific gene expression. Elimination of LRH-1 in adult mice reduced the concentration of several lipases and proteases in pancreatic fluid and impaired pancreatic fluid secretion in response to cholecystokinin. Thus, LRH-1 is a key regulator of the exocrine pancreas-specific transcriptional network required for the production and secretion of pancreatic fluid.

  15. PTF 10fqs: A LUMINOUS RED NOVA IN THE SPIRAL GALAXY MESSIER 99

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kasliwal, Mansi M.; Kulkarni, Shri R.; Quimby, Robert M.

    2011-04-01

    The Palomar Transient Factory (PTF) is systematically charting the optical transient and variable sky. A primary science driver of PTF is building a complete inventory of transients in the local universe (distance less than 200 Mpc). Here, we report the discovery of PTF 10fqs, a transient in the luminosity 'gap' between novae and supernovae. Located on a spiral arm of Messier 99, PTF 10fqs has a peak luminosity of M{sub r} = -12.3, red color (g - r = 1.0), and is slowly evolving (decayed by 1 mag in 68 days). It has a spectrum dominated by intermediate-width H{alpha} ({approx}930more » km s{sup -1}) and narrow calcium emission lines. The explosion signature (the light curve and spectra) is overall similar to that of M85 OT2006-1, SN 2008S, and NGC 300 OT. The origin of these events is shrouded in mystery and controversy (and in some cases, in dust). PTF 10fqs shows some evidence of a broad feature (around 8600 A) that may suggest very large velocities ({approx}10,000 km s{sup -1}) in this explosion. Ongoing surveys can be expected to find a few such events per year. Sensitive spectroscopy, infrared monitoring, and statistics (e.g., disk versus bulge) will eventually make it possible for astronomers to unravel the nature of these mysterious explosions.« less

  16. Spectroscopic and Photometric Analysis of the HW Vir Star PTF1 J011339.09+225739.1

    NASA Astrophysics Data System (ADS)

    Wolz, Maximilian; Kupfer, Thomas; Drechsel, Horst; Heber, Ulrich; Irrgang, Andreas; Hermes, J. J.; Bloemen, Steven; Levitan, David; Dhillon, Vik; Marsh, TomR.

    2018-05-01

    HW Vir systems are rare eclipsing binary systems including a subdwarf B star (sdB) with a faint companion, mostly M-dwarfs. Up to now, 19 HW Vir systems have been published, three of them with substellar companions. We report the spectroscopic as well as photometric observation of the eclipsing sdB binary PTF1 J011339.09+225739.1 (PTF1 J0113) in a close (a=0.722 ± 0.023 R⊙), short period (P = 0.0933731(3)d) orbit. A quantitative spectral analysis of the sdB yields Te.=29280 ± 720 K, log(g)=5.77 ± 0.09 dex, and log(y)=-2.32 ± 0.12. The circular orbital velocity of the sdB of K1=74.2 ± 1.7 km s-1 is derived from the radial velocity curve. Except for the strong reflection effect, no other light contribution of the companion could be detected. The light curves - recorded with ULTRACAM - were analyzed using the Wilson-Devinney code. We find an inclination angle of i=79.88 ± 0.18∘. Because our first attempts to determine q failed, we calculated large grids of synthetic lightcurves for several mass ratios. Because of degeneracy, good solutions for different mass ratios were found - the one at q = 0.24 is consistent with the sdB's canonical mass (MsdB = 0.47 M⊙). Accordingly, the mass of the companion is M2=0.112 ± 0.003 M⊙. The radii of the two components were also derived: RsdB=0.178 ± 0.006 R⊙ and R2 = 0.158 ± 0.009 R⊙. Thus, the results for the secondary are consistent with an M-dwarf as secondary

  17. iPTF14yb: The First Discovery of a Gamma-Ray Burst Afterglow Independent of a High-energy Trigger

    NASA Astrophysics Data System (ADS)

    Cenko, S. Bradley; Urban, Alex L.; Perley, Daniel A.; Horesh, Assaf; Corsi, Alessandra; Fox, Derek B.; Cao, Yi; Kasliwal, Mansi M.; Lien, Amy; Arcavi, Iair; Bloom, Joshua S.; Butler, Nat R.; Cucchiara, Antonino; de Diego, José A.; Filippenko, Alexei V.; Gal-Yam, Avishay; Gehrels, Neil; Georgiev, Leonid; Jesús González, J.; Graham, John F.; Greiner, Jochen; Kann, D. Alexander; Klein, Christopher R.; Knust, Fabian; Kulkarni, S. R.; Kutyrev, Alexander; Laher, Russ; Lee, William H.; Nugent, Peter E.; Prochaska, J. Xavier; Ramirez-Ruiz, Enrico; Richer, Michael G.; Rubin, Adam; Urata, Yuji; Varela, Karla; Watson, Alan M.; Wozniak, Przemek R.

    2015-04-01

    We report here the discovery by the Intermediate Palomar Transient Factory (iPTF) of iPTF14yb, a luminous ({{M}r}≈ -27.8 mag), cosmological (redshift 1.9733), rapidly fading optical transient. We demonstrate, based on probabilistic arguments and a comparison with the broader population, that iPTF14yb is the optical afterglow of the long-duration gamma-ray burst GRB 140226A. This marks the first unambiguous discovery of a GRB afterglow prior to (and thus entirely independent of) an associated high-energy trigger. We estimate the rate of iPTF14yb-like sources (i.e., cosmologically distant relativistic explosions) based on iPTF observations, inferring an all-sky value of {{\\Re }rel}=610 yr-1 (68% confidence interval of 110-2000 yr-1). Our derived rate is consistent (within the large uncertainty) with the all-sky rate of on-axis GRBs derived by the Swift satellite. Finally, we briefly discuss the implications of the nondetection to date of bona fide “orphan” afterglows (i.e., those lacking detectable high-energy emission) on GRB beaming and the degree of baryon loading in these relativistic jets.

  18. iPTF Discovery of the Rapid “Turn-on” of a Luminous Quasar

    DOE PAGES

    Gezari, S.; Hung, T.; Cenko, S. B.; ...

    2017-01-24

    We present a radio-quiet quasar at z = 0.237 discovered "turning on" by the intermediate Palomar Transient Factory (iPTF). The transient, iPTF 16bco, was detected by iPTF in the nucleus of a galaxy with an archival Sloan Digital Sky Survey spectrum with weak narrow-line emission characteristic of a low-ionization nuclear emission-line region (LINER). Our follow-up spectra show the dramatic appearance of broad Balmer lines and a power-law continuum characteristic of a luminous ( L bol ≈ 10 45 erg s -1) type 1 quasar 12 yr later. Our photometric monitoring with PTF from 2009-2012 and serendipitous X-ray observations from themore » XMM-Newton Slew Survey in 2011 and 2015 constrain the change of state to have occurred less than 500 days before the iPTF detection. An enhanced broad Hα/[O iii] λ5007 line ratio in the type 1 state relative to other changing-look quasars also is suggestive of the most rapid change of state yet observed in a quasar. Here, we argue that the > 10 increase in Eddington ratio inferred from the brightening in UV and X-ray continuum flux is more likely due to an intrinsic change in the accretion rate of a preexisting accretion disk than an external mechanism such as variable obscuration, microlensing, or the tidal disruption of a star. However, further monitoring will be helpful in better constraining the mechanism driving this change of state. The rapid "turn-on" of the quasar is much shorter than the viscous infall timescale of an accretion disk and requires a disk instability that can develop around a ~ 10 8 M ⊙ black hole on timescales less than 1 yr.« less

  19. iPTF14yb: The First Discovery of a Gamma-Ray Burst Afterglow Independent of a High-Energy Trigger

    DOE PAGES

    Cenko, S. Bradley; Urban, Alex L.; Perley, Daniel A.; ...

    2015-04-20

    We report here the discovery by the Intermediate Palomar Transient Factory (iPTF) of iPTF14yb, a luminous (Msub>r ≈ ₋27.8 mag), cosmological (redshift 1.9733), rapidly fading optical transient. We demonstrate, based on probabilistic arguments and a comparison with the broader population, that iPTF14yb is the optical afterglow of the long-duration gamma-ray burst GRB140226A. This marks the rst unambiguous discovery of a GRB afterglow prior to (and thus entirely independent of) an associated high-energy trigger. We estimate the rate of iPTF14yb-like sources (i.e., cosmologically dis- tant relativistic explosions) based on iPTF observations, inferring an all-sky value ofmore » $$R_{rel}$$ = 610yr -1 (68% con dence interval of 110{2000 yr -1). Our derived rate is consistent (within the large uncer- tainty) with the all-sky rate of on-axis GRBs derived by the Swift satellite. Finally, we brie y discuss the implications of the nondetection to date of bona de \\orphan" afterglows (i.e., those lacking de- tectable high-energy emission) on GRB beaming and the degree of baryon loading in these relativistic jets.« less

  20. VizieR Online Data Catalog: Bgri light curves of PTF11kmb and PTF12bho (Lunnan+, 2017)

    NASA Astrophysics Data System (ADS)

    Lunnan, R.; Kasliwal, M. M.; Cao, Y.; Hangard, L.; Yaron, O.; Parrent, J. T.; McCully, C.; Gal-Yam, A.; Mulchaey, J. S.; Ben-Ami, S.; Filippenko, A. V.; Fremling, C.; Fruchter, A. S.; Howell, D. A.; Koda, J.; Kupfer, T.; Kulkarni, S. R.; Laher, R.; Masci, F.; Nugent, P. E.; Ofek, E. O.; Yagi, M.; Yan, L.

    2017-09-01

    The objects PTF11kmb and PTF12bho were found as part of the Palomar Transient Factory (PTF). PTF11kmb was discovered in data taken with the 48 inch Samuel Oschin Telescope at Palomar Observatory (P48) on 2011 August 16.25 at a magnitude r=19.8mag. A spectrum was taken with the Low Resolution Imaging Spectrometer (LRIS) on the 10m Keck I telescope on 2011 August 28, showing SN features consistent with a SN Ib at a redshift z=0.017. The source PTF12bho was discovered in P48 data on 2012 February 25.25 at a magnitude of r=20.52mag. A spectrum taken with LRIS on 2012 March 15 yields z=0.023 based on the SN features. We obtained R- and g-band photometry of PTF11kmb and PTF12bho with the P48 CFH12K camera. Additional follow-up photometry was conducted with the automated 60-inch telescope at Palomar (P60) in the Bgri bands, and with the Las Cumbres Observatory (LCO) Faulkes Telescope North in gri. PTF12bho was also observed with the Swift Ultra-Violet/Optical Telescope (UVOT) and the Swift X-ray telescope (XRT) on 2012 March 17.8 for 3ks. We obtained a sequence of spectra for both PTF11kmb and PTF12bho using LRIS on Keck I, the DEep Imaging Multi-Object Spectrograph (DEIMOS) on the 10m Keck II telescope, and the Double Spectrograph (DPSP) on the 200-inch Hale telescope at Palomar Observatory (P200) spanning 2011 Aug 28.5 to 2014 Jul 2.5. We obtained deep imaging of the fields of PTF11kmb using WFC3/UVIS on the Hubble Space Telescope (HST) through program GO-13864 (PI Kasliwal) in 2015 Jul 12. This program also covered the field of SN 2005E (2014 Dec 10). (1 data file).

  1. A Multiple Ejecta-circumstellar Medium Interaction Model and Its Implications for Superluminous Supernovae iPTF15esb and iPTF13dcc

    NASA Astrophysics Data System (ADS)

    Liu, Liang-Duan; Wang, Ling-Jun; Wang, Shan-Qin; Dai, Zi-Gao

    2018-03-01

    In this paper, we investigate two hydrogen-poor superluminous supernovae (SLSNe), iPTF15esb and iPTF13dcc, whose light curves (LCs) show significant deviation from the smooth rise and fall. The LC of iPTF15esb exhibits two peaks and a post-peak plateau, and furthermore the late-time spectrum of iPTF15esb shows a strong, broad Hα emission line. The early-time LC of iPTF13dcc shows a long-duration bump followed by the second peak. Here, we propose an ejecta-circumstellar medium interaction model involving multiple shells/winds and use it to explain the LCs of iPTF15esb and iPTF13dcc. We find that the theoretical LCs reproduced by this model can match observations of iPTF15esb and iPTF13dcc. Based on our results, we infer that the progenitors have undergone multiple violent mass-loss processes before the SN explosion. In addition, we find that the variation trend of our inferred densities of the shells is consistent with that predicted by the stellar mass-loss history before an SN explosion. Further investigations for other bumpy SLSNe/SNe would shed light on their nature and provide a probe for the mass-loss history of their progenitors.

  2. iPTF14yb: The First Discovery of a Gamma-Ray Burst Afterglow Independent of a High-Energy Trigger

    NASA Technical Reports Server (NTRS)

    Cenko, S. Bradley; Urban, Alex L.; Perley, Daniel A.; Horesh, Assaf; Corsi, Alessandra; Fox, Derek B.; Cao, Yi; Kasliwal, Mansi M.; Lien, Amy; Arcavi, Iair; hide

    2015-01-01

    We report here the discovery by the Intermediate Palomar Transient Factory (iPTF) of iPTF14yb, a luminous (Mr >> -27.8 mag), cosmological (redshift 1.9733), rapidly fading optical transient. We demonstrate, based on probabilistic arguments and a comparison with the broader population, that iPTF14yb is the optical afterglow of the long-duration gamma-ray burst GRB 140226A. This marks the first unambiguous discovery of a GRB afterglow prior to (and thus entirely independent of) an associated high-energy trigger. We estimate the rate of iPTF14yb-like sources (i.e., cosmologically distant relativistic explosions) based on iPTF observations, inferring an all-sky value of Rrel = 610/yr (68% confidence interval of 110-2000/yr). Our derived rate is consistent (within the large uncertainty) with the all-sky rate of on-axis GRBs derived by the Swift satellite. Finally, we briefly discuss the implications of the nondetection to date of bona fide "orphan" afterglows (i.e., those lacking detectable high-energy emission) on GRB beaming and the degree of baryon loading in these relativistic jets.

  3. iPTF16fnl: A Faint and Fast Tidal Disruption Event in an E+A Galaxy

    DOE PAGES

    Blagorodnova, N.; Gezari, S.; Hung, T.; ...

    2017-07-20

    Here, we present ground-based and Swift observations of iPTF16fnl, a likely tidal disruption event (TDE) discovered by the intermediate Palomar Transient Factory (iPTF) survey at 66.6 Mpc. The light curve of the object peaked at an absolute magmore » $${M}_{g}=-17.2$$. The maximum bolometric luminosity (from optical and UV) was $${L}_{p}\\simeq (1.0\\pm 0.15)\\times {10}^{43}$$ erg s -1, an order of magnitude fainter than any other optical TDE discovered so far. The luminosity in the first 60 days is consistent with an exponential decay, with $$L\\propto {e}^{-(t-{t}_{0})/\\tau }$$, where t 0 = 57631.0 (MJD) and $$\\tau \\simeq 15$$ days. The X-ray shows a marginal detection at $${L}_{X}={2.4}_{-1.1}^{1.9}\\times {10}^{39}$$ erg s -1 (Swift X-ray Telescope). No radio counterpart was detected down to 3σ, providing upper limits for monochromatic radio luminosities of $${\

  4. iPTF16fnl: A Faint and Fast Tidal Disruption Event in an E+A Galaxy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Blagorodnova, N.; Gezari, S.; Hung, T.

    Here, we present ground-based and Swift observations of iPTF16fnl, a likely tidal disruption event (TDE) discovered by the intermediate Palomar Transient Factory (iPTF) survey at 66.6 Mpc. The light curve of the object peaked at an absolute magmore » $${M}_{g}=-17.2$$. The maximum bolometric luminosity (from optical and UV) was $${L}_{p}\\simeq (1.0\\pm 0.15)\\times {10}^{43}$$ erg s -1, an order of magnitude fainter than any other optical TDE discovered so far. The luminosity in the first 60 days is consistent with an exponential decay, with $$L\\propto {e}^{-(t-{t}_{0})/\\tau }$$, where t 0 = 57631.0 (MJD) and $$\\tau \\simeq 15$$ days. The X-ray shows a marginal detection at $${L}_{X}={2.4}_{-1.1}^{1.9}\\times {10}^{39}$$ erg s -1 (Swift X-ray Telescope). No radio counterpart was detected down to 3σ, providing upper limits for monochromatic radio luminosities of $${\

  5. iPTF Archival Search for Fast Optical Transients

    NASA Astrophysics Data System (ADS)

    Ho, Anna Y. Q.; Kulkarni, S. R.; Nugent, Peter E.; Zhao, Weijie; Rusu, Florin; Cenko, S. Bradley; Ravi, Vikram; Kasliwal, Mansi M.; Perley, Daniel A.; Adams, Scott M.; Bellm, Eric C.; Brady, Patrick; Fremling, Christoffer; Gal-Yam, Avishay; Kann, David Alexander; Kaplan, David; Laher, Russ R.; Masci, Frank; Ofek, Eran O.; Sollerman, Jesper; Urban, Alex

    2018-02-01

    There has been speculation about a class of relativistic explosions with an initial Lorentz factor Γinit smaller than that of classical gamma-ray bursts (GRBs). These “dirty fireballs” would lack prompt GRB emission but could be pursued via their optical afterglow, appearing as transients that fade overnight. Here we report a search for such transients (that fade by 5-σ in magnitude overnight) in four years of archival photometric data from the intermediate Palomar Transient Factory (iPTF). Our search criteria yielded 50 candidates. Of these, two were afterglows to GRBs that had been found in dedicated follow-up observations to triggers from the Fermi GRB Monitor. Another (iPTF14yb) was a GRB afterglow discovered serendipitously. Eight were spurious artifacts of reference image subtraction, and one was an asteroid. The remaining 38 candidates have red stellar counterparts in external catalogs. The photometric and spectroscopic properties of the counterparts identify these transients as strong flares from M dwarfs of spectral type M3–M7 at distances of d ≈ 0.15–2.1 kpc; three counterparts were already spectroscopically classified as late-type M stars. With iPTF14yb as the only confirmed relativistic outflow discovered independently of a high-energy trigger, we constrain the all-sky rate of transients that peak at m = 18 and fade by Δm = 2 mag in Δt = 3 hr to be 680 {{yr}}-1, with a 68% confidence interval of 119{--}2236 {{yr}}-1. This implies that the rate of visible dirty fireballs is at most comparable to that of the known population of long-duration GRBs.

  6. iPTF Archival Search for Fast Optical Transients

    DOE PAGES

    Ho, Anna Y. Q.; Kulkarni, S. R.; Nugent, Peter E.; ...

    2018-02-09

    There has been speculation about a class of relativistic explosions with an initial Lorentz factor Γ init smaller than that of classical gamma-ray bursts (GRBs). These "dirty fireballs" would lack prompt GRB emission but could be pursued via their optical afterglow, appearing as transients that fade overnight. We report a search for such transients (that fade by 5-σ in magnitude overnight) in four years of archival photometric data from the intermediate Palomar Transient Factory (iPTF). Our search criteria yielded 50 candidates. Of these, two were afterglows to GRBs that had been found in dedicated follow-up observations to triggers from themore » Fermi GRB Monitor. Another (iPTF14yb) was a GRB afterglow discovered serendipitously. Eight were spurious artifacts of reference image subtraction, and one was an asteroid. The remaining 38 candidates have red stellar counterparts in external catalogs. The photometric and spectroscopic properties of the counterparts identify these transients as strong flares from M dwarfs of spectral type M3-M7 at distances of d ≈ 0.15-2.1 kpc; three counterparts were already spectroscopically classified as late-type M stars. With iPTF14yb as the only confirmed relativistic outflow discovered independently of a high-energy trigger, we constrain the all-sky rate of transients that peak at m = 18 and fade by Δm = 2 mag in Δt = 3 hr to be 680 yr -1, with a 68% confidence interval of 1119-2236 yr -1. This implies that the rate of visible dirty fireballs is at most comparable to that of the known population of long-duration GRBs.« less

  7. Discovery, Progenitor and Early Evolution of a Stripped Envelope Supernova iPTF13bvn

    NASA Astrophysics Data System (ADS)

    Cao, Yi; Kasliwal, Mansi M.; Arcavi, Iair; Horesh, Assaf; Hancock, Paul; Valenti, Stefano; Cenko, S. Bradley; Kulkarni, S. R.; Gal-Yam, Avishay; Gorbikov, Evgeny; Ofek, Eran O.; Sand, David; Yaron, Ofer; Graham, Melissa; Silverman, Jeffrey M.; Wheeler, J. Craig; Marion, G. H.; Walker, Emma S.; Mazzali, Paolo; Howell, D. Andrew; Li, K. L.; Kong, A. K. H.; Bloom, Joshua S.; Nugent, Peter E.; Surace, Jason; Masci, Frank; Carpenter, John; Degenaar, Nathalie; Gelino, Christopher R.

    2013-09-01

    The intermediate Palomar Transient Factory reports our discovery of a young supernova, iPTF13bvn, in the nearby galaxy, NGC 5806 (22.5 Mpc). Our spectral sequence in the optical and infrared suggests a Type Ib classification. We identify a blue progenitor candidate in deep pre-explosion imaging within a 2σ error circle of 80 mas (8.7 pc). The candidate has an MB luminosity of -5.52 ± 0.39 mag and a B - I color of 0.25 ± 0.25 mag. If confirmed by future observations, this would be the first direct detection for a progenitor of a Type Ib. Fitting a power law to the early light curve, we find an extrapolated explosion date around 0.6 days before our first detection. We see no evidence of shock cooling. The pre-explosion detection limits constrain the radius of the progenitor to be smaller than a few solar radii. iPTF13bvn is also detected in centimeter and millimeter wavelengths. Fitting a synchrotron self-absorption model to our radio data, we find a mass-loading parameter of 1.3×1012 g cm-1. Assuming a wind velocity of 103 km s-1, we derive a progenitor mass-loss rate of 3 × 10-5 M ⊙ yr-1. Our observations, taken as a whole, are consistent with a Wolf-Rayet progenitor of the supernova iPTF13bvn.

  8. VizieR Online Data Catalog: PTF obs. of a precursor to SNHunt 275 2015 May event (Ofek+, 2016)

    NASA Astrophysics Data System (ADS)

    Ofek, E. O.; Cenko, S. B.; Shaviv, N. J.; Duggan, G.; Strotjohann, N.-L.; Rubin, A.; Kulkarni, S. R.; Gal-Yam, A.; Sullivan, M.; Cao, Y.; Nugent, P. E.; Kasliwal, M. M.; Sollerman, J.; Fransson, C.; Filippenko, A. V.; Perley, D. A.; Yaron, O.; Laher, R.

    2016-08-01

    The Palomar Transient Factory (PTF and iPTF; Law et al. 2009PASP..121.1395L; Rau et al. 2009PASP..121.1334R), using the 48inch Oschin Schmidt telescope, observed the field of SNHunt 275 starting in 2009 March. On 2013 December 12, PTF detected a new source at the location of the event, and the transient was named PTF 13efv (see Figure 1). Three images obtained between 2014 January 23 and April 25 were used as a reference. The PTF R-band photometry is listed in Table1. Most of the optical spectra were obtained with the Low Resolution Imaging Spectrometer (LRIS) on the Keck I 10m telescope, although a few spectra were also taken with the DEep Imaging Multi-Object Spectrograph (DEIMOS) on the Keck II 10m telescope, the Kast spectrograph on the Shane 3m telescope at Lick Observatory, and the Gemini-North Multiobject Spectrograph (GMOS) on the 8m Gemini-N telescope. The first spectrum was obtained during the 2013 December outburst. We used the Swift/UVOT observations of SNHunt 275, since 2008, to construct the bolometric light curve of the transient. The log of Swift-XRT observations, along with the source and background X-ray counts in the individual observations, is given in Table 5. (3 data files).

  9. Spatially resolved analysis of superluminous supernovae PTF 11hrq and PTF 12dam host galaxies

    NASA Astrophysics Data System (ADS)

    Cikota, Aleksandar; De Cia, Annalisa; Schulze, Steve; Vreeswijk, Paul M.; Leloudas, Giorgos; Gal-Yam, Avishay; Perley, Daniel A.; Cikota, Stefan; Kim, Sam; Patat, Ferdinando; Lunnan, Ragnhild; Quimby, Robert; Yaron, Ofer; Yan, Lin; Mazzali, Paolo A.

    2017-08-01

    Superluminous supernovae (SLSNe) are the most luminous supernovae in the Universe. They are found in extreme star-forming galaxies and are probably connected with the death of massive stars. One hallmark of very massive progenitors would be a tendency to explode in very dense, UV-bright and blue regions. In this paper, we investigate the resolved host galaxy properties of two nearby hydrogen-poor SLSNe, PTF 11hrq and PTF 12dam. For both galaxies Hubble Space Telescope multifilter images were obtained. Additionally, we perform integral field spectroscopy of the host galaxy of PTF 11hrq using the Very Large Telescope Multi Unit Spectroscopic Explorer (VLT/MUSE), and investigate the line strength, metallicity and kinematics. Neither PTF 11hrq nor PTF 12dam occurred in the bluest part of their host galaxies, although both galaxies have overall blue UV-to-optical colours. The MUSE data reveal a bright starbursting region in the host of PTF 11hrq, although far from the SN location. The SN exploded close to a region with disturbed kinematics, bluer colour, stronger [O III] and lower metallicity. The host galaxy is likely interacting with a companion. PTF 12dam occurred in one of the brightest pixels, in a starbursting galaxy with a complex morphology and a tidal tail, where interaction is also very likely. We speculate that SLSN explosions may originate from stars generated during star formation episodes triggered by interaction. High-resolution imaging and integral field spectroscopy are fundamental for a better understanding of SLSNe explosion sites and how star formation varies across their host galaxies.

  10. PTF12os and iPTF13bvn: Two stripped-envelope supernovae from low-mass progenitors in NGC 5806

    DOE PAGES

    Fremling, C.; Sollerman, J.; Taddia, F.; ...

    2016-09-22

    Context. In this paper, we investigate two stripped-envelope supernovae (SNe) discovered in the nearby galaxy NGC 5806 by the (intermediate) Palomar Transient Factory [(i)PTF]. These SNe, designated PTF12os/SN 2012P and iPTF13bvn, exploded within ~520 days of one another at a similar distance from the host-galaxy center. We classify PTF12os as a Type IIb SN based on our spectral sequence; iPTF13bvn has previously been classified as Type Ib having a likely progenitor with zero age main sequence (ZAMS) mass below ~17 M ⊙. Because of the shared and nearby host, we are presented with a unique opportunity to compare these twomore » SNe. Aims. Our main objective is to constrain the explosion parameters of iPTF12os and iPTF13bvn, and to put constraints on the SN progenitors. We also aim to spatially map the metallicity in the host galaxy, and to investigate the presence of hydrogen in early-time spectra of both SNe. Methods. We present comprehensive datasets collected on PTF12os and iPTF13bvn, and introduce a new automatic reference-subtraction photometry pipeline (FPipe) currently in use by the iPTF. We perform a detailed study of the light curves (LCs) and spectral evolution of the SNe. The bolometric LCs are modeled using the hydrodynamical code hyde. We analyze early spectra of both SNe to investigate the presence of hydrogen; for iPTF13bvn we also investigate the regions of the Paschen lines in infrared spectra. We perform spectral line analysis of helium and iron lines to map the ejecta structure of both SNe. We use nebular models and late-time spectroscopy to constrain the ZAMS mass of the progenitors. We also perform image registration of ground-based images of PTF12os to archival HST images of NGC 5806 to identify a potential progenitor candidate. Results. We find that our nebular spectroscopy of iPTF13bvn remains consistent with a low-mass progenitor, likely having a ZAMS mass of ~12M ⊙. Our late-time spectroscopy of PTF12os is consistent with a ZAMS mass

  11. PTF1 J191905.19+481506.2—A partially eclipsing AM CVn system discovered in the Palomar transient factory

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Levitan, David; Groot, Paul J.; Prince, Thomas A.

    2014-04-20

    We report on PTF1 J191905.19+481506.2, a newly discovered, partially eclipsing, outbursting AM CVn system found in the Palomar Transient Factory synoptic survey. This is only the second known eclipsing AM CVn system. We use high-speed photometric observations and phase-resolved spectroscopy to establish an orbital period of 22.4559(3) minutes. We also present a long-term light curve and report on the normal and super-outbursts regularly seen in this system, including a super-outburst recurrence time of 36.8(4) days. We use the presence of the eclipse to place upper and lower limits on the inclination of the system and discuss the number of knownmore » eclipsing AM CVn systems versus what would be expected.« less

  12. VizieR Online Data Catalog: PTF 12dam & iPTF 13dcc follow-up (Vreeswijk+, 2017)

    NASA Astrophysics Data System (ADS)

    Vreeswijk, P. M.; Leloudas, G.; Gal-Yam, A.; De Cia, A.; Perley, D. A.; Quimby, R. M.; Waldman, R.; Sullivan, M.; Yan, L.; Ofek, E. O.; Fremling, C.; Taddia, F.; Sollerman, J.; Valenti, S.; Arcavi, I.; Howell, D. A.; Filippenko, A. V.; Cenko, S. B.; Yaron, O.; Kasliwal, M. M.; Cao, Y.; Ben-Ami, S.; Horesh, A.; Rubin, A.; Lunnan, R.; Nugent, P. E.; Laher, R.; Rebbapragada, U. D.; Wozniak, P.; Kulkarni, S. R.

    2017-08-01

    Spectroscopic follow-up observations of PTF 12dam were performed with the Kast Spectrograph at the Lick 3m Shane telescope, and the Low Resolution Imaging Spectrograph (LRIS) at the Keck-I 10m telescope (on Mauna Kea, Hawaii) on 2012 May 20, 21, and 22. The full spectroscopic sequence of PTF 12dam will be presented by R. M. Quimby et al. (2016, in preparation). PTF 12dam was imaged with the Palomar Oschin 48 inch (P48) (i)PTF survey telescope in the Mould R filter, the Palomar 60 inch (P60) and CCD camera in Johnson B and Sloan Digital Sky Survey (SDSS) gri, the Las Cumbres Observatory Global Telescope Network (LCOGT) in SDSS r, and LRIS mounted on the 10m Keck-I telescope in Rs. iPTF 13dcc has not had any exposure in the literature yet. It was flagged as a transient source on 2013 August 29. Spectroscopic follow-up observations spanning 2013 Nov 26 to 2014 Jan 16 were performed with the Double Spectrograph (DBSP) at the Palomar 200 inch (P200), LRIS at Keck-I, and the Inamori-Magellan Areal Camera & Spectrograph (IMACS) at the Magellan Baade telescope, showing iPTF 13dcc to be an SLSN at z=0.4305. iPTF 13dcc was imaged with the P48 Oschin (i)PTF survey telescope in the Mould R filter, the P60 in SDSS gri, the 4.3m Discovery Channel Telescope (DCT, at Lowell Observatory, Arizona) with the Large Monolithic Imager (LMI) in SDSS ri, and finally with the Hubble Space Telescope (HST) Advanced Camera for Surveys (ACS) Wide-Field Camera using filter F625W (under program GO-13858; P.I. A. De Cia). (3 data files).

  13. VizieR Online Data Catalog: PTF stellar rotation periods for Pleiades members (Covey+, 2016)

    NASA Astrophysics Data System (ADS)

    Covey, K. R.; Agueros, M. A.; Law, N. M.; Liu, J.; Ahmadi, A.; Laher, R.; Levitan, D.; Sesar, B.; Surace, J.

    2018-02-01

    We monitored the Pleiades using time allocated to two PTF Key Projects: the PTF/M-dwarfs survey (Law et al. 2011ASPC..448.1367L, 2012ApJ...757..133L) and the PTF Open Cluster Survey (POCS; Agueros et al. 2011ApJ...740..110A; Douglas et al. 2014, J/ApJ/795/161). PTF was a time-domain experiment using the robotic 48-inch Samuel Oschin (P48) telescope at Palomar Observatory, CA, and involved real-time data-reduction and transient-detection pipelines and a dedicated follow-up telescope. The PTF infrastructure is described in Law et al. (2009PASP..121.1395L); we focus here on the components associated with the P48, which we used to conduct our monitoring campaign. The P48 is equipped with the CFH12K mosaic camera, which was significantly modified to optimize its performance on this telescope. The camera has 11 working CCDs, which cover a 7.26 square degree field of view with 92 megapixels at 1" sampling (Rahmer et al. 2008SPIE.7014E..4YR). Under typical observing conditions (1.1" seeing), it delivers 2" full-width half-maximum images that reach a 5σ limiting R~21 mag in 60 s (Law et al. 2010SPIE.7735E..3ML). (2 data files).

  14. EVIDENCE FOR A COMPACT WOLF-RAYET PROGENITOR FOR THE TYPE Ic SUPERNOVA PTF 10vgv

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Corsi, A.; Ofek, E. O.; Gal-Yam, A.

    We present the discovery of PTF 10vgv, a Type Ic supernova (SN) detected by the Palomar Transient Factory, using the Palomar 48 inch telescope (P48). R-band observations of the PTF 10vgv field with P48 probe the SN emission from its very early phases (about two weeks before R-band maximum) and set limits on its flux in the week prior to the discovery. Our sensitive upper limits and early detections constrain the post-shock-breakout luminosity of this event. Via comparison to numerical (analytical) models, we derive an upper-limit of R {approx}< 4.5 R{sub Sun} (R {approx}< 1 R{sub Sun }) on themore » radius of the progenitor star, a direct indication in favor of a compact Wolf-Rayet star. Applying a similar analysis to the historical observations of SN 1994I yields R {approx}< 1/4 R{sub Sun} for the progenitor radius of this SN.« less

  15. Color Me Intrigued: the Discovery of iPTF 16fnm, a Supernova 2002cx-like Object

    DOE PAGES

    Miller, A. A.; Kasliwal, M. M.; Cao, Y.; ...

    2017-10-12

    Modern wide-field, optical time-domain surveys must solve a basic optimization problem: maximize the number of transient discoveries or minimize the follow-up needed for the new discoveries. Here, we describe the Color Me Intrigued experiment, the first from the intermediate Palomar Transient Factory (iPTF) to search for transients simultaneously in themore » $$g_\\mathrm{PTF}$$- and $$R_\\mathrm{PTF}$$-bands. During the course of this experiment we discovered iPTF$$\\,$$16fnm, a new member of the 02cx-like subclass of type Ia supernovae (SNe). iPTF$$\\,$$16fnm peaked at $$M_{g_\\mathrm{PTF}} = -15.09 \\pm 0.17 \\; \\mathrm{mag}$$, making it the second least-luminous known type Ia SN. iPTF 16fnm exhibits all the hallmarks of the 02cx-like class: (i) low luminosity at peak, (ii) low ejecta velocities, and (iii) a non-nebular spectra several months after peak. Spectroscopically, iPTF$$\\,$$16fnm exhibits a striking resemblence to 2 other low-luminosity 02cx-like SNe: SNe 2007qd and 2010ae. iPTF$$\\,$$16fnm and SN 2005hk decline at nearly the same rate, despite a 3 mag difference in brightness at peak. When considering the full subclass of 02cx-like SNe, we do not find evidence for a tight correlation between peak luminosity and decline rate in either the $g'$ or $r'$ band. We further examine the $g' - r'$ evolution of 02cx-like SNe and find that their unique color evolution can be used to separate them from 91bg-like and normal type Ia SNe. This selection function will be especially important in the spectroscopically incomplete Zwicky Transient Facility/Large Synoptic Survey Telescope era. We measure the relative rate of 02cx-like SNe to normal SNe Ia and find $$r_{N_{02cx}/N_{Ia}} = 25^{+75}_{-18.5}\\%$$. Finally, we close by recommending that LSST periodically evaluate, and possibly update, its observing cadence to maximize transient science.« less

  16. Color Me Intrigued: the Discovery of iPTF 16fnm, a Supernova 2002cx-like Object

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Miller, A. A.; Kasliwal, M. M.; Cao, Y.

    Modern wide-field, optical time-domain surveys must solve a basic optimization problem: maximize the number of transient discoveries or minimize the follow-up needed for the new discoveries. Here, we describe the Color Me Intrigued experiment, the first from the intermediate Palomar Transient Factory (iPTF) to search for transients simultaneously in themore » $$g_\\mathrm{PTF}$$- and $$R_\\mathrm{PTF}$$-bands. During the course of this experiment we discovered iPTF$$\\,$$16fnm, a new member of the 02cx-like subclass of type Ia supernovae (SNe). iPTF$$\\,$$16fnm peaked at $$M_{g_\\mathrm{PTF}} = -15.09 \\pm 0.17 \\; \\mathrm{mag}$$, making it the second least-luminous known type Ia SN. iPTF 16fnm exhibits all the hallmarks of the 02cx-like class: (i) low luminosity at peak, (ii) low ejecta velocities, and (iii) a non-nebular spectra several months after peak. Spectroscopically, iPTF$$\\,$$16fnm exhibits a striking resemblence to 2 other low-luminosity 02cx-like SNe: SNe 2007qd and 2010ae. iPTF$$\\,$$16fnm and SN 2005hk decline at nearly the same rate, despite a 3 mag difference in brightness at peak. When considering the full subclass of 02cx-like SNe, we do not find evidence for a tight correlation between peak luminosity and decline rate in either the $g'$ or $r'$ band. We further examine the $g' - r'$ evolution of 02cx-like SNe and find that their unique color evolution can be used to separate them from 91bg-like and normal type Ia SNe. This selection function will be especially important in the spectroscopically incomplete Zwicky Transient Facility/Large Synoptic Survey Telescope era. We measure the relative rate of 02cx-like SNe to normal SNe Ia and find $$r_{N_{02cx}/N_{Ia}} = 25^{+75}_{-18.5}\\%$$. Finally, we close by recommending that LSST periodically evaluate, and possibly update, its observing cadence to maximize transient science.« less

  17. iPTF 16asu: A Luminous, Rapidly Evolving, and High-velocity Supernova

    DOE PAGES

    Whitesides, L.; Lunnan, R.; Kasliwal, M. M.; ...

    2017-12-18

    Wide-field surveys are discovering a growing number of rare transients whose physical origin is not yet well understood. We present optical and UV data and analysis of intermediate Palomar Transient Factory (iPTF) 16asu, a luminous, rapidly evolving, high-velocity, stripped-envelope supernova (SN). With a rest-frame rise time of just four days and a peak absolute magnitude of M g = -20.4 mag, the light curve of iPTF 16asu is faster and more luminous than that of previous rapid transients. The spectra of iPTF 16asu show a featureless blue continuum near peak that develops into an SN Ic-BL spectrum on the decline.more » We show that while the late-time light curve could plausibly be powered by 56Ni decay, the early emission requires a different energy source. Nondetections in the X-ray and radio strongly constrain the energy coupled to relativistic ejecta to be at most comparable to the class of low-luminosity gamma-ray bursts (GRBs). We suggest that the early emission may have been powered by either a rapidly spinning-down magnetar or by shock breakout in an extended envelope of a very energetic explosion. In either scenario a central engine is required, making iPTF 16asu an intriguing transition object between superluminous SNe, SNe Ic-BL, and low-luminosity GRBs.« less

  18. iPTF 16asu: A Luminous, Rapidly Evolving, and High-velocity Supernova

    NASA Astrophysics Data System (ADS)

    Whitesides, L.; Lunnan, R.; Kasliwal, M. M.; Perley, D. A.; Corsi, A.; Cenko, S. B.; Blagorodnova, N.; Cao, Y.; Cook, D. O.; Doran, G. B.; Frederiks, D. D.; Fremling, C.; Hurley, K.; Karamehmetoglu, E.; Kulkarni, S. R.; Leloudas, G.; Masci, F.; Nugent, P. E.; Ritter, A.; Rubin, A.; Savchenko, V.; Sollerman, J.; Svinkin, D. S.; Taddia, F.; Vreeswijk, P.; Wozniak, P.

    2017-12-01

    Wide-field surveys are discovering a growing number of rare transients whose physical origin is not yet well understood. Here we present optical and UV data and analysis of intermediate Palomar Transient Factory (iPTF) 16asu, a luminous, rapidly evolving, high-velocity, stripped-envelope supernova (SN). With a rest-frame rise time of just four days and a peak absolute magnitude of {M}{{g}}=-20.4 mag, the light curve of iPTF 16asu is faster and more luminous than that of previous rapid transients. The spectra of iPTF 16asu show a featureless blue continuum near peak that develops into an SN Ic-BL spectrum on the decline. We show that while the late-time light curve could plausibly be powered by 56Ni decay, the early emission requires a different energy source. Nondetections in the X-ray and radio strongly constrain the energy coupled to relativistic ejecta to be at most comparable to the class of low-luminosity gamma-ray bursts (GRBs). We suggest that the early emission may have been powered by either a rapidly spinning-down magnetar or by shock breakout in an extended envelope of a very energetic explosion. In either scenario a central engine is required, making iPTF 16asu an intriguing transition object between superluminous SNe, SNe Ic-BL, and low-luminosity GRBs.

  19. PTF11mnb: First analog of supernova 2005bf. Long-rising, double-peaked supernova Ic from a massive progenitor

    NASA Astrophysics Data System (ADS)

    Taddia, F.; Sollerman, J.; Fremling, C.; Karamehmetoglu, E.; Quimby, R. M.; Gal-Yam, A.; Yaron, O.; Kasliwal, M. M.; Kulkarni, S. R.; Nugent, P. E.; Smadja, G.; Tao, C.

    2018-01-01

    Aims: We study PTF11mnb, a He-poor supernova (SN) whose light curves resemble those of SN 2005bf, a peculiar double-peaked stripped-envelope (SE) SN, until the declining phase after the main peak. We investigate the mechanism powering its light curve and the nature of its progenitor star. Methods: Optical photometry and spectroscopy of PTF11mnb are presented. We compared light curves, colors and spectral properties to those of SN 2005bf and normal SE SNe. We built a bolometric light curve and modeled this light curve with the SuperNova Explosion Code (SNEC) hydrodynamical code explosion of a MESA progenitor star and semi-analytic models. Results: The light curve of PTF11mnb turns out to be similar to that of SN 2005bf until 50 d when the main (secondary) peaks occur at -18.5 mag. The early peak occurs at 20 d and is about 1.0 mag fainter. After the main peak, the decline rate of PTF11mnb is remarkably slower than what was observed in SN 2005bf, and it traces well the 56Co decay rate. The spectra of PTF11mnb reveal a SN Ic and have no traces of He unlike in the case of SN Ib 2005bf, although they have velocities comparable to those of SN 2005bf. The whole evolution of the bolometric light curve is well reproduced by the explosion of a massive (Mej = 7.8 M⊙), He-poor star characterized by a double-peaked 56Ni distribution, a total 56Ni mass of 0.59 M⊙, and an explosion energy of 2.2 × 1051 erg. Alternatively, a normal SN Ib/c explosion (M(56Ni) = 0.11 M⊙, EK = 0.2 × 1051 erg, Mej = 1 M⊙) can power the first peak while a magnetar, with a magnetic field characterized by B = 5.0 × 1014 G, and a rotation period of P = 18.1 ms, provides energy for the main peak. The early g-band light curve can be fit with a shock-breakout cooling tail or an extended envelope model from which a radius of at least 30 R⊙ is obtained. Conclusions: We presented a scenario where PTF11mnb was the explosion of a massive, He-poor star, characterized by a double-peaked 56Ni

  20. PTF11mnb: First analog of supernova 2005bf: Long-rising, double-peaked supernova Ic from a massive progenitor*

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Taddia, F.; Sollerman, J.; Fremling, C.

    The aim is to study PTF11mnb, a He-poor supernova (SN) whose light curves resemble those of SN 2005bf, a peculiar double-peaked stripped-envelope (SE) SN, until the declining phase after the main peak. We investigate the mechanism powering its light curve and the nature of its progenitor star. Methods. Optical photometry and spectroscopy of PTF11mnb are presented. We compared light curves, colors and spectral properties to those of SN 2005bf and normal SE SNe. We built a bolometric light curve and modeled this light curve with the SuperNova Explosion Code (SNEC) hydrodynamical code explosion of a MESA progenitor star and semi-analyticmore » models. Results. The light curve of PTF11mnb turns out to be similar to that of SN 2005bf until ~50 d when the main (secondary) peaks occur at -18.5 mag. The early peak occurs at ~20 d and is about 1.0 mag fainter. After the main peak, the decline rate of PTF11mnb is remarkably slower than what was observed in SN 2005bf, and it traces well the 56Co decay rate. The spectra of PTF11mnb reveal a SN Ic and have no traces of He unlike in the case of SN Ib 2005bf, although they have velocities comparable to those of SN 2005bf. The whole evolution of the bolometric light curve is well reproduced by the explosion of a massive (M ej = 7.8 M ⊙ ), He-poor star characterized by a double-peaked 56 Ni distribution, a total 56 Ni mass of 0.59 M ⊙ , and an explosion energy of 2.2 × 10 51 erg. Alternatively, a normal SN Ib/c explosion (M( 56Ni) = 0.11 M ⊙ , E K = 0.2 × 10 51 erg, M ej = 1 M ⊙ ) can power the first peak while a magnetar, with a magnetic field characterized by B = 5.0 × 10 14 G, and a rotation period of P = 18.1 ms, provides energy for the main peak. The early g-band light curve can be fit with a shock-breakout cooling tail or an extended envelope model from which a radius of at least 30 R ⊙ is obtained. Conclusions. We presented a scenario where PTF11mnb was the explosion of a massive, He-poor star, characterized

  1. iPTF report of bright transients

    NASA Astrophysics Data System (ADS)

    Cannella, Chris; Kuesters, Daniel; Ferretti, Raphael; Blagorodnova, Nadejda; Adams, Scott; Kupfer, Thomas; Neill, James D.; Walters, Richard; Yan, Lin; Kulkarni, Shri

    2017-02-01

    The intermediate Palomar Transient Factory (iPTF; ATel #4807) reports the following bright ( Our automated candidate vetting to distinguish a real astrophysical source (1.0) from bogus artifacts (0.0) is powered by three generations of machine learning algorithms: RB2 (Brink et al. 2013MNRAS.435.1047B), RB4 (Rebbapragada et al. 2015AAS...22543402R), and RB5 (Wozniak et al. 2013AAS...22143105W).

  2. iPTF17cw: An Engine-driven Supernova Candidate Discovered Independent of a Gamma-Ray Trigger

    NASA Astrophysics Data System (ADS)

    Corsi, A.; Cenko, S. B.; Kasliwal, M. M.; Quimby, R.; Kulkarni, S. R.; Frail, D. A.; Goldstein, A. M.; Blagorodnova, N.; Connaughton, V.; Perley, D. A.; Singer, L. P.; Copperwheat, C. M.; Fremling, C.; Kupfer, T.; Piascik, A. S.; Steele, I. A.; Taddia, F.; Vedantham, H.; Kutyrev, A.; Palliyaguru, N. T.; Roberts, O.; Sollerman, J.; Troja, E.; Veilleux, S.

    2017-09-01

    We present the discovery, classification, and radio-to-X-ray follow-up observations of iPTF17cw, a broad-lined (BL) type Ic supernova (SN) discovered by the intermediate Palomar Transient Factory (iPTF). Although it is unrelated to the gravitational wave trigger, this SN was discovered as a happy by-product of the extensive observational campaign dedicated to the follow-up of Advanced LIGO event GW 170104. The spectroscopic properties and inferred peak bolometric luminosity of iPTF17cw are most similar to the gamma-ray-burst (GRB)-associated SN, SN 1998bw, while the shape of the r-band light curve is most similar to that of the relativistic SN, SN 2009bb. Karl G. Jansky Very Large Array (VLA) observations of the iPTF17cw field reveal a radio counterpart ≈10 times less luminous than SN 1998bw, and with a peak radio luminosity comparable to that of SN 2006aj/GRB 060218 and SN 2010bh/GRB 100316D. Our radio observations of iPTF17cw imply a relativistically expanding outflow. However, further late-time observations with the VLA in its most extended configuration are needed to confirm fading of the iPTF17cw radio counterpart at all frequencies. X-ray observations carried out with Chandra reveal the presence of an X-ray counterpart with a luminosity similar to that of SN 2010bh/GRB 100316D. Searching the Fermi catalog for possible γ-rays reveals that GRB 161228B is spatially and temporally compatible with iPTF17cw. The similarity to SN 1998bw and SN 2009bb, the radio and X-ray detections, and the potential association with GRB 161228B all point to iPTF17cw being a new candidate member of the rare sample of optically discovered engine-driven BL-Ic SNe associated with relativistic ejecta.

  3. iPTF17cw: An Engine-driven Supernova Candidate Discovered Independent of a Gamma-Ray Trigger

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Corsi, A.; Palliyaguru, N. T.; Cenko, S. B.

    We present the discovery, classification, and radio-to-X-ray follow-up observations of iPTF17cw, a broad-lined (BL) type Ic supernova (SN) discovered by the intermediate Palomar Transient Factory (iPTF). Although it is unrelated to the gravitational wave trigger, this SN was discovered as a happy by-product of the extensive observational campaign dedicated to the follow-up of Advanced LIGO event GW 170104. The spectroscopic properties and inferred peak bolometric luminosity of iPTF17cw are most similar to the gamma-ray-burst (GRB)-associated SN, SN 1998bw, while the shape of the r -band light curve is most similar to that of the relativistic SN, SN 2009bb. Karl G.more » Jansky Very Large Array (VLA) observations of the iPTF17cw field reveal a radio counterpart ≈10 times less luminous than SN 1998bw, and with a peak radio luminosity comparable to that of SN 2006aj/GRB 060218 and SN 2010bh/GRB 100316D. Our radio observations of iPTF17cw imply a relativistically expanding outflow. However, further late-time observations with the VLA in its most extended configuration are needed to confirm fading of the iPTF17cw radio counterpart at all frequencies. X-ray observations carried out with Chandra reveal the presence of an X-ray counterpart with a luminosity similar to that of SN 2010bh/GRB 100316D. Searching the Fermi catalog for possible γ -rays reveals that GRB 161228B is spatially and temporally compatible with iPTF17cw. The similarity to SN 1998bw and SN 2009bb, the radio and X-ray detections, and the potential association with GRB 161228B all point to iPTF17cw being a new candidate member of the rare sample of optically discovered engine-driven BL-Ic SNe associated with relativistic ejecta.« less

  4. EVLA Observations of PTF10vdl

    NASA Astrophysics Data System (ADS)

    Kasliwal, Mansi; Kulkarni, Shri; Arcavi, Iair; Gal-Yam, Avishay; Quimby, Robert; Ofek, Eran; Frail, Dale; Yuan, Fang; Akerlof, Carl; McKay, Time

    2010-09-01

    We triggered our NRAO Target Of Opportunity program "Exploring Transients in the Local Universe" and used the Expanded Very Large Array (EVLA) to observe the field of view toward PTF10vdl (ATEL#2862 an ATEL#2863), discovered by the <a href='http://www.astro.caltech.edu/ptf'> Palomar Transient Factory a>. The EVLA observations were made on September 18.26 UT at a center frequency of 8.46 GHz.

  5. CARMA Observations of PTF10vdl

    NASA Astrophysics Data System (ADS)

    Carpenter, John M.

    2010-09-01

    We used the Combined Array for Research in Millimeter-wave Astronomy (CARMA) to observe the field of view toward PTF10vdl (ATEL#2862), discovered by the <a href='http://www.astro.caltech.edu/ptf'> Palomar Transient Factory a>. The observations began at September 18, 2010 04:18 UT and continued for 4.9 hours. The mean frequency of the observations was 97.5 GHz with a total bandwidth of 8 GHz.

  6. Tidal Disruption Events: From iPTF to ZTF

    NASA Astrophysics Data System (ADS)

    Hung, Tiara; Gezari, Suvi; Cenko, Bradley; Kulkarni, Shri; Blagorodnova, Nadia; Yan, Lin

    2018-01-01

    The biggest challenge to finding tidal disruption events (TDEs) in optical transient sky surveys is to get rid of the numerous interlopers such as AGN and Type Ia supernovae that are at least 100 times more common. We will describe our selection process that led to the prompt discoveries of two TDEs (iPTF16axa and iPTF16fnl) in a 4-month long experiment to study nuclear transients in the intermediate Palomar Transient Factory (iPTF) together with UV and X-ray imaging follow-up from our Swift Cycle 12 Key Project. Subsequent multi-wavelength follow-up observations were triggered in order to study these rare events. We found that most of the optically-bright TDEs share similar peak luminosities, light curves, and temperature evolution except iPTF16fnl, which is the nearest, faintest, and fastest optical TDE ever found. Based on our detection rate in iPTF, we expect to discover ~30 TDEs in the first year of the Zwicky Transient Factory (ZTF), doubling the current TDE sample aggregated over ~7 years of wide-field optical surveys.

  7. VizieR Online Data Catalog: Panchromatic observations of PTF11qcj (Corsi+, 2014)

    NASA Astrophysics Data System (ADS)

    Corsi, A.; Ofek, E. O.; Gal-Yam, A.; Frail, D. A.; Kulkarni, S. R.; Fox, D. B.; Kasliwal, M. M.; Sullivan, M.; Horesh, A.; Carpenter, J.; Maguire, K.; Arcavi, I.; Cenko, S. B.; Cao, Y.; Mooley, K.; Pan, Y.-C.; Sesar, B.; Sternberg, A.; Xu, D.; Bersier, D.; James, P.; Bloom, J. S.; Nugent, P. E.

    2016-02-01

    On 2011 November 1, we discovered PTF11qcj in an R-band image from the 48 inch Samuel Oschin telescope at Palomar Observatory (P48), which is routinely used by the Palomar Transient Factory (PTF). Subsequent observations with the P48 were conducted with the Mould-R and Gunn-g filters. Photometry (Table2) was performed relative to the SDSS r-band and g-band magnitudes of stars in the field. Multi-color optical (gri) optical light curves were also obtained using the Palomar 60 inch telescope (P60) and the RATCAM optical imager on the robotic 2m Liverpool Telescope (LT) located at the Roque de Los Muchachos Observatory on La Palma. On 2011 November 15, we started a long-term monitoring campaign of PTF11qcj (along with calibrators J1327+4326 and 3C 286) with the Karl G. Jansky Very Large Array (VLA; http://public.nrao.edu/telescopes/vla) in its D, DnC, C, CnB, and A configurations, under our Target of Opportunity programs (VLA/11A-227, VLA/11B-034, VLA/11B-247, VLA/12B-195; PI: A. Corsi). The light curves of PTF11qcj at frequencies of 2.5GHz, 3.5GHz, 5GHz, 7.4GHz, 13.5GHz, 16GHz are reported in Table3. We also observed the field of PTF11qcj (together with the test calibrator J1203+480) using the Combined Array for Research in Millimeter-wave Astronomy (CARMA; http://www.mmarray.org/), at a frequency of 93GHz. The data collected on 2011 November 19 and 2011 November 26 (CARMA program no. c0857; PI: A. Horesh) both resulted in a detection of PTF11qcj (Table3). We have carried out an X-ray monitoring campaign of PTF11qcj with Chandra and Swift. All our Swift-XRT observations yielded non detections (see Table 4), while Chandra detected PTF11qcj in three epochs (DDT proposals nos. 501793, 501794, 501797; PI: A. Corsi). The results of our X-ray follow-up are reported in Table4. We observed the position of PTF11qcj with Spitzer on two epochs (on 2012 March 28.747 and 2012 June 25.643; Table5; DDT proposal no. 31731; PI: A. Corsi). On 2012 March 28 (Table5), we also observed

  8. Revisiting Optical Tidal Disruption Events with iPTF16axa

    NASA Astrophysics Data System (ADS)

    Hung, T.; Gezari, S.; Blagorodnova, N.; Roth, N.; Cenko, S. B.; Kulkarni, S. R.; Horesh, A.; Arcavi, I.; McCully, C.; Yan, Lin; Lunnan, R.; Fremling, C.; Cao, Y.; Nugent, P. E.; Wozniak, P.

    2017-06-01

    We report the discovery by the intermediate Palomar Transient Factory (iPTF) of a candidate tidal disruption event (TDE) iPTF16axa at z = 0.108 and present its broadband photometric and spectroscopic evolution from three months of follow-up observations with ground-based telescopes and Swift. The light curve is well fitted with a t -5/3 decay, and we constrain the rise time to peak to be <49 rest-frame days after disruption, which is roughly consistent with the fallback timescale expected for the ˜5 × 106 M ⊙ black hole inferred from the stellar velocity dispersion of the host galaxy. The UV and optical spectral energy distribution is well described by a constant blackbody temperature of T ˜ 3 × 104 K over the monitoring period, with an observed peak luminosity of 1.1 × 1044 erg s-1. The optical spectra are characterized by a strong blue continuum and broad He II and Hα lines, which are characteristic of TDEs. We compare the photometric and spectroscopic signatures of iPTF16axa with 11 TDE candidates in the literature with well-sampled optical light curves. Based on a single-temperature fit to the optical and near-UV photometry, most of these TDE candidates have peak luminosities confined between log(L [erg s-1]) = 43.4-44.4, with constant temperatures of a few ×104 K during their power-law declines, implying blackbody radii on the order of 10 times the tidal disruption radius, that decrease monotonically with time. For TDE candidates with hydrogen and helium emission, the high helium-to-hydrogen ratios suggest that the emission arises from high-density gas, where nebular arguments break down. We find no correlation between the peak luminosity and the black hole mass, contrary to the expectations for TDEs to have \\dot{M}\\propto {M}{BH}-1/2.

  9. iPTF15dtg: a double-peaked Type Ic supernova from a massive progenitor

    DOE PAGES

    Taddia, Francesco; Fremling, C.; Sollerman, J.; ...

    2016-08-04

    Type Ic supernovae (SNe Ic) arise from the core-collapse of H- (and He-) poor stars, which could either be single Wolf-Rayet (WR) stars or lower-mass stars stripped of their envelope by a companion. Their light curves are radioactively powered and usually show a fast rise to peak (~10-15 d), without any early (in the first few days) emission bumps (with the exception of broad-lined SNe Ic) as sometimes seen for other types of stripped-envelope SNe (e.g., Type IIb SN 1993J and Type Ib SN 2008D). Here, we have studied iPTF15dtg, a spectroscopically normal SN Ic with an early excess inmore » the optical light curves followed by a long (~30 d) rise to the main peak. It is the first spectroscopically-normal double-peaked SN Ic to be observed. Our aim is to determine the properties of this explosion and of its progenitor star. Methods. Optical photometry and spectroscopy of iPTF15dtg was obtained with multiple telescopes. The resulting light curves and spectral sequence are analyzed and modeled with hydrodynamical and analytical models, with particular focus on the early emission. iPTF15dtg is a slow rising SN Ic, similar to SN 2011bm. Hydrodynamical modeling of the bolometric properties reveals a large ejecta mass (~10 M ⊙) and strong 56Ni mixing. The luminous early emission can be reproduced if we account for the presence of an extended (≳500 R ⊙), low-mass (≳0.045 M ⊙) envelope around the progenitor star. Alternative scenarios for the early peak, such as the interaction with a companion, a shock-breakout (SBO) cooling tail from the progenitor surface, or a magnetar-driven SBO are not favored. In conclusion, the large ejecta mass and the presence of H- and He-free extended material around the star suggest that the progenitor of iPTF15dtg was a massive (≳35 M ⊙) WR star that experienced strong mass loss.« less

  10. Revisiting Optical Tidal Disruption Events with iPTF16axa

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hung, T.; Gezari, S.; Blagorodnova, N.

    We report the discovery by the intermediate Palomar Transient Factory (iPTF) of a candidate tidal disruption event (TDE) iPTF16axa at z = 0.108 and present its broadband photometric and spectroscopic evolution from three months of follow-up observations with ground-based telescopes and Swift. The light curve is well fitted with a t -5/3 decay, and we constrain the rise time to peak to be <49 rest-frame days after disruption, which is roughly consistent with the fallback timescale expected for the ~5 × 10 6 M ⊙ black hole inferred from the stellar velocity dispersion of the host galaxy. The UV and optical spectral energy distribution is well described by a constant blackbody temperature of T ~ 3 × 10 4 K over the monitoring period, with an observed peak luminosity of 1.1 × 10 44 erg s -1. The optical spectra are characterized by a strong blue continuum and broad He ii and Hα lines, which are characteristic of TDEs. We compare the photometric and spectroscopic signatures of iPTF16axa with 11 TDE candidates in the literature with well-sampled optical light curves. Based on a single-temperature fit to the optical and near-UV photometry, most of these TDE candidates have peak luminosities confined between log(L [erg s -1]) = 43.4–44.4, with constant temperatures of a few ×104 K during their power-law declines, implying blackbody radii on the order of 10 times the tidal disruption radius, that decrease monotonically with time. For TDE candidates with hydrogen and helium emission, the high helium-to-hydrogen ratios suggest that the emission arises from high-density gas, where nebular arguments break down. In conclusion, we find no correlation between the peak luminosity and the black hole mass, contrary to the expectations for TDEs to havemore » $$\\dot{M}\\propto {M}_{\\mathrm{BH}}^{-1/2}$$.« less

  11. Revisiting Optical Tidal Disruption Events with iPTF16axa

    DOE PAGES

    Hung, T.; Gezari, S.; Blagorodnova, N.; ...

    2017-06-08

    We report the discovery by the intermediate Palomar Transient Factory (iPTF) of a candidate tidal disruption event (TDE) iPTF16axa at z = 0.108 and present its broadband photometric and spectroscopic evolution from three months of follow-up observations with ground-based telescopes and Swift. The light curve is well fitted with a t -5/3 decay, and we constrain the rise time to peak to be <49 rest-frame days after disruption, which is roughly consistent with the fallback timescale expected for the ~5 × 10 6 M ⊙ black hole inferred from the stellar velocity dispersion of the host galaxy. The UV and optical spectral energy distribution is well described by a constant blackbody temperature of T ~ 3 × 10 4 K over the monitoring period, with an observed peak luminosity of 1.1 × 10 44 erg s -1. The optical spectra are characterized by a strong blue continuum and broad He ii and Hα lines, which are characteristic of TDEs. We compare the photometric and spectroscopic signatures of iPTF16axa with 11 TDE candidates in the literature with well-sampled optical light curves. Based on a single-temperature fit to the optical and near-UV photometry, most of these TDE candidates have peak luminosities confined between log(L [erg s -1]) = 43.4–44.4, with constant temperatures of a few ×104 K during their power-law declines, implying blackbody radii on the order of 10 times the tidal disruption radius, that decrease monotonically with time. For TDE candidates with hydrogen and helium emission, the high helium-to-hydrogen ratios suggest that the emission arises from high-density gas, where nebular arguments break down. In conclusion, we find no correlation between the peak luminosity and the black hole mass, contrary to the expectations for TDEs to havemore » $$\\dot{M}\\propto {M}_{\\mathrm{BH}}^{-1/2}$$.« less

  12. VizieR Online Data Catalog: Rotation periods of asteroids using iPTF (Chang+, 2016)

    NASA Astrophysics Data System (ADS)

    Chang, C.-K.; Lin, H.-W.; Ip, W.-H.; Prince, T. A.; Kulkarni, S. R.; Levitan, D.; Laher, R.; Surace, J.

    2017-01-01

    To explore the transient and variable sky synoptically, the PTF/iPTF employs the Palomar 48-inch Oschin Schmidt Telescope to create a field of view of ~7.26deg2 and a pixel scale of 1.01". The available filters include the Mould-R band, with which most exposures were taken, Gunn-g', and two different Hα-bands. The exposure time is fixed at 60 seconds, which can reach a median limiting magnitude of R~21mag at the 5σ level. In order to look for large super-fast rotators, we conducted five asteroid rotation-period surveys during 2014 October 29-31 and November 10-13, and 2015 January 18-19, February 20-21 and 25-26. Each survey continuously scanned six consecutive PTF fields over the ecliptic plane in the R-band, with a cadence of 10min. We ended up with a total sky coverage of ~188deg2. (3 data files).

  13. Early Observations of the Type Ia Supernova iPTF 16abc

    NASA Astrophysics Data System (ADS)

    Miller, Adam; iPTF Collaboration

    2018-01-01

    Early observations of Type Ia supernovae (SNe) provide a unique probe of their progenitor systems and explosion physics. Here, we report the intermediate Palomar Transient Factory (iPTF) discovery of an extraordinarily young SN Ia, iPTF 16abc. By fitting a power law to our early light curve, we infer that first light for the SN only occurred 0.15 +0.15-0.07 d before our first detection. In the ~24 hr after discovery, iPTF 16abc rose by ~2 mag, following a near-linear rise in flux for ~3 d. Strong C II absorption is detected in the early spectra of iPTF 16abc, before disappearing after ~7 d. Unlike the extensively-observed Type Ia SN 2011fe, the (B-V)_0 colors of iPTF 16abc are blue and nearly constant in the days after explosion. We show that our early observations of iPTF 16abc cannot be explained by either SN shock breakout and the associated, subsequent cooling, or the SN ejecta colliding with a stellar companion. Instead, we argue that the early characteristics of iPTF 16abc, including: (i) the rapid, near-linear rise, (ii) the non-evolving blue colors, and (iii) the strong absorption from ionized carbon, are the result of either vigorous mixing of radioactive-Ni in the SN ejecta, or ejecta interaction with diffuse material, or a combination of the two. In the next few years, dozens of very young normal SNe Ia will be discovered, and observations similar to those presented here will constrain the white dwarf explosion mechanism.

  14. The bumpy light curve of Type IIn supernova iPTF13z over 3 years

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nyholm, A.; Sollerman, J.; Taddia, F.

    A core-collapse (CC) supernova (SN) of Type IIn is dominated by the interaction of SN ejecta with the circumstellar medium (CSM). Some SNe IIn (e.g. SN 2006jd) have episodes of re-brightening ("bumps") in their light curves. We present iPTF13z, a Type IIn SN discovered on 2013 February 1 by the intermediate Palomar Transient Factory (iPTF). This SN showed at least five bumps in its declining light curve between 130 and 750 days after discovery. We analyse this peculiar behaviour and try to infer the properties of the CSM, of the SN explosion, and the nature of the progenitor star. Wemore » obtained multi-band optical photometry for over 1000 days after discovery with the P48 and P60 telescopes at Palomar Observatory. We obtained low-resolution optical spectra during the same period. We did an archival search for progenitor outbursts. We analyse the photometry and the spectra, and compare iPTF13z to other SNe IIn. In particular we derive absolute magnitudes, colours, a pseudo-bolometric light curve, and the velocities of the different components of the spectral lines. A simple analytical model is used to estimate the properties of the CSM. iPTF13z had a light curve peaking at M r ≤ 18.3 mag. The five bumps during its decline phase had amplitudes ranging from 0.4 to 0.9 mag and durations between 20 and 120 days. The most prominent bumps appeared in all the different optical bands, when covered. The spectra of this SN showed typical SN IIn characteristics, with emission lines of Hα (with broad component FWHM ~ 10 3 - 10 4 km s -1 and narrow component FWHM ~ 10 2 km s -1 ) and He i, but also with Fe ii, Ca ii, Na i D and Hβ P Cygni profiles (with velocities of ~ 10 3 km s -1). A pre-explosion outburst was identified lasting ≳ 50 days, with M r ≤ 15 mag around 210 days before discovery. Large, variable progenitor mass-loss rates (≳ 0.01M ⊙ yr -1) and CSM densities (10 -16 g cm -3) are derived. The SN was hosted by a metal-poor dwarf galaxy at redshift z

  15. A magnetar model for the hydrogen-rich super-luminous supernova iPTF14hls

    NASA Astrophysics Data System (ADS)

    Dessart, Luc

    2018-02-01

    Transient surveys have recently revealed the existence of H-rich super-luminous supernovae (SLSN; e.g., iPTF14hls, OGLE-SN14-073) that are characterized by an exceptionally high time-integrated bolometric luminosity, a sustained blue optical color, and Doppler-broadened H I lines at all times. Here, I investigate the effect that a magnetar (with an initial rotational energy of 4 × 1050 erg and field strength of 7 × 1013 G) would have on the properties of a typical Type II supernova (SN) ejecta (mass of 13.35 M⊙, kinetic energy of 1.32 × 1051 erg, 0.077 M⊙ of 56Ni) produced by the terminal explosion of an H-rich blue supergiant star. I present a non-local thermodynamic equilibrium time-dependent radiative transfer simulation of the resulting photometric and spectroscopic evolution from 1 d until 600 d after explosion. With the magnetar power, the model luminosity and brightness are enhanced, the ejecta is hotter and more ionized everywhere, and the spectrum formation region is much more extended. This magnetar-powered SN ejecta reproduces most of the observed properties of SLSN iPTF14hls, including the sustained brightness of ‑18 mag in the R band, the blue optical color, and the broad H I lines for 600 d. The non-extreme magnetar properties, combined with the standard Type II SN ejecta properties, offer an interesting alternative to the pair-unstable super-massive star model recently proposed, which involves a highly energetic and super-massive ejecta. Hence, such Type II SLSNe may differ from standard Type II SNe exclusively through the influence of a magnetar.

  16. Identification of a functional enhancer variant within the chronic pancreatitis-associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype.

    PubMed

    Boulling, Arnaud; Masson, Emmanuelle; Zou, Wen-Bin; Paliwal, Sumit; Wu, Hao; Issarapu, Prachand; Bhaskar, Seema; Génin, Emmanuelle; Cooper, David N; Li, Zhao-Shen; Chandak, Giriraj R; Liao, Zhuan; Chen, Jian-Min; Férec, Claude

    2017-08-01

    The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser) variant (also known as rs17107315:T>C) represents the most important heritable risk factor for idiopathic chronic pancreatitis identified to date. The causal variant contained within this risk haplotype has however remained stubbornly elusive. Herein, we set out to resolve this enigma by employing a hypothesis-driven approach. First, we searched for variants in strong linkage disequilibrium (LD) with rs17107315:T>C using HaploReg v4.1. Second, we identified two candidate SNPs by visual inspection of sequences spanning all 25 SNPs found to be in LD with rs17107315:T>C, guided by prior knowledge of pancreas-specific transcription factors and their cognate binding sites. Third, employing a novel cis-regulatory module (CRM)-guided approach to further filter the two candidate SNPs yielded a solitary candidate causal variant. Finally, combining data from phylogenetic conservation and chromatin accessibility, cotransfection transactivation experiments, and population genetic studies, we suggest that rs142703147:C>A, which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L CRM located ∼4 kb upstream of the SPINK1 promoter, contributes to the aforementioned chronic pancreatitis risk haplotype. Further studies are required not only to improve the characterization of this functional SNP but also to identify other functional components that might contribute to this high-risk haplotype. © 2017 Wiley Periodicals, Inc.

  17. Strong late-time circumstellar interaction in the peculiar supernova iPTF14hls

    NASA Astrophysics Data System (ADS)

    Andrews, Jennifer E.; Smith, Nathan

    2018-06-01

    We present a moderate-resolution spectrum of the peculiar Type II supernova (SN) iPTF14hls taken on day 1153 after discovery. This spectrum reveals the clear signature of shock interaction with dense circumstellar material (CSM). We suggest that this CSM interaction may be an important clue for understanding the extremely unusual photometric and spectroscopic evolution seen over the first 600 d of iPTF14hls. The late-time spectrum shows a double-peaked intermediate-width H α line indicative of expansion speeds around 1000 km s-1, with the double-peaked shape hinting at a disc-like geometry in the CSM. If the CSM were highly asymmetric, perhaps in a disc or torus that was ejected from the star 3-6 yr prior to explosion, the CSM interaction could have been overrun and hidden below the SN ejecta photosphere from a wide range of viewing angles. In that case, CSM interaction luminosity would have been thermalized well below the photosphere, potentially sustaining the high luminosity without exhibiting the traditional observational signatures of strong CSM interaction (narrow H α emission and X-rays). Variations in density structure of the CSM could account for the multiple rebrightenings of the light curve. We propose that a canonical 1 × 1051 erg explosion energy with enveloped CSM interaction as seen in some recent SNe, rather than an entirely new explosion mechanism, may be adequate to explain the peculiar evolution of iPTF14hls.

  18. The bumpy light curve of Type IIn supernova iPTF13z over 3 years

    NASA Astrophysics Data System (ADS)

    Nyholm, A.; Sollerman, J.; Taddia, F.; Fremling, C.; Moriya, T. J.; Ofek, E. O.; Gal-Yam, A.; De Cia, A.; Roy, R.; Kasliwal, M. M.; Cao, Y.; Nugent, P. E.; Masci, F. J.

    2017-08-01

    A core-collapse (CC) supernova (SN) of Type IIn is dominated by the interaction of SN ejecta with the circumstellar medium (CSM). Some SNe IIn (e.g. SN 2006jd) have episodes of re-brightening ("bumps") in their light curves. We present iPTF13z, a Type IIn SN discovered on 2013 February 1 by the intermediate Palomar Transient Factory (iPTF). This SN showed at least five bumps in its declining light curve between 130 and 750 days after discovery. We analyse this peculiar behaviour and try to infer the properties of the CSM, of the SN explosion, and the nature of the progenitor star. We obtained multi-band optical photometry for over 1000 days after discovery with the P48 and P60 telescopes at Palomar Observatory. We obtained low-resolution optical spectra during the same period. We did an archival search for progenitor outbursts. We analyse the photometry and the spectra, and compare iPTF13z to other SNe IIn. In particular we derive absolute magnitudes, colours, a pseudo-bolometric light curve, and the velocities of the different components of the spectral lines. A simple analytical model is used to estimate the properties of the CSM. iPTF13z had a light curve peaking at Mr ≲ - 18.3 mag. The five bumps during its decline phase had amplitudes ranging from 0.4 to 0.9 mag and durations between 20 and 120 days. The most prominent bumps appeared in all the different optical bands, when covered. The spectra of this SN showed typical SN IIn characteristics, with emission lines of Hα (with broad component FWHM 103 - 104 km s-1 and narrow component FWHM 102 km s-1) and He I, but also with Fe II, Ca II, Na I D and Hβ P Cygni profiles (with velocities of 103km s-1). A pre-explosion outburst was identified lasting ≳ 50 days, with Mr ≈ - 15 mag around 210 days before discovery. Large, variable progenitor mass-loss rates (≳0.01M⊙ yr-1) and CSM densities (≳10-16 g cm-3) are derived. The SN was hosted by a metal-poor dwarf galaxy at redshift z = 0.0328. We suggest that

  19. VizieR Online Data Catalog: Photometry of the transient event iPTF16fnl (Blagorodnova+, 2017)

    NASA Astrophysics Data System (ADS)

    Blagorodnova, N.; Gezari, S.; Hung, T.; Kulkarni, S. R.; Cenko, S. B.; Pasham, D. R.; Yan, L.; Arcavi, I.; Ben-Ami, S.; Bue, B. D.; Cantwell, T.; Cao, Y.; Castro-Tirado, A. J.; Fender, R.; Fremling, C.; Gal-Yam, A.; Ho, A. Y. Q.; Horesh, A.; Hosseinzadeh, G.; Kasliwal, M. M.; Kong, A. K. H.; Laher, R. R.; Leloudas, G.; Lunnan, R.; Masci, F. J.; Mooley, K.; Neill, J. D.; Nugent, P.; Powell, M.; Valeev, A. F.; Vreeswijk, P. M.; Walters, R.; Wozniak, P.

    2018-03-01

    On the night after discovery (2016 August 29th), we observed the source with the FLOYDS spectrograph on the Las Cumbres Observatory (LCO) 2m telescope and the Spectral Energy Distribution Machine (SEDM) on the Palomar 60 inch (P60) telescope. The SEDM is a ultra-low resolution (R~100) integral-field-unit (IFU) spectrograph. Following spectroscopic identification of iPTF16fnl as a tidal disruption event (TDE) candidate, the source was monitored at Palomar and by the Ultraviolet and Optical Telescope (UVOT) on board the Swift observatory. The UVOT observations were taken in UVW2, UVM2, UVW1, U, B, and V. At Palomar, photometry in the g and Mould-R bands were obtained with the iPTF mosaic wide-field camera on the Palomar 48-inch telescope (P48). Table 3 reports the measured Swift aperture photometry magnitudes and the difference-imaging photometry for the Palomar data spanning 2016 Aug to 2016 Dec. Radio follow-up observations of iPTF16fnl were taken with the Jansky Very Large Array (VLA; PI A. Horesh), the Arcminute Microkelvin Imager (AMI; PI K. Mooley) and the James Clerk Maxwell Telescope and the Submillimetre Common-User Bolometer Array 2 (JCMT/SCUBA-2; PI A. K. H. Kong). We also observed the location of iPTF16fnl with the X-Ray Telescope (XRT) on board the Swift satellite beginning at 19:32 UT on 30 August 2016. Regular monitoring of the field in photon counting mode continued over the course of the next four months (PIs T. Holoien and B. Cenko). (1 data file).

  20. The Rise and Fall of the Type Ib Supernova iPTF13bvn Not a Massive Wolf-Rayet Star

    NASA Technical Reports Server (NTRS)

    Fremling, C.; Sollerman, J.; Taddia, F.; Ergon, M.; Valenti, S.; Arcavi, I.; Ben-Ami, S.; Cao, Y.; Cenko, S. B.; Filippenko, A. V.; hide

    2014-01-01

    Context. We investigate iPTF13bvn, a core-collapse (CC) supernova (SN) in the nearby spiral galaxy NGC 5806. This object was discovered by the intermediate Palomar Transient Factory (iPTF) very close to the estimated explosion date and was classified as a stripped-envelope CC SN, likely of Type Ib. Furthermore, a possible progenitor detection in pre-explosion Hubble Space Telescope (HST) images was reported, making this the only SN Ib with such an identification. Based on the luminosity and color of the progenitor candidate, as well as on early-time spectra and photometry of the SN, it was argued that the progenitor candidate is consistent with a single, massive Wolf-Rayet (WR) star. Aims. We aim to confirm the progenitor detection, to robustly classify the SN using additional spectroscopy, and to investigate if our follow-up photometric and spectroscopic data on iPTF13bvn are consistent with a single-star WR progenitor scenario. Methods. We present a large set of observational data, consisting of multi-band light curves (UBVRI, g'r'i'z') and optical spectra. We perform standard spectral line analysis to track the evolution of the SN ejecta. We also construct a bolometric light curve and perform hydrodynamical calculations to model this light curve to constrain the synthesized radioactive nickel mass and the total ejecta mass of the SN. Late-time photometry is analyzed to constrain the amount of oxygen. Furthermore, image registration of pre- and post-explosion HST images is performed. Results. Our HST astrometry confirms the location of the progenitor candidate of iPTF13bvn, and follow-up spectra securely classify this as a SN Ib. We use our hydrodynamical model to fit the observed bolometric light curve, estimating the total ejecta mass to be 1.9 solar mass and the radioactive nickel mass to be 0.05 solar mass. The model fit requires the nickel synthesized in the explosion to be highly mixed out in the ejecta. We also find that the late-time nebular r

  1. iPTF15eqv: Multiwavelength Exposé of a Peculiar Calcium-rich Transient

    NASA Astrophysics Data System (ADS)

    Milisavljevic, Dan; Patnaude, Daniel J.; Raymond, John C.; Drout, Maria R.; Margutti, Raffaella; Kamble, Atish; Chornock, Ryan; Guillochon, James; Sanders, Nathan E.; Parrent, Jerod T.; Lovisari, Lorenzo; Chilingarian, Igor V.; Challis, Peter; Kirshner, Robert P.; Penny, Matthew T.; Itagaki, Koichi; Eldridge, J. J.; Moriya, Takashi J.

    2017-09-01

    The progenitor systems of the class of “Ca-rich transients” is a key open issue in time domain astrophysics. These intriguing objects exhibit unusually strong calcium line emissions months after explosion, fall within an intermediate luminosity range, are often found at large projected distances from their host galaxies, and may play a vital role in enriching galaxies and the intergalactic medium. Here we present multiwavelength observations of iPTF15eqv in NGC 3430, which exhibits a unique combination of properties that bridge those observed in Ca-rich transients and SNe Ib/c. iPTF15eqv has among the highest [Ca II]/[O I] emission line ratios observed to date, yet is more luminous and decays more slowly than other Ca-rich transients. Optical and near-infrared photometry and spectroscopy reveal signatures consistent with the supernova explosion of a ≲ 10 {M}⊙ star that was stripped of its H-rich envelope via binary interaction. Distinct chemical abundances and ejecta kinematics suggest that the core collapse occurred through electron-capture processes. Deep limits on possible radio emission made with the Jansky Very Large Array imply a clean environment (n ≲ 0.1 cm-3) within a radius of ˜ {10}17 cm. Chandra X-ray Observatory observations rule out alternative scenarios involving the tidal disruption of a white dwarf (WD) by a black hole, for masses >100 M ⊙. Our results challenge the notion that spectroscopically classified Ca-rich transients only originate from WD progenitor systems, complicate the view that they are all associated with large ejection velocities, and indicate that their chemical abundances may vary widely between events.

  2. iPTF16geu: A multiply imaged, gravitationally lensed type Ia supernova

    DOE PAGES

    Goobar, A.; Amanullah, R.; Kulkarni, S. R.; ...

    2017-04-21

    We report the discovery of a multiply imaged, gravitationally lensed type Ia supernova, iPTF16geu (SN 2016geu), at redshift z = 0.409. This phenomenon was identified because the light from the stellar explosion was magnified more than 50 times by the curvature of space around matter in an intervening galaxy.We used high-spatial-resolution observations to resolve four images of the lensed supernova, approximately 0.3 arc seconds from the center of the foreground galaxy. The observations probe a physical scale of ~1 kiloparsec, smaller than is typical in other studies of extragalactic gravitational lensing. The large magnification and symmetric image configuration imply closemore » alignment between the lines of sight to the supernova and to the lens. In conclusion, the relative magnifications of the four images provide evidence for substructures in the lensing galaxy.« less

  3. iPTF16geu: A multiply imaged, gravitationally lensed type Ia supernova.

    PubMed

    Goobar, A; Amanullah, R; Kulkarni, S R; Nugent, P E; Johansson, J; Steidel, C; Law, D; Mörtsell, E; Quimby, R; Blagorodnova, N; Brandeker, A; Cao, Y; Cooray, A; Ferretti, R; Fremling, C; Hangard, L; Kasliwal, M; Kupfer, T; Lunnan, R; Masci, F; Miller, A A; Nayyeri, H; Neill, J D; Ofek, E O; Papadogiannakis, S; Petrushevska, T; Ravi, V; Sollerman, J; Sullivan, M; Taddia, F; Walters, R; Wilson, D; Yan, L; Yaron, O

    2017-04-21

    We report the discovery of a multiply imaged, gravitationally lensed type Ia supernova, iPTF16geu (SN 2016geu), at redshift z = 0.409. This phenomenon was identified because the light from the stellar explosion was magnified more than 50 times by the curvature of space around matter in an intervening galaxy. We used high-spatial-resolution observations to resolve four images of the lensed supernova, approximately 0.3 arc seconds from the center of the foreground galaxy. The observations probe a physical scale of ~1 kiloparsec, smaller than is typical in other studies of extragalactic gravitational lensing. The large magnification and symmetric image configuration imply close alignment between the lines of sight to the supernova and to the lens. The relative magnifications of the four images provide evidence for substructures in the lensing galaxy. Copyright © 2017, American Association for the Advancement of Science.

  4. Effect of salinity medium on antioxidant and antidiabetic activity marine endophytic fungus of asperegillus elegans ptf 9

    NASA Astrophysics Data System (ADS)

    Mulyani, Hani; Artanti, Nina; Fitria, Irni; Filailla, Euis; Kandace, Yoice Sri; Udin, Linar Zalinar

    2017-11-01

    Our previous studies on screening of antioxidant activities from various endophytic fungi isolated from marine bioata showed that A. elegans PTF9 isolated from sea weed is one of the fungus that has good antioxidant activity. In current study we reported the effect of medium salinity (0, 3 and 10% salt in PDB medium) on antioxidant and antidiabetes activity of mycelium and filtrate ethyl acetate extracts of A. elegans Ptf 9. The antioxidant assay was conducted using DPPH free radical scavenging activity method. The antidiabetes assay was conducted using a-glucosidase inhibitory activity method. The results showed that the best antioxidant activity was obtained from filtrate extract of fungus cultures with 0% salt (IC50=1.56 ppm), whereas the best antidiabetes activity was obtained from filtrate extract of fungus culture with 10% salt (IC50= 3.64 ppm). Addition of salt reduced the antioxidant activity, but not the antidiabetes activity. The results suggest that A. elegans PTF9 showed potential for further studies on isolation of antioxidant and antidiabetes lead compounds that could be use for further development of new drugs.

  5. THE DETECTION RATE OF EARLY UV EMISSION FROM SUPERNOVAE: A DEDICATED GALEX/PTF SURVEY AND CALIBRATED THEORETICAL ESTIMATES

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ganot, Noam; Gal-Yam, Avishay; Ofek, Eran O.

    The radius and surface composition of an exploding massive star, as well as the explosion energy per unit mass, can be measured using early UV observations of core-collapse supernovae (SNe). We present the first results from a simultaneous GALEX/PTF search for early ultraviolet (UV) emission from SNe. Six SNe II and one Type II superluminous SN (SLSN-II) are clearly detected in the GALEX near-UV (NUV) data. We compare our detection rate with theoretical estimates based on early, shock-cooling UV light curves calculated from models that fit existing Swift and GALEX observations well, combined with volumetric SN rates. We find thatmore » our observations are in good agreement with calculated rates assuming that red supergiants (RSGs) explode with fiducial radii of 500 R{sub ⊙}, explosion energies of 10{sup 51} erg, and ejecta masses of 10 M{sub ⊙}. Exploding blue supergiants and Wolf–Rayet stars are poorly constrained. We describe how such observations can be used to derive the progenitor radius, surface composition, and explosion energy per unit mass of such SN events, and we demonstrate why UV observations are critical for such measurements. We use the fiducial RSG parameters to estimate the detection rate of SNe during the shock-cooling phase (<1 day after explosion) for several ground-based surveys (PTF, ZTF, and LSST). We show that the proposed wide-field UV explorer ULTRASAT mission is expected to find >85 SNe per year (∼0.5 SN per deg{sup 2}), independent of host galaxy extinction, down to an NUV detection limit of 21.5 mag AB. Our pilot GALEX/PTF project thus convincingly demonstrates that a dedicated, systematic SN survey at the NUV band is a compelling method to study how massive stars end their life.« less

  6. The Detection Rate of Early UV Emission from Supernovae: A Dedicated Galex/PTF Survey and Calibrated Theoretical Estimates

    NASA Astrophysics Data System (ADS)

    Ganot, Noam; Gal-Yam, Avishay; Ofek, Eran. O.; Sagiv, Ilan; Waxman, Eli; Lapid, Ofer; Kulkarni, Shrinivas R.; Ben-Ami, Sagi; Kasliwal, Mansi M.; The ULTRASAT Science Team; Chelouche, Doron; Rafter, Stephen; Behar, Ehud; Laor, Ari; Poznanski, Dovi; Nakar, Ehud; Maoz, Dan; Trakhtenbrot, Benny; WTTH Consortium, The; Neill, James D.; Barlow, Thomas A.; Martin, Christofer D.; Gezari, Suvi; the GALEX Science Team; Arcavi, Iair; Bloom, Joshua S.; Nugent, Peter E.; Sullivan, Mark; Palomar Transient Factory, The

    2016-03-01

    The radius and surface composition of an exploding massive star, as well as the explosion energy per unit mass, can be measured using early UV observations of core-collapse supernovae (SNe). We present the first results from a simultaneous GALEX/PTF search for early ultraviolet (UV) emission from SNe. Six SNe II and one Type II superluminous SN (SLSN-II) are clearly detected in the GALEX near-UV (NUV) data. We compare our detection rate with theoretical estimates based on early, shock-cooling UV light curves calculated from models that fit existing Swift and GALEX observations well, combined with volumetric SN rates. We find that our observations are in good agreement with calculated rates assuming that red supergiants (RSGs) explode with fiducial radii of 500 R ⊙, explosion energies of 1051 erg, and ejecta masses of 10 M ⊙. Exploding blue supergiants and Wolf-Rayet stars are poorly constrained. We describe how such observations can be used to derive the progenitor radius, surface composition, and explosion energy per unit mass of such SN events, and we demonstrate why UV observations are critical for such measurements. We use the fiducial RSG parameters to estimate the detection rate of SNe during the shock-cooling phase (<1 day after explosion) for several ground-based surveys (PTF, ZTF, and LSST). We show that the proposed wide-field UV explorer ULTRASAT mission is expected to find >85 SNe per year (˜0.5 SN per deg2), independent of host galaxy extinction, down to an NUV detection limit of 21.5 mag AB. Our pilot GALEX/PTF project thus convincingly demonstrates that a dedicated, systematic SN survey at the NUV band is a compelling method to study how massive stars end their life.

  7. Color Me Intrigued: The Discovery of iPTF 16fnm, an SN 2002cx-like Object

    NASA Astrophysics Data System (ADS)

    Miller, A. A.; Kasliwal, M. M.; Cao, Y.; Adams, S. M.; Goobar, A.; Knežević, S.; Laher, R. R.; Lunnan, R.; Masci, F. J.; Nugent, P. E.; Perley, D. A.; Petrushevska, T.; Quimby, R. M.; Rebbapragada, U. D.; Sollerman, J.; Taddia, F.; Kulkarni, S. R.

    2017-10-01

    Modern wide-field, optical time-domain surveys must solve a basic optimization problem: maximize the number of transient discoveries or minimize the follow-up needed for the new discoveries. Here, we describe the Color Me Intrigued experiment, the first from the intermediate Palomar Transient Factory (iPTF) to search for transients simultaneously in the g PTF and R PTF bands. During the course of this experiment, we discovered iPTF 16fnm, a new member of the 02cx-like subclass of Type Ia supernovae (SNe). iPTF 16fnm peaked at {M}{g{PTF}}=-15.09+/- 0.17 {mag}, making it the second-least-luminous known SN Ia. iPTF 16fnm exhibits all the hallmarks of the 02cx-like class: (I) low luminosity at peak, (II) low ejecta velocities, and (III) a non-nebular spectrum several months after peak. Spectroscopically, iPTF 16fnm exhibits a striking resemblance to two other low-luminosity 02cx-like SNe: SN 2007qd and SN 2010ae. iPTF 16fnm and SN 2005hk decline at nearly the same rate, despite a 3 mag difference in brightness at peak. When considering the full subclass of 02cx-like SNe, we do not find evidence for a tight correlation between peak luminosity and decline rate in either the g‧ or r‧ band. We measure the relative rate of 02cx-like SNe to normal SNe Ia and find {r}{N02{cx}/{N}{Ia}}={33}-25+158 % . We further examine the g‧ - r‧ evolution of 02cx-like SNe and find that their unique color evolution can be used to separate them from 91bg-like and normal SNe Ia. This selection function will be especially important in the spectroscopically incomplete Zwicky Transient Facility/Large Synoptic Survey Telescope (LSST) era. Finally, we close by recommending that LSST periodically evaluate, and possibly update, its observing cadence to maximize transient science.

  8. Optical Follow-Up Observations of PTF10qts, a Luminous Broad-Lined Type Ic Supernova Found by the Palomar Transient Factory

    NASA Technical Reports Server (NTRS)

    Walker, E. S.; Mazzali, P. A.; Pian, E.; Hurley, K.; Arcavi, I.; Cenko, S. B.; Gal-Yam, A.; Horesh, A.; Kasliwal, M.; Poznanski, D.; hide

    2014-01-01

    We present optical photometry and spectroscopy of the broad-lined Type Ic supernova (SN Ic-BL) PTF10qts, which was discovered as part of the Palomar Transient Factory. The supernova was located in a dwarf galaxy of magnitude r = 21.1 at a redshift z = 0.0907.We find that the R-band light curve is a poor proxy for bolometric data and use photometric and spectroscopic data to construct and constrain the bolometric light curve. The derived bolometric magnitude at maximum light is Mbol = -18.51 +/- 0.2 mag, comparable to that of SN1998bw (Mbol = -18.7 mag) which was associated with a gamma-ray burst (GRB). PTF10qts is one of the most luminous SN Ic-BL observed without an accompanying GRB. We estimate the physical parameters of the explosion using data from our programme of follow-up observations, finding that it produced a larger mass of radioactive nickel compared to other SNeIc-BL with similar inferred ejecta masses and kinetic energies. The progenitor of the event was likely a approximately 20 solar mass star.

  9. Carbohydrates and activity of natural and recombinant tissue factor.

    PubMed

    Krudysz-Amblo, Jolanta; Jennings, Mark E; Mann, Kenneth G; Butenas, Saulius

    2010-01-29

    The effect of glycosylation on tissue factor (TF) activity was evaluated, and site-specific glycosylation of full-length recombinant TF (rTF) and that of natural TF from human placenta (pTF) were studied by liquid chromatography-tandem mass spectrometry. The amidolytic activity of the TF.factor VIIa (FVIIa) complex toward a fluorogenic substrate showed that the catalytic efficiency (V(max)) of the complex increased in the order rTF(1-243) (Escherichia coli) < rTF(1-263) (Sf9 insect cells) < pTF for the glycosylated and deglycosylated forms. Substrate hydrolysis was unaltered by deglycosylation. In FXase, the K(m) of FX for rTF(1-263)-FVIIa remained unchanged after deglycosylation, whereas the k(cat) decreased slightly. A pronounced decrease, 4-fold, in k(cat) was observed for pTF.FVIIa upon deglycosylation, whereas the K(m) was minimally altered. The parameters of FX activation by both rTF(1-263D)-FVIIa and pTF(D)-FVIIa were identical and similar to those for rTF(1-243)-FVIIa. In conclusion, carbohydrates significantly influence the activity of TF proteins. Carbohydrate analysis revealed glycosylation on asparagines 11, 124, and 137 in both rTF(1-263) and pTF. The carbohydrates of rTF(1-263) contain high mannose, hybrid, and fucosylated glycans. Natural pTF contains no high mannose glycans but is modified with hybrid, highly fucosylated, and sialylated sugars.

  10. VizieR Online Data Catalog: PTF11mnb Bgri light curves (Taddia+, 2018)

    NASA Astrophysics Data System (ADS)

    Taddia, F.; Sollerman, J.; Fremling, C.; Karamehmetoglu, E.; Quimby, R. M.; Gal-Yam, A.; Yaron, O.; Kasliwal, M. M.; Kulkarni, S. R.; Nugent, P. E.; Smadja, G.; Tao, C.

    2018-01-01

    The Palomar Transient Factory first detected PTF11mnb at RA=00:34:13.25 and DE=+02:48:31.4 (J2000.0) on JD 2455804.857 (Aug. 31 2011) (g = 21:07+/-0.31mag ) using the 48-inch Samuel Oschin telescope (P48) at Palomar Observatory, equipped with the 96 Mpixel mosaic camera CFH12K. PTF11mnb was observed with P48 in the g band until ~60d and until ~50-days in the r band. We also made use of the Palomar 60-inch telescope (P60), with which we observed the SN in Bgri bands, starting at ~20d with the r band (Bgi band coverage started from ~40d). The SN was detected for the last time at ~140-days with P60. (1 data file).

  11. Optical and near-infrared study of the Ca-rich transient iPTF15eqv in the early phase

    NASA Astrophysics Data System (ADS)

    Kawahara, Naoki; Yamanaka, Masayuki; Kawabata, Koji; Nakaoka, Tatsuya; Kawabata, Miho; Maeda, Keiichi; Takaki, Katsutoshi; Akitaya, Hiroshi; Itoh, Ryosuke; Moritani, Yuki; Uemura, Makoto; Yoshida, Michitoshi

    2018-01-01

    Supernovae (SNe) exhibiting strong calcium features in their spectra are called Ca-rich transients. Frequently their early-phase spectra also exhibit helium absorption lines. They are mostly discovered in elliptical galaxies or at a remote location far from the host galaxy center. Well-observed samples are still too limited to clarify the explosion and progenitor properties. We present optical and near-infrared observations of a Ca-rich transient iPTF15eqv in the spiral galaxy NGC 3430. The data are obtained using 1.5-m Kanata telescope since Sep 28, 2015. While the discovery was at a post-maximum-phase, we infer the maximum date to be 30 days before the discovery date, by comparing its light curve and spectroscopic evolution to those of well-observed samples. The spectra exhibit absorption lines of He I and prominent emission lines of Ca II IR and [Ca II] from +31 to 69 d after the maximum date. We find that iPTF15eqv is more luminous than other Ca-rich transients by 1.5 to 2 mag on +31 d, and we estimate that the peak absolute magnitude in the R band is approximately -18 to -16.5 mag. The decline rate of the light curve between 30 and 60 d is similar to those of SNe Ib/c. The line velocity of the helium is similar to those of Ca-rich transients but also to SNe Ib. The ejecta properties inferred from our observations indicate that iPTF15eqv has a larger nickel mass than typical Ca-rich transients. While these properties show similarity to SNe Ib, we show that most of these properties are indeed shared by other Ca-rich transients. The properties of iPTF15eqv may thus still be regarded to be within the diversities among the Ca-rich transients.

  12. Early Observations of the Type Ia Supernova iPTF 16abc: A Case of Interaction with Nearby, Unbound Material and/or Strong Ejecta Mixing

    NASA Astrophysics Data System (ADS)

    Miller, A. A.; Cao, Y.; Piro, A. L.; Blagorodnova, N.; Bue, B. D.; Cenko, S. B.; Dhawan, S.; Ferretti, R.; Fox, O. D.; Fremling, C.; Goobar, A.; Howell, D. A.; Hosseinzadeh, G.; Kasliwal, M. M.; Laher, R. R.; Lunnan, R.; Masci, F. J.; McCully, C.; Nugent, P. E.; Sollerman, J.; Taddia, F.; Kulkarni, S. R.

    2018-01-01

    Early observations of Type Ia supernovae (SNe Ia) provide a unique probe of their progenitor systems and explosion physics. Here we report the intermediate Palomar Transient Factory (iPTF) discovery of an extraordinarily young SN Ia, iPTF 16abc. By fitting a power law to our early light curve, we infer that first light for the SN, that is, when the SN could have first been detected by our survey, occurred only 0.15{+/- }0.070.15 days before our first detection. In the ∼24 hr after discovery, iPTF 16abc rose by ∼2 mag, featuring a near-linear rise in flux for ≳ 3 days. Early spectra show strong C II absorption, which disappears after ∼7 days. Unlike the extensively observed Type Ia SN 2011fe, the {(B-V)}0 colors of iPTF 16abc are blue and nearly constant in the days after explosion. We show that our early observations of iPTF 16abc cannot be explained by either SN shock breakout and the associated, subsequent cooling or the SN ejecta colliding with a stellar companion. Instead, we argue that the early characteristics of iPTF 16abc, including (i) the rapid, near-linear rise, (ii) the nonevolving blue colors, and (iii) the strong C II absorption, are the result of either ejecta interaction with nearby, unbound material or vigorous mixing of radioactive 56Ni in the SN ejecta, or a combination of the two. In the next few years, dozens of very young normal SNe Ia will be discovered, and observations similar to those presented here will constrain the white dwarf explosion mechanism.

  13. The peculiar Type Ia supernova iPTF14atg: Chandrasekhar-mass explosion or violent merger?

    NASA Astrophysics Data System (ADS)

    Kromer, M.; Fremling, C.; Pakmor, R.; Taubenberger, S.; Amanullah, R.; Cenko, S. B.; Fransson, C.; Goobar, A.; Leloudas, G.; Taddia, F.; Röpke, F. K.; Seitenzahl, I. R.; Sim, S. A.; Sollerman, J.

    2016-07-01

    iPTF14atg, a subluminous peculiar Type Ia supernova (SN Ia) similar to SN 2002es, is the first SN Ia for which a strong UV flash was observed in the early-time light curves. This has been interpreted as evidence for a single-degenerate (SD) progenitor system, where such a signal is expected from interactions between the SN ejecta and the non-degenerate companion star. Here, we compare synthetic observables of multidimensional state-of-the-art explosion models for different progenitor scenarios to the light curves and spectra of iPTF14atg. From our models, we have difficulties explaining the spectral evolution of iPTF14atg within the SD progenitor channel. In contrast, we find that a violent merger of two carbon-oxygen white dwarfs with 0.9 and 0.76 M⊙, respectively, provides an excellent match to the spectral evolution of iPTF14atg from 10 d before to several weeks after maximum light. Our merger model does not naturally explain the initial UV flash of iPTF14atg. We discuss several possibilities like interactions of the SN ejecta with the circumstellar medium and surface radioactivity from an He-ignited merger that may be able to account for the early UV emission in violent merger models.

  14. Steroidogenic factor-1 (SF-1, NR5A1) and human disease

    PubMed Central

    Ferraz-de-Souza, Bruno; Lin, Lin; Achermann, John C.

    2011-01-01

    Steroidogenic factor-1 (SF-1, Ad4BP, encoded by NR5A1) is a key regulator of adrenal and reproductive development and function. Based upon the features found in Nr5a1 null mice, initial attempts to identify SF-1 changes in humans focused on those rare individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis and Müllerian structures. Although alterations affecting DNA-binding of SF-1 were found in two such cases, disruption of SF-1 is not commonly found in patients with adrenal failure. In contrast, it is emerging that variations in SF-1 can be found in association with a range of human reproductive phenotypes such as 46,XY disorders of sex development (DSD), hypospadias, anorchia, male factor infertility, or primary ovarian insufficiency in women. Overexpression or overactivity of SF-1 is also reported in some adrenal tumors or endometriosis. Therefore, the clinical spectrum of phenotypes associated with variations in SF-1 is expanding and the importance of this nuclear receptor in human endocrine disease is now firmly established. PMID:21078366

  15. Early Observations of the Type Ia Supernova iPTF 16abc: A Case of Interaction with Nearby, Unbound Material and/or Strong Ejecta Mixing

    DOE PAGES

    Miller, A. A.; Cao, Y.; Piro, A. L.; ...

    2018-01-11

    Early observations of Type Ia supernovae (SNe Ia) provide a unique probe of their progenitor systems and explosion physics. Here we report the intermediate Palomar Transient Factory (iPTF) discovery of an extraordinarily young SN Ia, iPTF 16abc. By fitting a power law to our early light curve, we infer that first light for the SN, that is when the SN could have first been detected by our survey, occurred onlymore » $$0.15\\pm_{0.07}^{0.15}$$ days before our first detection. In the $$\\sim$$24 hr after discovery, iPTF 16abc rose by $$\\sim$$2 mag, featuring a near-linear rise in flux for $$\\gtrsim$$3 days. Early spectra show strong C II absorption, which disappears after $$\\sim$$7 days. Unlike the extensivelyobserved SN Ia SN 2011fe, the $$(B-V)_0$$ colors of iPTF 16abc are blue and nearly constant in the days after explosion. We show that our early observations of iPTF 16abc cannot be explained by either SN shock breakout and the associated, subsequent cooling or the SN ejecta colliding with a stellar companion. Instead, we argue that the early characteristics of iPTF 16abc, including (i) the rapid, near-linear rise, (ii) the nonevolving blue colors, and (iii) the strong C II absorption, are the result of either ejecta interaction with nearby, unbound material or vigorous mixing of radioactive 56Ni in the SN ejecta, or a combination of the two. Finally, in the next few years, dozens of very young normal SNe Ia will be discovered, and observations similar to those presented here will constrain the white dwarf explosion mechanism.« less

  16. Early Observations of the Type Ia Supernova iPTF 16abc: A Case of Interaction with Nearby, Unbound Material and/or Strong Ejecta Mixing

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Miller, A. A.; Cao, Y.; Piro, A. L.

    Early observations of Type Ia supernovae (SNe Ia) provide a unique probe of their progenitor systems and explosion physics. Here we report the intermediate Palomar Transient Factory (iPTF) discovery of an extraordinarily young SN Ia, iPTF 16abc. By fitting a power law to our early light curve, we infer that first light for the SN, that is when the SN could have first been detected by our survey, occurred onlymore » $$0.15\\pm_{0.07}^{0.15}$$ days before our first detection. In the $$\\sim$$24 hr after discovery, iPTF 16abc rose by $$\\sim$$2 mag, featuring a near-linear rise in flux for $$\\gtrsim$$3 days. Early spectra show strong C II absorption, which disappears after $$\\sim$$7 days. Unlike the extensivelyobserved SN Ia SN 2011fe, the $$(B-V)_0$$ colors of iPTF 16abc are blue and nearly constant in the days after explosion. We show that our early observations of iPTF 16abc cannot be explained by either SN shock breakout and the associated, subsequent cooling or the SN ejecta colliding with a stellar companion. Instead, we argue that the early characteristics of iPTF 16abc, including (i) the rapid, near-linear rise, (ii) the nonevolving blue colors, and (iii) the strong C II absorption, are the result of either ejecta interaction with nearby, unbound material or vigorous mixing of radioactive 56Ni in the SN ejecta, or a combination of the two. Finally, in the next few years, dozens of very young normal SNe Ia will be discovered, and observations similar to those presented here will constrain the white dwarf explosion mechanism.« less

  17. Strong near-infrared carbon in the Type Ia supernova iPTF13ebh

    DOE PAGES

    Hsiao, E. Y.; Burns, C. R.; Contreras, C.; ...

    2015-05-22

    We present near-infrared (NIR) time-series spectroscopy, as well as complementary ultraviolet (UV), optical, and NIR data, of the Type Ia supernova (SN Ia) iPTF13ebh, which was discovered within two days from the estimated time of explosion. The first NIR spectrum was taken merely 2.3 days after explosion and may be the earliest NIR spectrum yet obtained of a SN Ia. The most striking features in the spectrum are several NIR C I lines, and the C Iλ1.0693 μm line is the strongest ever observed in a SN Ia. Interestingly, no strong optical C II counterparts were found, even though themore » optical spectroscopic time series began early and is densely cadenced. Except at the very early epochs, within a few days from the time of explosion, we show that the strong NIR C I compared to the weaker optical C II appears to be general in SNe Ia. iPTF13ebh is a fast decliner with Δm15(B) = 1.79 ± 0.01, and its absolute magnitude obeys the linear part of the width-luminosity relation. It is therefore categorized as a “transitional” event, on the fast-declining end of normal SNe Ia as opposed to subluminous/91bg-like objects. iPTF13ebh shows NIR spectroscopic properties that are distinct from both the normal and subluminous/91bg-like classes, bridging the observed characteristics of the two classes. These NIR observations suggest that composition and density of the inner core are similar to that of 91bg-like events, and that it has a deep-reaching carbon burning layer that is not observed in more slowly declining SNe Ia. Furthermore, there is also a substantial difference between the explosion times inferred from the early-time light curve and the velocity evolution of the Si II λ0.6355 μm line, implying a long dark phase of ~4 days.« less

  18. PTF11kx: A Type Ia Supernova with Hydrogen Emission Persisting after 3.5 Years

    DOE PAGES

    Graham, M. L.; Harris, C. E.; Fox, O. D.; ...

    2017-07-11

    The optical transient PTF11kx exhibited both the characteristic spectral features of Type Ia supernovae (SNe Ia) and the signature of ejecta interacting with circumstellar material (CSM) containing hydrogen, indicating the presence of a nondegenerate companion. In this paper, we present an optical spectrum at 1342 days after peak from Keck Observatory, in which the broad component of Hα emission persists with a similar profile as in early-time observations. We also present Spitzer IRAC detections obtained 1237 and 1818 days after peak, and an upper limit from Hubble Space Telescope ultraviolet imaging at 2133 days. We interpret our late-time observations inmore » the context of published results—and reinterpret the early-time observations—in order to constrain the CSM's physical parameters and to compare to theoretical predictions for recurrent-nova systems. We find that the CSM's radial extent may be several times the distance between the star and the CSM's inner edge, and that the CSM column density may be two orders of magnitude lower than previous estimates. We show that the Hα luminosity decline is similar to other SNe with CSM interaction and demonstrate how our infrared photometry is evidence for newly formed, collisionally heated dust. We create a model for PTF11kx's late-time CSM interaction and find that X-ray reprocessing by photoionization and recombination cannot reproduce the observed Hα luminosity, suggesting that the X-rays are thermalized and that Hα radiates from collisional excitation. In conclusion, we discuss the implications of our results regarding the progenitor scenario and the geometric properties of the CSM for the PTF11kx system.« less

  19. PTF11kx: A Type Ia Supernova with Hydrogen Emission Persisting after 3.5 Years

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Graham, M. L.; Harris, C. E.; Fox, O. D.

    The optical transient PTF11kx exhibited both the characteristic spectral features of Type Ia supernovae (SNe Ia) and the signature of ejecta interacting with circumstellar material (CSM) containing hydrogen, indicating the presence of a nondegenerate companion. In this paper, we present an optical spectrum at 1342 days after peak from Keck Observatory, in which the broad component of Hα emission persists with a similar profile as in early-time observations. We also present Spitzer IRAC detections obtained 1237 and 1818 days after peak, and an upper limit from Hubble Space Telescope ultraviolet imaging at 2133 days. We interpret our late-time observations inmore » the context of published results—and reinterpret the early-time observations—in order to constrain the CSM's physical parameters and to compare to theoretical predictions for recurrent-nova systems. We find that the CSM's radial extent may be several times the distance between the star and the CSM's inner edge, and that the CSM column density may be two orders of magnitude lower than previous estimates. We show that the Hα luminosity decline is similar to other SNe with CSM interaction and demonstrate how our infrared photometry is evidence for newly formed, collisionally heated dust. We create a model for PTF11kx's late-time CSM interaction and find that X-ray reprocessing by photoionization and recombination cannot reproduce the observed Hα luminosity, suggesting that the X-rays are thermalized and that Hα radiates from collisional excitation. In conclusion, we discuss the implications of our results regarding the progenitor scenario and the geometric properties of the CSM for the PTF11kx system.« less

  20. PTF discovers and follows-up nearby, young, Type II supernova

    NASA Astrophysics Data System (ADS)

    Kasliwal, M. M.; Quimby, R. M.; Ofek, E. O.; Kulkarni, S. R.; Gal-Yam, A.; Arcavi, I.; Green, Y.; Walker, E.; Mazzali, P.; Nugent, P. E.; Poznanski, D.; Howell, D. A.; Dilday, B.; Fox, D. B.

    2010-09-01

    On UT 2010 Sep 15.243, the <a href='http://www.astro.caltech.edu/ptf'> Palomar Transient Factory a> discovered an optical transient, PTF10vdl at RA(J2000) = 23:05:49.001 and DEC(J2000)=03:31:20.50 near NGC 7483. We obtained Target Of Opportunity spectra with Gemini-S/GMOS (PI Kasliwal) on Sep 16.29. The spectrum was extremely blue (f_nu proportional to nu^4.5) and nearly featureless. We further obtained a spectrum with the TNG/DOLORES (PI Walker) on Sep 17.40 and P-Cygni profiles of four Balmer lines were clearly visible, consistent with the redshift of NGC 7483, suggesting this is a Type II supernova.

  1. PTF13efv—AN OUTBURST 500 DAYS PRIOR TO THE SNHUNT 275 EXPLOSION AND ITS RADIATIVE EFFICIENCY

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ofek, E. O.; Strotjohann, N.-L.; Rubin, A.

    The progenitors of some supernovae (SNe) exhibit outbursts with super-Eddington luminosities prior to their final explosions. This behavior is common among SNe IIn, but the driving mechanisms of these precursors are not yet well-understood. SNHunt 275 was announced as a possible new SN during 2015 May. Here we report on pre-explosion observations of the location of this event by the Palomar Transient Factory (PTF) and report the detection of a precursor about 500 days prior to the 2015 May activity (PTF 13efv). The observed velocities in the 2015 transient and its 2013 precursor absorption spectra are low (1000–2000 km s{supmore » −1}), so it is not clear yet if the recent activity indeed marks the final disruption of the progenitor. Regardless of the nature of this event, we use the PTF photometric and spectral observations, as well as Swift -UVOT observations, to constrain the efficiency of the radiated energy relative to the total kinetic energy of the precursor. We find that, using an order-of-magnitude estimate and under the assumption of spherical symmetry, the ratio of the radiated energy to the kinetic energy is in the range of 4 × 10{sup −2} to 3.4 × 10{sup 3}.« less

  2. Nebular phase observations of the Type-Ib supernova iPTF13bvn favour a binary progenitor

    NASA Astrophysics Data System (ADS)

    Kuncarayakti, H.; Maeda, K.; Bersten, M. C.; Folatelli, G.; Morrell, N.; Hsiao, E. Y.; González-Gaitán, S.; Anderson, J. P.; Hamuy, M.; de Jaeger, T.; Gutiérrez, C. P.; Kawabata, K. S.

    2015-07-01

    Aims: We present and analyse late-time observations of the Type-Ib supernova with possible pre-supernova progenitor detection, iPTF13bvn, which were done ~300 days after the explosion. We discuss them in the context of constraints on the supernova's progenitor. Previous studies have proposed two possible natures for the progenitor of the supernova, i.e. a massive Wolf-Rayet star or a lower-mass star in a close binary system. Methods: Our observations show that the supernova has entered the nebular phase, with the spectrum dominated by Mg I]λλ4571, [O I]λλ6300, 6364, and [Ca II]λλ7291, 7324 emission lines. We measured the emission line fluxes to estimate the core oxygen mass and compared the [O I]/[Ca II] line ratio with other supernovae. Results.The core oxygen mass of the supernova progenitor was estimated to be ≲0.7 M⊙, which implies initial progenitor mass that does not exceed ~15-17 M⊙.Since the derived mass is too low for a single star to become a Wolf-Rayet star, this result lends more support to the binary nature of the progenitor star of iPTF13bvn. The comparison of [O I]/[Ca II] line ratio with other supernovae also shows that iPTF13bvn appears to be in close association with the lower mass progenitors of stripped-envelope and Type-II supernovae. Based on observations obtained at the Southern Astrophysical Research (SOAR) telescope, which is a joint project of the Ministério da Ciência, Tecnologia, e Inovação (MCTI) da República Federativa do Brasil, the US National Optical Astronomy Observatory (NOAO), the University of North Carolina at Chapel Hill (UNC), and Michigan State University (MSU); Chilean Telescope Time Allocation Committee proposal CN2014A-91.

  3. VizieR Online Data Catalog: Imaging observations of iPTF 13ajg (Vreeswijk+, 2014)

    NASA Astrophysics Data System (ADS)

    Vreeswijk, P. M.; Savaglio, S.; Gal-Yam, A.; De Cia, A.; Quimby, R. M.; Sullivan, M.; Cenko, S. B.; Perley, D. A.; Filippenko, A. V.; Clubb, K. I.; Taddia, F.; Sollerman, J.; Leloudas, G.; Arcavi, I.; Rubin, A.; Kasliwal, M. M.; Cao, Y.; Yaron, O.; Tal, D.; Ofek, E. O.; Capone, J.; Kutyrev, A. S.; Toy, V.; Nugent, P. E.; Laher, R.; Surace, J.; Kulkarni, S. R.

    2017-08-01

    iPTF 13ajg was imaged with the Palomar 48 inch (P48) Oschin iPTF survey telescope equipped with a 12kx8k CCD mosaic camera (Rahmer et al. 2008SPIE.7014E..4YR) in the Mould R filter, the Palomar 60 inch and CCD camera (Cenko et al. 2006PASP..118.1396C) in Johnson B and Sloan Digital Sky Survey (SDSS) gri, the 2.56 m Nordic Optical Telescope (on La Palma, Canary Islands) with the Andalucia Faint Object Spectrograph and Camera (ALFOSC) in SDSS ugriz, the 4.3 m Discovery Channel Telescope (at Lowell Observatory, Arizona) with the Large Monolithic Imager (LMI) in SDSS r, and with LRIS (Oke et al. 1995PASP..107..375O) and the Multi-Object Spectrometer for Infrared Exploration (MOSFIRE; McLean et al. 2012SPIE.8446E..0JM), both mounted on the 10 m Keck-I telescope (on Mauna Kea, Hawaii), in g and Rs with LRIS and J and Ks with MOSFIRE. (1 data file).

  4. Interpreting the Strongly Lensed Supernova iPTF16geu: Time Delay Predictions, Microlensing, and Lensing Rates

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    More, Anupreeta; Oguri, Masamune; More, Surhud

    2017-02-01

    We present predictions for time delays between multiple images of the gravitationally lensed supernova, iPTF16geu, which was recently discovered from the intermediate Palomar Transient Factory (iPTF). As the supernova is of Type Ia where the intrinsic luminosity is usually well known, accurately measured time delays of the multiple images could provide tight constraints on the Hubble constant. According to our lens mass models constrained by the Hubble Space Telescope F814W image, we expect the maximum relative time delay to be less than a day, which is consistent with the maximum of 100 hr reported by Goobar et al. but placesmore » a stringent upper limit. Furthermore, the fluxes of most of the supernova images depart from expected values suggesting that they are affected by microlensing. The microlensing timescales are small enough that they may pose significant problems to measure the time delays reliably. Our lensing rate calculation indicates that the occurrence of a lensed SN in iPTF is likely. However, the observed total magnification of iPTF16geu is larger than expected, given its redshift. This may be a further indication of ongoing microlensing in this system.« less

  5. Metallicity from Type II supernovae from the (i)PTF

    DOE PAGES

    Taddia, F.; Moquist, P.; Sollerman, J.; ...

    2016-03-01

    Type IIP supernovae (SNe IIP) have recently been proposed as metallicity (Z) probes. The spectral models of Dessart et al. (2014, MNRAS, 440, 1856) showed that the pseudo-equivalent width of Fe ii λ5018 (pEW 5018) during the plateau phase depends on the primordial Z, but there was a paucity of SNe IIP exhibiting pEW 5018 that were compatible with Z < 0.4 Z ⊙. This lack might be due to some physical property of the SN II population or to the fact that those SNe have been discovered in luminous, metal-rich targeted galaxies. In this paper, we use SN IImore » observations from the untargeted (intermediate) Palomar Transient Factory [(i)PTF] survey, aiming to investigate the pEW 5018 distribution of this SN population and, in particular, to look for the presence of SNe II at lower Z. We perform pEW 5018 measurements on the spectra of a sample of 39 (i)PTF SNe II, selected to have well-constrained explosion epochs and light-curve properties. Based on the comparison with the pEW 5018 spectral models, we subgrouped our SNe into four Z bins from Z ≈ 0.1 Z ⊙ up to Z ≈ 2 Z ⊙. We also independently investigated the Z of the hosts by using their absolute magnitudes and colors and, in a few cases, using strong-line diagnostics from spectra. We searched for possible correlations between SN observables, such as their peak magnitudes and the Z inferred from pEW 5018. We found 11 events with pEW 5018 that were small enough to indicate Z ≈ 0.1 Z ⊙. The trend of pEW 5018 with Z matches the Z estimates obtained from the host-galaxy photometry, although the significance of the correlation is weak. Finally, we also found that SNe with brighter peak magnitudes have smaller pEW 5018 and occur at lower Z.« less

  6. ptf1a+ , ela3l- cells are developmentally maintained progenitors for exocrine regeneration following extreme loss of acinar cells in zebrafish larvae.

    PubMed

    Schmitner, Nicole; Kohno, Kenji; Meyer, Dirk

    2017-03-01

    The exocrine pancreas displays a significant capacity for regeneration and renewal. In humans and mammalian model systems, the partial loss of exocrine tissue, such as after acute pancreatitis or partial pancreatectomy induces rapid recovery via expansion of surviving acinar cells. In mouse it was further found that an almost complete removal of acinar cells initiates regeneration from a currently not well-defined progenitor pool. Here, we used the zebrafish as an alternative model to study cellular mechanisms of exocrine regeneration following an almost complete removal of acinar cells. We introduced and validated two novel transgenic approaches for genetically encoded conditional cell ablation in the zebrafish, either by caspase-8-induced apoptosis or by rendering cells sensitive to diphtheria toxin. By using the ela3l promoter for exocrine-specific expression, we show that both approaches allowed cell-type-specific removal of >95% of acinar tissue in larval and adult zebrafish without causing any signs of unspecific side effects. We find that zebrafish larvae are able to recover from a virtually complete acinar tissue ablation within 2 weeks. Using short-term lineage-tracing experiments and EdU incorporation assays, we exclude duct-associated Notch-responsive cells as the source of regeneration. Rather, a rare population of slowly dividing ela3l- negative cells expressing ptf1a and CPA was identified as the origin of the newly forming exocrine cells. Cells are actively maintained, as revealed by a constant number of these cells at different larval stages and after repeated cell ablation. These cells establish ela3l expression about 4-6 days after ablation without signs of increased proliferation in between. With onset of ela3l expression, cells initiate rapid proliferation, leading to fast expansion of the ela3l -positive population. Finally, we show that this proliferation is blocked by overexpression of the Wnt-signaling antagonist dkk1b In conclusion, we

  7. ptf1a+, ela3l− cells are developmentally maintained progenitors for exocrine regeneration following extreme loss of acinar cells in zebrafish larvae

    PubMed Central

    Schmitner, Nicole; Kohno, Kenji

    2017-01-01

    ABSTRACT The exocrine pancreas displays a significant capacity for regeneration and renewal. In humans and mammalian model systems, the partial loss of exocrine tissue, such as after acute pancreatitis or partial pancreatectomy induces rapid recovery via expansion of surviving acinar cells. In mouse it was further found that an almost complete removal of acinar cells initiates regeneration from a currently not well-defined progenitor pool. Here, we used the zebrafish as an alternative model to study cellular mechanisms of exocrine regeneration following an almost complete removal of acinar cells. We introduced and validated two novel transgenic approaches for genetically encoded conditional cell ablation in the zebrafish, either by caspase-8-induced apoptosis or by rendering cells sensitive to diphtheria toxin. By using the ela3l promoter for exocrine-specific expression, we show that both approaches allowed cell-type-specific removal of >95% of acinar tissue in larval and adult zebrafish without causing any signs of unspecific side effects. We find that zebrafish larvae are able to recover from a virtually complete acinar tissue ablation within 2 weeks. Using short-term lineage-tracing experiments and EdU incorporation assays, we exclude duct-associated Notch-responsive cells as the source of regeneration. Rather, a rare population of slowly dividing ela3l-negative cells expressing ptf1a and CPA was identified as the origin of the newly forming exocrine cells. Cells are actively maintained, as revealed by a constant number of these cells at different larval stages and after repeated cell ablation. These cells establish ela3l expression about 4-6 days after ablation without signs of increased proliferation in between. With onset of ela3l expression, cells initiate rapid proliferation, leading to fast expansion of the ela3l-positive population. Finally, we show that this proliferation is blocked by overexpression of the Wnt-signaling antagonist dkk1b. In

  8. Early Radio and X-Ray Observations of the Youngest Nearby Type Ia Supernova PTF 11kly (SN 2011fe)

    NASA Technical Reports Server (NTRS)

    Horesh, Assaf; Kulkarni, S. R.; Fox, Derek B.; Carpenter, John; Kasliwal, Mansi M.; Ofek, Eran O.; Quimby, Robert; Gal-Yam, Avishay; Cenko, S. Bradley; deBruyn, A. G.; hide

    2012-01-01

    On August 24 (UT) the Palomar Transient Factory (PTF) discovered PTF11kly (SN 2011fe), the youngest and most nearby type Ia supernova (SN Ia) in decades. We followed this event up in the radio (centimeter and millimeter bands) and X-ray bands, starting about a day after the estimated explosion time. We present our analysis of the radio and X-ray observations, yielding the tightest constraints yet placed on the pre-explosion mass-loss rate from the progenitor system of this supernova. We find a robust limit of M(raised dot) less than or equal to 10(exp -8) (w /100 kilometers per second ) solar mass yr(exp -1) from sensitive X-ray non-detections, as well as a similar limit from radio data, which depends, however, on assumptions about microphysical parameters. We discuss our results in the context of single-degenerate models for SNe Ia and find that our observations modestly disfavor symbiotic progenitor models involving a red giant donor, but cannot constrain systems accreting from main sequence or sub-giant stars, including the popular supersoft channel. In view of the proximity of PTF11kly and the sensitivity of our prompt observations we would have to wait for a long time (decade or longer) in order to more meaningfully probe the circumstellar matter of Ia supernovae.

  9. Radio Observations of a Sample of Broad-Line Type IC Supernovae Discovered by PTF/IPTF: A Search for Relativistic Explosions

    DOE PAGES

    Corsi, Alessandra; Gal-Yam, A.; Kulkarni, S. R.; ...

    2016-10-10

    Long duration γ-ray bursts are a rare subclass of stripped-envelope core-collapse supernovae (SNe) that launch collimated relativistic outflows (jets). All γ-ray-burst-associated SNe are spectroscopically Type Ic, with broad-lines, but the fraction of broad-lined SNe Ic harboring low-luminosity γ-ray bursts remains largely unconstrained. Some SNe should be accompanied by off-axis γ-ray burst jets that initially remain invisible, but then emerge as strong radio sources (as the jets decelerate). However, this critical prediction of the jet model for γ-ray bursts has yet to be verified observationally. Here, we present K. G. Jansky Very Large Array observations of 15 broad-lined SNe of Type Ic discovered by the Palomar Transient Factory in an untargeted manner. Most of the SNe in our sample exclude radio emission observationally similar to that of the radio-loud, relativistic SN 1998bw. We constrain the fraction of 1998bw-like broad-lined SNe Ic to bemore » $$\\lesssim 41 \\% $$ (99.865% confidence). Most of the events in our sample also exclude off-axis jets similar to GRB 031203 and GRB 030329, but we cannot rule out off-axis γ-ray bursts expanding in a low-density wind environment. Three SNe in our sample are detected in the radio. PTF11qcj and PTF14dby show late-time radio emission with average ejecta speeds of ≈0.3–0.4 c, on the dividing line between relativistic and "ordinary" SNe. The speed of PTF11cmh radio ejecta is poorly constrained. We estimate that $$\\lesssim 85 \\% $$ (99.865% confidence) of the broad-lined SNe Ic in our sample may harbor off-axis γ-ray bursts expanding in media with densities in the range probed by this study.« less

  10. Fructose Degradation in the Haloarchaeon Haloferax volcanii Involves a Bacterial Type Phosphoenolpyruvate-Dependent Phosphotransferase System, Fructose-1-Phosphate Kinase, and Class II Fructose-1,6-Bisphosphate Aldolase

    PubMed Central

    Pickl, Andreas; Johnsen, Ulrike

    2012-01-01

    The halophilic archaeon Haloferax volcanii utilizes fructose as a sole carbon and energy source. Genes and enzymes involved in fructose uptake and degradation were identified by transcriptional analyses, deletion mutant experiments, and enzyme characterization. During growth on fructose, the gene cluster HVO_1495 to HVO_1499, encoding homologs of the five bacterial phosphotransferase system (PTS) components enzyme IIB (EIIB), enzyme I (EI), histidine protein (HPr), EIIA, and EIIC, was highly upregulated as a cotranscript. The in-frame deletion of HVO_1499, designated ptfC (ptf stands for phosphotransferase system for fructose) and encoding the putative fructose-specific membrane component EIIC, resulted in a loss of growth on fructose, which could be recovered by complementation in trans. Transcripts of HVO_1500 (pfkB) and HVO_1494 (fba), encoding putative fructose-1-phosphate kinase (1-PFK) and fructose-1,6-bisphosphate aldolase (FBA), respectively, as well as 1-PFK and FBA activities were specifically upregulated in fructose-grown cells. pfkB and fba knockout mutants did not grow on fructose, whereas growth on glucose was not inhibited, indicating the functional involvement of both enzymes in fructose catabolism. Recombinant 1-PFK and FBA obtained after homologous overexpression were characterized as having kinetic properties indicative of functional 1-PFK and a class II type FBA. From these data, we conclude that fructose uptake in H. volcanii involves a fructose-specific PTS generating fructose-1-phosphate, which is further converted via fructose-1,6-bisphosphate to triose phosphates by 1-PFK and FBA. This is the first report of the functional involvement of a bacterial-like PTS and of class II FBA in the sugar metabolism of archaea. PMID:22493022

  11. Disc origin of broad optical emission lines of the TDE candidate PTF09djl

    NASA Astrophysics Data System (ADS)

    Liu, F. K.; Zhou, Z. Q.; Cao, R.; Ho, L. C.; Komossa, S.

    2017-11-01

    An otherwise dormant supermassive black hole (SMBH) in a galactic nucleus flares up when it tidally disrupts a star passing by. Most of the tidal disruption events (TDEs) and candidates discovered in the optical/UV have broad optical emission lines with complex and diverse profiles of puzzling origin. In this Letter, we show that the double-peaked broad H α line of the TDE candidate PTF09djl can be well modelled with a relativistic elliptical accretion disc and the peculiar substructures with one peak at the line rest wavelength and the other redshifted to about 3.5 × 104 km s-1 are mainly due to the orbital motion of the emitting matter within the disc plane of large inclination 88° and pericentre orientation nearly vertical to the observer. The accretion disc has an extreme eccentricity 0.966 and semimajor axis of 340 BH Schwarzschild radii. The viewing angle effects of large disc inclination lead to significant attenuation of He emission lines originally produced at large electron scattering optical depth and to the absence/weakness of He emission lines in the spectra of PTF09djl. Our results suggest that the diversities of line intensity ratios among the line species in optical TDEs are probably due to the differences of disc inclinations.

  12. Thermoelectric Power Factor Limit of a 1D Nanowire

    NASA Astrophysics Data System (ADS)

    Chen, I.-Ju; Burke, Adam; Svilans, Artis; Linke, Heiner; Thelander, Claes

    2018-04-01

    In the past decade, there has been significant interest in the potentially advantageous thermoelectric properties of one-dimensional (1D) nanowires, but it has been challenging to find high thermoelectric power factors based on 1D effects in practice. Here we point out that there is an upper limit to the thermoelectric power factor of nonballistic 1D nanowires, as a consequence of the recently established quantum bound of thermoelectric power output. We experimentally test this limit in quasiballistic InAs nanowires by extracting the maximum power factor of the first 1D subband through I -V characterization, finding that the measured maximum power factors conform to the theoretical limit. The established limit allows the prediction of the achievable power factor of a specific nanowire material system with 1D electronic transport based on the nanowire dimension and mean free path. The power factor of state-of-the-art semiconductor nanowires with small cross section and high crystal quality can be expected to be highly competitive (on the order of mW /m K2 ) at low temperatures. However, they have no clear advantage over bulk materials at, or above, room temperature.

  13. Thermoelectric Power Factor Limit of a 1D Nanowire.

    PubMed

    Chen, I-Ju; Burke, Adam; Svilans, Artis; Linke, Heiner; Thelander, Claes

    2018-04-27

    In the past decade, there has been significant interest in the potentially advantageous thermoelectric properties of one-dimensional (1D) nanowires, but it has been challenging to find high thermoelectric power factors based on 1D effects in practice. Here we point out that there is an upper limit to the thermoelectric power factor of nonballistic 1D nanowires, as a consequence of the recently established quantum bound of thermoelectric power output. We experimentally test this limit in quasiballistic InAs nanowires by extracting the maximum power factor of the first 1D subband through I-V characterization, finding that the measured maximum power factors conform to the theoretical limit. The established limit allows the prediction of the achievable power factor of a specific nanowire material system with 1D electronic transport based on the nanowire dimension and mean free path. The power factor of state-of-the-art semiconductor nanowires with small cross section and high crystal quality can be expected to be highly competitive (on the order of mW/m K^{2}) at low temperatures. However, they have no clear advantage over bulk materials at, or above, room temperature.

  14. Pretreatment Engineering Platform Phase 1 Final Test Report

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kurath, Dean E.; Hanson, Brady D.; Minette, Michael J.

    2009-12-23

    Pacific Northwest National Laboratory (PNNL) was tasked by Bechtel National Inc. (BNI) on the River Protection Project, Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to conduct testing to demonstrate the performance of the WTP Pretreatment Facility (PTF) leaching and ultrafiltration processes at an engineering-scale. In addition to the demonstration, the testing was to address specific technical issues identified in Issue Response Plan for Implementation of External Flowsheet Review Team (EFRT) Recommendations - M12, Undemonstrated Leaching Processes.( ) Testing was conducted in a 1/4.5-scale mock-up of the PTF ultrafiltration system, the Pretreatment Engineering Platform (PEP). Parallel laboratory testing wasmore » conducted in various PNNL laboratories to allow direct comparison of process performance at an engineering-scale and a laboratory-scale. This report presents and discusses the results of those tests.« less

  15. Nfatc1 Is a Functional Transcriptional Factor Mediating Nell-1-Induced Runx3 Upregulation in Chondrocytes.

    PubMed

    Li, Chenshuang; Zheng, Zhong; Zhang, Xinli; Asatrian, Greg; Chen, Eric; Song, Richard; Culiat, Cymbeline; Ting, Kang; Soo, Chia

    2018-01-06

    Neural EGFL like 1 (Nell-1) is essential for chondrogenic differentiation, maturation, and regeneration. Our previous studies have demonstrated that Nell-1's pro-chondrogenic activities are predominantly reliant upon runt-related transcription factor 3 (Runx3)-mediated Indian hedgehog (Ihh) signaling. Here, we identify the nuclear factor of activated T-cells 1 (Nfatc1) as the key transcriptional factor mediating the Nell-1 → Runx3 signal transduction in chondrocytes. Using chromatin immunoprecipitation assay, we were able to determine that Nfatc1 binds to the -833--810 region of the Runx3 -promoter in response to Nell-1 treatment. By revealing the Nell-1 → Nfatc1 → Runx3 → Ihh cascade, we demonstrate the involvement of Nfatc1, a nuclear factor of activated T-cells, in chondrogenesis, while providing innovative insights into developing a novel therapeutic strategy for cartilage regeneration and other chondrogenesis-related conditions.

  16. Ecological factors associated with pandemic influenza A (H1N1) hospitalization rates in California, USA: a geospatial analysis.

    PubMed

    Maliszewski, Paul J; Wei, Ran

    2011-11-01

    The 2009 H1N1 influenza A virus subtype (H1N1) pandemic had a large impact in the United States of America (USA), causing an estimated 192,000 to 398,000 hospitalizations and 8,720 to 18,050 deaths between April 2009 and mid-March 2010. Recent research on the 2009 H1N1 pandemic has largely focused on individual, non-spatial demographic characterizations (e.g. age and race/ethnicity) associated with H1N1 hospitalizations. Broader ecological factors such as transportation use, land use and other socioeconomic factors are important aspects of influenza studies that have not been empirically examined. This research explores and identifies ecological factors associated with 2009 H1N1 pandemic hospitalization rates. We conducted a spatial regression analysis of county level hospitalization rates from 3 April to 15 September, 2009 obtained via the California Department of Public Health. Hospitalization rates were found to be spatially dependent. Public transportation usage rates and agricultural land use proportions were significant environmental factors positively related to hospitalization rates. Consistent with public health official's assumptions and existing evidence, county percentages of persons less than 18 years of age were positively associated with hospitalization. These findings help to clarify the limited consensus and dubious evidence on the role of broader ecological factors associated with pandemic influenza. A better understanding of the ecological risk factors associated with hospitalizations should also benefit public health officials with respect to their work aiming at improving emergency supply allocation and non-pharmaceutical intervention strategies in the context of an influenza pandemic.

  17. The Mouse Model of Pancreatic Cancer Atlas (MMPCA) for classification of pancreatic cancer lesions: A large histological investigation of the Ptf1aCre/+;LSL-KrasG12D/+ transgenic mouse model of pancreatic cancer

    PubMed Central

    Veite-Schmahl, Michelle J.; Rivers, Adam C.; Regan, Daniel P.

    2017-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the leading forms of cancer related deaths in the United States. With limited treatment options and unreliable diagnostic methods, long-term survival rates following a diagnosis of pancreatic cancer remain poor. Pancreatic intraepithelial neoplasia (PanIN) are precancerous lesions that precede progression towards PDAC. PanIN occur in increasing complexity as the disease progresses and the description of PanIN plays a critical role in describing, staging and diagnosing PDAC. Inconsistencies in PanIN classifications exist even amongst leading pathologists. This has led to debate and confusion among researchers and pathologists involved in pancreatic cancer research, diagnosis and treatment. We have sought to initiate a discussion with leading pathologists with a goal of increasing consensus in the interpretation of PanIN and associated structures within the precancerous pancreas. Toward achieving this goal, we are in the process of conducting an extensive study of over 1000 male and female pancreata in varying stages of PanIN progression isolated from the Ptf1aCre/+;LSL-KrasG12D/+ transgenic mouse model of pancreatic cancer. Using this extensive database, we have established the Mouse Model of Pancreatic Cancer Atlas (MMPCA) to serve as a platform for meaningful and interactive discussion among researchers and pathologists who study pancreatic disease. We hope that the MMPCA will be an effective tool for promoting a more consistent and accurate consensus of PanIN classifications in the future. PMID:29121082

  18. Insulin-like growth factor 1 (IGF-1): a growth hormone

    PubMed Central

    Laron, Z

    2001-01-01

    Aim—To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process. Methods—To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice. Results—Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42–47 cm) than healthy babies (49–52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100–136 cm for female and 109–138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8–9 cm in the first year of treatment, compared with 10–12 cm/year during GH treatment of IGHD. The growth rate in following years was 5–6.5 cm/year. Conclusion—IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH. PMID:11577173

  19. Simulation of herbicide degradation in different soils by use of Pedo-transfer functions (PTF) and non-linear kinetics.

    PubMed

    von Götz, N; Richter, O

    1999-03-01

    The degradation behaviour of bentazone in 14 different soils was examined at constant temperature and moisture conditions. Two soils were examined at different temperatures. On the basis of these data the influence of soil properties and temperature on degradation was assessed and modelled. Pedo-transfer functions (PTF) in combination with a linear and a non-linear model were found suitable to describe the bentazone degradation in the laboratory as related to soil properties. The linear PTF can be combined with a rate related to the temperature to account for both soil property and temperature influence at the same time.

  20. The yeast Hot1 transcription factor is critical for activating a single target gene, STL1

    PubMed Central

    Bai, Chen; Tesker, Masha; Engelberg, David

    2015-01-01

    Transcription factors are commonly activated by signal transduction cascades and induce expression of many genes. They therefore play critical roles in determining the cell's fate. The yeast Hog1 MAP kinase pathway is believed to control the transcription of hundreds of genes via several transcription factors. To identify the bona fide target genes of Hog1, we inducibly expressed the spontaneously active variant Hog1D170A+F318L in cells lacking the Hog1 activator Pbs2. This system allowed monitoring the effects of Hog1 by itself. Expression of Hog1D170A+F318L in pbs2∆ cells imposed induction of just 105 and suppression of only 26 transcripts by at least twofold. We looked for the Hog1-responsive element within the promoter of the most highly induced gene, STL1 (88-fold). A novel Hog1 responsive element (HoRE) was identified and shown to be the direct target of the transcription factor Hot1. Unexpectedly, we could not find this HoRE in any other yeast promoter. In addition, the only gene whose expression was abolished in hot1∆ cells was STL1. Thus Hot1 is essential for transcription of just one gene, STL1. Hot1 may represent a class of transcription factors that are essential for transcription of a very few genes or even just one. PMID:25904326

  1. Explaining iPTF14hls as a common-envelope jets supernova

    NASA Astrophysics Data System (ADS)

    Soker, Noam; Gilkis, Avishai

    2018-03-01

    We propose a common-envelope jets supernova scenario for the enigmatic supernova iPTF14hls where a neutron star that spirals-in inside the envelope of a massive giant star accretes mass and launches jets that power the ejection of the circumstellar shell and a few weeks later the explosion itself. To account for the kinetic energy of the circumstellar gas and the explosion, the neutron star should accrete a mass of ≈0.3 M⊙. The tens× M⊙ of circumstellar gas that accounts for some absorption lines is ejected, while the neutron star orbits for about one to several weeks inside the envelope of the giant star. In the last hours of the interaction, the neutron star merges with the core, accretes mass, and launches jets that eject the core and the inner envelope to form the explosion itself and the medium where the supernova photosphere resides. The remaining neutron star accretes fallback gas and further powers the supernova. We attribute the 1954 pre-explosion outburst to an eccentric orbit and temporary mass accretion by the neutron star at periastron passage prior to the onset of the common envelope phase.

  2. Posterior Temporary Fixation Versus Nonoperative Treatment for Anderson-D'Alonzo Type III Odontoid Fractures: Functional Computed Tomography Evaluation of C1-C2 Rotation.

    PubMed

    Guo, Qunfeng; Wang, Liang; Lu, Xuhua; Guo, Xiang; Ni, Bin

    2017-04-01

    To evaluate differences in radiologic and functional outcomes between C1-C2 posterior temporary fixation (PTF) and cephalocervicothoracic cast fixation for type III odontoid fractures. Data from 13 patients who underwent PTF and 13 cases who underwent cephalocervicothoracic cast fixation due to fresh type III odontoid fractures were reviewed retrospectively. All patients with fracture healing underwent a functional computed tomography scan at the final follow-up to evaluate the range of motion in C1-C2 rotation. Functional outcomes were evaluated in the form of visual analog scale for neck pain, neck stiffness, patient satisfaction, and Neck Disability Index. The outcomes were compared between the 2 groups. At the final follow up, all 26 patients achieved healing of their fractures. There were no complications associated with either treatment. The left-to-right ranges of motion of C1-C2 rotation were 41.9° ± 11.9° in the PTF group and 43.5° ± 12.0° in the cephalocervicothoracic cast fixation group. There was no statistical difference between the 2 groups regarding the C1-C2 rotation angle (P > 0.05). There also were no significant differences between 2 groups in functional outcomes evaluated by visual analog scale for neck pain, neck stiffness, Neck Disability Index, and patient satisfaction (all P > 0.05). The outcomes of PTF and cephalocervicothoracic cast fixation were comparable in the treatment of type III odontoid fractures. For type III odontoid fractures that cannot be managed by nonoperative fixation or anterior screw fixation, PTF may be the treatment of choice, because it spares the motion of the C1-C2 complex. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. LRP1 protects the vasculature by regulating levels of connective tissue growth factor and HtrA1.

    PubMed

    Muratoglu, Selen C; Belgrave, Shani; Hampton, Brian; Migliorini, Mary; Coksaygan, Turhan; Chen, Ling; Mikhailenko, Irina; Strickland, Dudley K

    2013-09-01

    Low-density lipoprotein receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is abundant in vascular smooth muscle cells. Mice in which the lrp1 gene is deleted in smooth muscle cells (smLRP1(-/-)) on a low-density lipoprotein receptor-deficient background display excessive platelet derived growth factor-signaling, smooth muscle cell proliferation, aneurysm formation, and increased susceptibility to atherosclerosis. The objectives of the current study were to examine the potential of LRP1 to modulate vascular physiology under nonatherogenic conditions. We found smLRP1(-/-) mice to have extensive in vivo aortic dilatation accompanied by disorganized and degraded elastic lamina along with medial thickening of the arterial vessels resulting from excess matrix deposition. Surprisingly, this was not attributable to excessive platelet derived growth factor-signaling. Rather, quantitative differential proteomic analysis revealed that smLRP1(-/-) vessels contain a 4-fold increase in protein levels of high-temperature requirement factor A1 (HtrA1), which is a secreted serine protease that is known to degrade matrix components and to impair elastogenesis, resulting in fragmentation of elastic fibers. Importantly, our study discovered that HtrA1 is a novel LRP1 ligand. Proteomics analysis also identified excessive accumulation of connective tissue growth factor, an LRP1 ligand and a key mediator of fibrosis. Our findings suggest a critical role for LRP1 in maintaining the integrity of vessels by regulating protease activity as well as matrix deposition by modulating HtrA1 and connective tissue growth factor protein levels. This study highlights 2 new molecules, connective tissue growth factor and HtrA1, which contribute to detrimental changes in the vasculature and, therefore, represent new target molecules for potential therapeutic intervention to maintain vessel wall homeostasis.

  4. Pulsational Pair-instability Model for Superluminous Supernova PTF12dam: Interaction and Radioactive Decay

    NASA Astrophysics Data System (ADS)

    Tolstov, Alexey; Nomoto, Ken'ichi; Blinnikov, Sergei; Sorokina, Elena; Quimby, Robert; Baklanov, Petr

    2017-02-01

    Being a superluminous supernova, PTF12dam can be explained by a 56Ni-powered model, a magnetar-powered model, or an interaction model. We propose that PTF12dam is a pulsational pair-instability supernova, where the outer envelope of a progenitor is ejected during the pulsations. Thus, it is powered by a double energy source: radioactive decay of 56Ni and a radiative shock in a dense circumstellar medium. To describe multicolor light curves and spectra, we use radiation-hydrodynamics calculations of the STELLA code. We found that light curves are well described in the model with 40 M⊙ ejecta and 20-40 M⊙ circumstellar medium. The ejected 56Ni mass is about 6 M⊙, which results from explosive nucleosynthesis with large explosion energy (2-3) × 1052 erg. In comparison with alternative scenarios of pair-instability supernova and magnetar-powered supernova, in the interaction model, all the observed main photometric characteristics are well reproduced: multicolor light curves, color temperatures, and photospheric velocities.

  5. Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice.

    PubMed

    He, Ping; Yang, Jong Won; Yang, Vincent W; Bialkowska, Agnieszka B

    2018-04-01

    Activating mutations in KRAS are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Krüppel-like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs. We performed studies in adult mice with conditional disruption of Klf5 (Klf5 fl/fl ) and/or expression of Kras G12D (LSL-Kras G12D ) via Cre ERTM recombinase regulated by an acinar cell-specific promoter (Ptf1a). Activation of Kras G12D and loss of KLF5 was achieved by administration of tamoxifen. Pancreatitis was induced in mice by administration of cerulein; pancreatic tissues were collected, analyzed by histology and immunohistochemistry, and transcriptomes were compared between mice that did or did not express KLF5. We performed immunohistochemical analyses of human tissue microarrays, comparing levels of KLF5 among 96 human samples of PDAC. UN-KC-6141 cells (pancreatic cancer cells derived from Pdx1-Cre;LSL-Kras G12D mice) were incubated with inhibitors of different kinases and analyzed in proliferation assays and by immunoblots. Expression of KLF5 was knocked down with small hairpin RNAs or CRISPR/Cas9 strategies; cells were analyzed in proliferation and gene expression assays, and compared with cells expressing control vectors. Cells were subcutaneously injected into flanks of syngeneic mice and tumor growth was assessed. Of the 96 PDAC samples analyzed, 73% were positive for KLF5 (defined as nuclear staining in more than 5% of tumor cells). Pancreata from Ptf1a-Cre ERTM ;LSL-Kras G12D mice contained ADM and PanIN lesions, which contained high levels of nuclear KLF5 within these structures. In contrast, Ptf1a-Cre ERTM ;LSL-Kras G12D ;Klf5 fl

  6. Hypoxia-inducible factor 1α is a critical downstream mediator for hypoxia-induced mitogenic factor (FIZZ1/RELMα)-induced pulmonary hypertension

    PubMed Central

    Johns, Roger A.; Takimoto, Eiki; Meuchel, Lucas W.; Elsaigh, Esra; Zhang, Ailan; Heller, Nicola M.; Semenza, Gregg L.; Yamaji-Kegan, Kazuyo

    2017-01-01

    Objective Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or RELMα) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/−) mice. HIMF-induced PH was significantly diminished in HIF-1α+/− mice and was accompanied by a dysregulated VEGF-A–VEGF receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β (RELMβ), significantly increased IL-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human RELMβ significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6–expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, VEGF-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology. PMID:26586659

  7. Risk Factors for Severe Outcomes following 2009 Influenza A (H1N1) Infection: A Global Pooled Analysis

    PubMed Central

    Van Kerkhove, Maria D.; Vandemaele, Katelijn A. H.; Shinde, Vivek; Jaramillo-Gutierrez, Giovanna; Koukounari, Artemis; Donnelly, Christl A.; Carlino, Luis O.; Owen, Rhonda; Paterson, Beverly; Pelletier, Louise; Vachon, Julie; Gonzalez, Claudia; Hongjie, Yu; Zijian, Feng; Chuang, Shuk Kwan; Au, Albert; Buda, Silke; Krause, Gerard; Haas, Walter; Bonmarin, Isabelle; Taniguichi, Kiyosu; Nakajima, Kensuke; Shobayashi, Tokuaki; Takayama, Yoshihiro; Sunagawa, Tomi; Heraud, Jean Michel; Orelle, Arnaud; Palacios, Ethel; van der Sande, Marianne A. B.; Wielders, C. C. H. Lieke; Hunt, Darren; Cutter, Jeffrey; Lee, Vernon J.; Thomas, Juno; Santa-Olalla, Patricia; Sierra-Moros, Maria J.; Hanshaoworakul, Wanna; Ungchusak, Kumnuan; Pebody, Richard; Jain, Seema; Mounts, Anthony W.

    2011-01-01

    Background Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures. Methods and Findings Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions—Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom—to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients <5 y and 5–14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50–64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each

  8. Rice homeobox transcription factor HOX1a positively regulates gibberellin responses by directly suppressing EL1.

    PubMed

    Wen, Bi-Qing; Xing, Mei-Qing; Zhang, Hua; Dai, Cheng; Xue, Hong-Wei

    2011-11-01

    Homeobox transcription factors are involved in various aspects of plant development, including maintenance of the biosynthesis and signaling pathways of different hormones. However, few direct targets of homeobox proteins have been identified. We here show that overexpression of rice homeobox gene HOX1a resulted in enhanced gibberellin (GA) response, indicating a positive effect of HOX1a in GA signaling. HOX1a is induced by GA and encodes a homeobox transcription factor with transcription repression activity. In addition, HOX1a suppresses the transcription of early flowering1 (EL1), a negative regulator of GA signaling, and further electrophoretic mobility shift assay and chromatin immunoprecipitation analysis revealed that HOX1a directly bound to the promoter region of EL1 to suppress its expression and stimulate GA signaling. These results demonstrate that HOX1a functions as a positive regulator of GA signaling by suppressing EL1, providing informative hints on the study of GA signaling. © 2011 Institute of Botany, Chinese Academy of Sciences.

  9. Factors Influencing School Closure and Dismissal Decisions: Influenza A (H1N1), Michigan 2009

    ERIC Educational Resources Information Center

    Dooyema, Carrie A.; Copeland, Daphne; Sinclair, Julie R.; Shi, Jianrong; Wilkins, Melinda; Wells, Eden; Collins, Jim

    2014-01-01

    Background: In fall 2009, many US communities experienced school closures during the influenza A H1N1 pandemic (pH1N1) and the state of Michigan reported 567 closures. We conducted an investigation in Michigan to describe pH1N1-related school policies, practices, and identify factors related to school closures. Methods: We distributed an online…

  10. Can insulin-like growth factor 1 (IGF-1), IGF-1 receptor connective tissue growth factor and Ki-67 labelling index have a prognostic role in pulmonary carcinoids?

    PubMed

    Kanakis, Georgios A; Grimelius, Lars; Papaioannou, Dimitrios; Kaltsas, Gregory; Tsolakis, Apostolos V

    2018-04-27

    Altered expression of Insulin-like Growth Factor-1 (IGF-1), its receptor (IGF-1R), Connective Tissue Growth Factor (CTGF) and Hypoxia Inducible Factor-1 (HIF-1), has been implicated in tumorigenesis. So far, these factors have not been studied systematically in Pulmonary Carcinoids (PCs). To examine IGF-1, IGF-1R, CTGF and HIF-1 expression in PCs, and assess their prognostic value over established factors. Retrospective study of 121 PCs (104 Typical and 17 Atypical). The expression of growth factors was studied immunohistochemically and tumors were considered positive if immunoreactivity appeared in >50% of cells. All studied parameters were expressed in the majority of tumors (IGF-1, IGF-1R, CTGF and HIF-1, in 78.5%, 67%, 72% and 78%, respectively). Their expression tended to be more frequent in TCs and in tumors with Ki-67≤2% (significant only for HIF-1; 82 vs. 53%; p=0.023 and 83 vs. 63%; p=0.025 respectively). CTGF was the only factor correlated with more extensive disease (larger size; presence of lymph node and distant metastases). According to logistic regression analysis, only advanced age, Ki-67≥3.4% and lymph node involvement could predict the development of distant metastases. IGF-1, IGF-1R, CTGF and HIF-1 are avidly expressed in PCs; however, their presence did not appear to be of statistically significant value over established prognostic factors.

  11. Glutathione S-transferase polymorphisms (GSTM1, GSTT1, GSTP1) and male factor infertility risk: a pooled analysis of studies.

    PubMed

    Safarinejad, Mohammad Reza; Dadkhah, Farid; Ali Asgari, Majid; Hosseini, Seyed Yousef; Kolahi, Ali Asgar; Iran-Pour, Elham

    2012-01-01

    To determine the role of glutathione S-transferases (GSTs; GSTM1, GSTT1, and GSTP1) gene polymorphisms in susceptibility to male factor infertility. We report a pooled analysis of 11 studies on the association of GSTM1, GSTT1, and GSTP1 polymorphisms and male factor infertility, including 1323 cases and 1054 controls. An overall significant association was determined between the GSTM1 null genotype [odds ratio (OR), 2.74; 95% confidence interval (CI), 1.72 to 3.84; P = .003], GSTT1 null genotype (OR, 1.54; 95% CI, 1.43 to 3.47; P = .02), and male factor infertility. The GSTP1 Ile/Val genotype had overall protective effect against development of infertility (OR, 0.48; 95% CI, 0.27 to 0.77), while there was significant heterogeneity between studies. In sensitivity analysis, two studies were excluded; the association and direction between GSTM1 and GSTT1 null genotypes and GSTP1 Ile/Val genotype and male infertility remained unchanged. There was no significant interaction between smoking status and studied genotypes on male infertility risk (P = .26). These results demonstrated that amongst populations studied to date, GSTM1 and GSTT1 null genotypes are associated with strong and modest increase in the risk of male infertility, respectively. On the contrary, GSTP1 Ile/Val genotype has protective effect.

  12. Identification of fibroblast growth factor 1 (FGF-1) in a black market product.

    PubMed

    Walpurgis, Katja; Thomas, Andreas; Laussmann, Tim; Horta, Luis; Metzger, Sabine; Schänzer, Wilhelm; Thevis, Mario

    2011-01-01

    The use of growth factors for accelerated healing of sports injuries is restricted under the terms of the World Anti-Doping Agency (WADA) anti-doping code. Cheating athletes have used the black market as a source of performance-enhancing substances. Drugs that currently undergo clinical trials are frequently offered--despite the unknown health risks associated with the administration of unapproved pharmaceuticals. Recently, a new growth factor (referred to as fibroblast growth factor 1/FGF-1) with known effects on the repair and regeneration of damaged tissue was detected in an unlabelled black market product confiscated by the German customs. The identification of the protein was achieved by one- and two-dimensional polyacrylamide gel electrophoresis (SDS-PAGE and 2D-PAGE), different proteolytic digestions, immunological methods and nano-liquid chromatography high-resolution/high-accuracy Orbitrap mass spectrometry. The SDS-PAGE analysis revealed slight differences concerning the molecular weight of recombinant human and black market FGF-1. Using in-gel proteolysis, a truncation or modification located at the N-terminus of the protein was suggested. These findings demonstrate that drug candidates without clinical approval can be readily obtained from the black market, regardless of potential dangerous consequences for the consumer, which corroborates the necessity of proactive and preventive doping control approaches. In that regard, physiological concentrations of blood and urine specimens collected from healthy individuals were analyzed and were found to range below 28 pg/ml in urine, while there was no detectable FGF-1 in plasma. Copyright © 2011 John Wiley & Sons, Ltd.

  13. Pulsational Pair-instability Model for Superluminous Supernova PTF12dam:Interaction and Radioactive Decay

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tolstov, Alexey; Nomoto, Ken’ichi; Blinnikov, Sergei

    2017-02-01

    Being a superluminous supernova, PTF12dam can be explained by a {sup 56}Ni-powered model, a magnetar-powered model, or an interaction model. We propose that PTF12dam is a pulsational pair-instability supernova, where the outer envelope of a progenitor is ejected during the pulsations. Thus, it is powered by a double energy source: radioactive decay of {sup 56}Ni and a radiative shock in a dense circumstellar medium. To describe multicolor light curves and spectra, we use radiation-hydrodynamics calculations of the STELLA code. We found that light curves are well described in the model with 40 M {sub ⊙} ejecta and 20–40 M {submore » ⊙} circumstellar medium. The ejected {sup 56}Ni mass is about 6 M {sub ⊙}, which results from explosive nucleosynthesis with large explosion energy (2–3)×10{sup 52} erg. In comparison with alternative scenarios of pair-instability supernova and magnetar-powered supernova, in the interaction model, all the observed main photometric characteristics are well reproduced: multicolor light curves, color temperatures, and photospheric velocities.« less

  14. Steroidogenic Factor-1 (SF-1, Ad4BP, NR5A1) and Disorders of Testis Development

    PubMed Central

    Lin, L.; Achermann, J.C.

    2009-01-01

    Steroidogenic factor-1 (SF-1) (Ad4BP, NR5A1) is a nuclear receptor that regulates many aspects of adrenal and reproductive development and function. Consequently, deletion of the gene (Nr5a1) encoding Sf-1 in XY mice results in impaired adrenal development, complete testicular dysgenesis with Müllerian structures, and female external genitalia. Initial efforts to identify NR5A1 changes in humans focused on 46,XY individuals with combined adrenogonadal failure and Müllerian structures. Although this combination of clinical features is rare, 2 such patients harboring NR5A1 mutations have been described within the past decade. More recently, however, it has emerged that heterozygous loss of function mutations in NR5A1 can be found relatively frequently in children and adults with 46,XY disorders of sex development (DSD) but with apparently normal adrenal function. The phenotypic spectrum associated with these changes ranges from complete testicular dysgenesis with Müllerian structures, through individuals with mild clitoromegaly or genital ambiguity, to severe penoscrotal hypospadias or even anorchia. Furthermore, a non-synonymous polymorphism in NR5A1 may be associated with micropenis or undescended testes within the population. Taken together, these reports suggest that variable loss of SF-1 function can be associated with a wide range of reproductive phenotypes in humans. PMID:18987494

  15. Comparative analysis of the ternary complex factors Elk-1, SAP-1a and SAP-2 (ERP/NET).

    PubMed Central

    Price, M A; Rogers, A E; Treisman, R

    1995-01-01

    A transcription factor ternary complex composed of Serum Response Factor (SRF) and Ternary Complex Factor (TCF) mediates the response of the c-fos Serum Response Element (SRE) to growth factors and mitogens. Three Ets domain proteins, Elk-1, SAP-1 and ERP/NET, have been reported to have the properties of TCF. Here we compare Elk-1 and SAP-1a with the human ERP/NET homologue SAP-2. All three TCF RNAs are ubiquitously expressed at similar relative levels. All three proteins contain conserved regions that interact with SRF and the c-fos SRE with comparable efficiency, but in vitro complex formation by SAP-2 is strongly inhibited by its C-terminal sequences. Similarly, only Elk-1 and SAP-1a efficiently bind the c-fos SRE in vivo; ternary complex formation by SAP-2 is weak and is substantially unaffected by serum stimulation or v-ras co-expression. All three TCFs contain C-terminal transcriptional activation domains that are phosphorylated following growth factor stimulation. Activation requires conserved S/T-P motifs found in all the TCF family members. Each TCF activation domain can be phosphorylated in vitro by partially purified ERK2, and ERK activation in vivo is sufficient to potentiate transcriptional activation. Images PMID:7540136

  16. Comparative analysis of the ternary complex factors Elk-1, SAP-1a and SAP-2 (ERP/NET).

    PubMed

    Price, M A; Rogers, A E; Treisman, R

    1995-06-01

    A transcription factor ternary complex composed of Serum Response Factor (SRF) and Ternary Complex Factor (TCF) mediates the response of the c-fos Serum Response Element (SRE) to growth factors and mitogens. Three Ets domain proteins, Elk-1, SAP-1 and ERP/NET, have been reported to have the properties of TCF. Here we compare Elk-1 and SAP-1a with the human ERP/NET homologue SAP-2. All three TCF RNAs are ubiquitously expressed at similar relative levels. All three proteins contain conserved regions that interact with SRF and the c-fos SRE with comparable efficiency, but in vitro complex formation by SAP-2 is strongly inhibited by its C-terminal sequences. Similarly, only Elk-1 and SAP-1a efficiently bind the c-fos SRE in vivo; ternary complex formation by SAP-2 is weak and is substantially unaffected by serum stimulation or v-ras co-expression. All three TCFs contain C-terminal transcriptional activation domains that are phosphorylated following growth factor stimulation. Activation requires conserved S/T-P motifs found in all the TCF family members. Each TCF activation domain can be phosphorylated in vitro by partially purified ERK2, and ERK activation in vivo is sufficient to potentiate transcriptional activation.

  17. HEAT-INDUCED TAS1 TARGET1 Mediates Thermotolerance via HEAT STRESS TRANSCRIPTION FACTOR A1a–Directed Pathways in Arabidopsis[C][W

    PubMed Central

    Li, Shuxia; Liu, Jinxin; Liu, Zhongyuan; Li, Xiaorong; Wu, Feijie; He, Yuke

    2014-01-01

    Many heat stress transcription factors (Hsfs) and heat shock proteins (Hsps) have been identified to play important roles in the heat tolerance of plants. However, many of the key factors mediating the heat response pathways remain unknown. Here, we report that two genes, which are targets of TAS1 (trans-acting siRNA precursor 1)–derived small interfering RNAs that we named HEAT-INDUCED TAS1 TARGET1 (HTT1) and HTT2, are involved in thermotolerance. Microarray analysis revealed that the HTT1 and HTT2 genes were highly upregulated in Arabidopsis thaliana seedlings in response to heat shock. Overexpression of TAS1a, whose trans-acting small interfering RNAs target the HTT genes, elevated accumulation of TAS1-siRNAs and reduced expression levels of the HTT genes, causing weaker thermotolerance. By contrast, overexpression of HTT1 and HTT2 upregulated several Hsf genes, leading to stronger thermotolerance. In heat-tolerant plants overexpressing HsfA1a, the HTT genes were upregulated, especially at high temperatures. Meanwhile, HsfA1a directly activated HTT1 and HTT2 through binding to their promoters. HTT1 interacted with the heat shock proteins Hsp70-14 and Hsp40 and NUCLEAR FACTOR Y, SUBUNIT C2. Taken together, these results suggest that HTT1 mediates thermotolerance pathways because it is targeted by TAS1a, mainly activated by HsfA1a, and acts as cofactor of Hsp70-14 complexes. PMID:24728648

  18. A 46,XX Ovotesticular Disorder of Sex Development Likely Caused by a Steroidogenic Factor-1 (NR5A1) Variant.

    PubMed

    Swartz, Jonathan M; Ciarlo, Ryan; Guo, Michael H; Abrha, Aser; Weaver, Benjamin; Diamond, David A; Chan, Yee-Ming; Hirschhorn, Joel N

    2017-01-01

    A variant in steroidogenic factor-1 (SF-1, encoded by the gene NR5A1), p.Arg92Trp, has recently been reported in multiple families with 46,XX ovotesticular or testicular disorders of sex development (DSD). This amino acid change impacts the DNA-binding domain and perturbs gonadal differentiation pathways. Whole-exome sequencing was performed on a 46,XX subject with ovotesticular DSD. Exome results identified a heterozygous NR5A1 variant, p.Arg92Gln, in the 46,XX ovotesticular DSD proband. This arginine-to-glutamine change has been previously reported in the homozygous state in a 46,XY patient with gonadal and adrenal dysgenesis, though 46,XY and 46,XX heterozygous carriers of this variant have not been previously reported to have any clinical phenotype. The NR5A1 p.Arg92Gln variant, which has thus far only been seen in a family with 46,XY DSD, most likely contributes to the ovotesticular DSD in this case. In light of the recent reports of unrelated 46,XX subjects with testicular or ovotesticular DSD with the NR5A1 variant p.Arg92Trp, it appears that other mutations in the DNA binding domain have the potential to impact the factors determining testicular and ovarian differentiation. This case demonstrates the variability of phenotypes with the same genotype and broadens our understanding of the role of SF-1 in gonadal differentiation. © 2016 S. Karger AG, Basel.

  19. BRCA1/BARD1 Complex Interacts with Steroidogenic Factor 1----a Potential Mechanism for Regulation of Aromatase Expression by BRCA1

    PubMed Central

    Lu, Yunzhe; Kang, Tao; Hu, Yanfen

    2010-01-01

    Germline mutations in BRCA1 predispose women to early onset of breast and ovarian cancers. Findings from previous studies support the notion that the tissue- and gender-specific tumor suppression function of BRCA1 is associated with its role in negative regulation of aromatase expression, the rate-limiting step in estrogen biosynthesis. The molecular mechanism of BRCA1 in regulating aromatase promoter activity remains to be elucidated. In this study, we demonstrate that, in an ovarian granulosa cell line KGN, steroidogenic factor 1 (SF-1) is required for aromatase PII promoter basal activity as well as the elevated aromatase expression mediated by BRCA1 knockdown. Furthermore, BRCA1 in KGN cells exists mainly as a heterodimer with BARD1. We provide evidence that the BRCA1/BARD1 complex interacts with SF-1 both in vivo and in vitro. However, the intrinsic ubiquitin E3 ligase activity of BRCA1/BARD1 does not appear to contribute to ubiquitynation of SF-1. We propose that the interaction between SF-1 and BRCA1/BARD1 may recruit BRCA1/BARD1 complex to the aromatase PII promoter for BRCA1/BARD1-mediate transcriptional repression. PMID:21087664

  20. A quantitative assay measuring the function of lipase maturation factor 1

    PubMed Central

    Yin, Fen; Doolittle, Mark H.; Péterfy, Miklós

    2009-01-01

    Newly synthesized lipoprotein lipase (LPL) and related members of the lipase gene family require an endoplasmic reticulum maturation factor for attainment of enzyme activity. This factor has been identified as lipase maturation factor 1 (Lmf1), and mutations affecting its function and/or expression result in combined lipase deficiency (cld) and hypertriglyceridemia. To assess the functional impact of Lmf1 sequence variations, both naturally occurring and induced, we report the development of a cell-based assay using LPL activity as a quantitative reporter of Lmf1 function. The assay uses a cell line homozygous for the cld mutation, which renders endogenous Lmf1 nonfunctional. LPL transfected into the mutant cld cell line fails to attain activity; however, cotransfection of LPL with wild-type Lmf1 restores its ability to support normal lipase maturation. In this report, we describe optimized conditions that ensure the detection of a complete range of Lmf1 function (full, partial, or complete loss of function) using LPL activity as the quantitative reporter. To illustrate the dynamic range of the assay, we tested several novel mutations in mouse Lmf1. Our results demonstrate the ability of the assay to detect and analyze Lmf1 mutations having a wide range of effects on Lmf1 function and protein expression. PMID:19471043

  1. Risk Factors and Immunity in a Nationally Representative Population following the 2009 Influenza A(H1N1) Pandemic

    PubMed Central

    Bandaranayake, Don; Huang, Q. Sue; Bissielo, Ange; Wood, Tim; Mackereth, Graham; Baker, Michael G.; Beasley, Richard; Reid, Stewart; Roberts, Sally; Hope, Virginia

    2010-01-01

    Background Understanding immunity, incidence and risk factors of the 2009 influenza A(H1N1) pandemic (2009 H1N1) through a national seroprevalence study is necessary for informing public health interventions and disease modelling. Methods and Findings We collected 1687 serum samples and individual risk factor data between November-2009 to March-2010, three months after the end of the 2009 H1N1 wave in New Zealand. Participants were randomly sampled from selected general practices countrywide and hospitals in the Auckland region. Baseline immunity was measured from 521 sera collected during 2004 to April-2009. Haemagglutination inhibition (HI) antibody titres of ≥1∶40 against 2009 H1N1 were considered seroprotective as well as seropositive. The overall community seroprevalence was 26.7% (CI:22.6–29.4). The seroprevalence varied across age and ethnicity. Children aged 5–19 years had the highest seroprevalence (46.7%;CI:38.3–55.0), a significant increase from the baseline (14%;CI:7.2–20.8). Older adults aged ≥60 had no significant difference in seroprevalence between the serosurvey (24.8%;CI:18.7–30.9) and baseline (22.6%;CI:15.3–30.0). Pacific peoples had the highest seroprevalence (49.5%;CI:35.1–64.0). There was no significant difference in seroprevalence between both primary (29.6%;CI:22.6–36.5) and secondary healthcare workers (25.3%;CI:20.8–29.8) and community participants. No significant regional variation was observed. Multivariate analysis indicated age as the most important risk factor followed by ethnicity. Previous seasonal influenza vaccination was associated with higher HI titres. Approximately 45.2% of seropositive individuals reported no symptoms. Conclusions Based on age and ethnicity standardisation to the New Zealand Population, about 29.5% of New Zealanders had antibody titers at a level consistent with immunity to 2009 H1N1. Around 18.3% of New Zealanders were infected with the virus during the first wave including about one

  2. FBI-1, a factor that binds to the HIV-1 inducer of short transcripts (IST), is a POZ domain protein.

    PubMed

    Morrison, D J; Pendergrast, P S; Stavropoulos, P; Colmenares, S U; Kobayashi, R; Hernandez, N

    1999-03-01

    The HIV-1 promoter directs the synthesis of two classes of transcripts, short, non-polyadenylated transcripts and full-length, polyadenylated transcripts. The synthesis of short transcripts is activated by a bipartite DNA element, the inducer of short transcripts or IST, located downstream of the HIV-1 transcriptional start site, while the synthesis of full-length transcripts is activated by the viral activator Tat. Tat binds to the RNA element TAR, which is encoded largely between the two IST half-elements. Upon activation by Tat, the synthesis of short RNAs is repressed. We have previously purified a factor called FBI-1 (for factor that binds to IST) whose binding to wild-type and mutated ISTs correlated well with the abilities of these ISTs to direct the synthesis of short transcripts. Here, we report the cloning of cDNAs encoding FBI-1. FBI-1 contains a POZ domain at its N-terminus and four Krüppel-type zinc fingers at its C-terminus. The C-terminus is sufficient for specific binding, and FBI-1 can form homomers through its POZ domain and, in vivo, through its zinc finger domain as well. In addition, FBI-1 associates with Tat, suggesting that repression of the short transcripts by Tat may be mediated through interactions between the two factors.

  3. Risk Factors for Influenza A(H1N1)pdm09 among Students, Beijing, China

    PubMed Central

    Zheng, Yang; Duan, Wei; Yang, Peng; Zhang, Yi; Wang, Xiaoli; Zhang, Li; Liyanage, Surabhi S.

    2013-01-01

    To identify risk factors associated with influenza A(H1N1)pdm09 among students in Beijing, China, we conducted a case–control study. Participants (304 case-patients and 608 controls, age range 6–19 years) were interviewed by using a standardized questionnaire. We found that in addition to vaccination, nonpharmaceutical interventions appeared to be protective. PMID:23347500

  4. FBI-1, a factor that binds to the HIV-1 inducer of short transcripts (IST), is a POZ domain protein.

    PubMed Central

    Morrison, D J; Pendergrast, P S; Stavropoulos, P; Colmenares, S U; Kobayashi, R; Hernandez, N

    1999-01-01

    The HIV-1 promoter directs the synthesis of two classes of transcripts, short, non-polyadenylated transcripts and full-length, polyadenylated transcripts. The synthesis of short transcripts is activated by a bipartite DNA element, the inducer of short transcripts or IST, located downstream of the HIV-1 transcriptional start site, while the synthesis of full-length transcripts is activated by the viral activator Tat. Tat binds to the RNA element TAR, which is encoded largely between the two IST half-elements. Upon activation by Tat, the synthesis of short RNAs is repressed. We have previously purified a factor called FBI-1 (for factor that binds to IST) whose binding to wild-type and mutated ISTs correlated well with the abilities of these ISTs to direct the synthesis of short transcripts. Here, we report the cloning of cDNAs encoding FBI-1. FBI-1 contains a POZ domain at its N-terminus and four Krüppel-type zinc fingers at its C-terminus. The C-terminus is sufficient for specific binding, and FBI-1 can form homomers through its POZ domain and, in vivo, through its zinc finger domain as well. In addition, FBI-1 associates with Tat, suggesting that repression of the short transcripts by Tat may be mediated through interactions between the two factors. PMID:9973611

  5. Hypoxia inducible factor 1 (HIF-1) and cardioprotection

    PubMed Central

    Tekin, Demet; Dursun, Ali D; Xi, Lei

    2010-01-01

    Since its discovery in early 1990s, hypoxia inducible factor 1 (HIF-1) has been increasingly recognized for its key role in transcriptional control of more than a hundred genes that regulate a wide-spectrum of cellular functional events, including angiogenesis, vasomotor control, glucose and energy metabolism, erythropoiesis, iron homeostasis, pH regulation, cell proliferation and viability. Evidence accumulated during the past 7 years suggests a critical role for HIF-1α in mediating cardioprotection. The purpose of our present article is to provide an updated overview on this important regulator of gene expression in the cellular stress-responsive and adaptive process. We have particularly emphasized the involvement of HIF-1 in the induction of cardioprotective molecules, such as inducible nitric oxide synthase (iNOS), hemeoxygenase 1 (HO-1), and erythropoietin (EPO), which in turn alleviate myocardial damages caused by harmful events such as ischemia-reperfusion injury. Despite these advances, further in-depth studies are needed to elucidate the possible coordination or interaction between HIF-1α and other key transcription factors in regulating protein expression that leads to cardioprotection. PMID:20711226

  6. Sphingosine-1-phosphate: a novel nonhypoxic activator of hypoxia-inducible factor-1 in vascular cells.

    PubMed

    Michaud, Maude D; Robitaille, Geneviève A; Gratton, Jean-Philippe; Richard, Darren E

    2009-06-01

    Sphingosine-1-phosphate (S1P) is a potent bioactive phospholipid responsible for a variety of vascular cell responses. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of genes essential for adaptation to low oxygen. S1P and HIF-1 are both important mediators of vascular cell responses such as migation, proliferation, and survival. Studies have shown that nonhypoxic stimuli can activate HIF-1 in oxygenated conditions. Here, we attempt to determine whether S1P can modulate the vascular activation of HIF-1. We show that in vascular endothelial and smooth muscle cells, activation of the S1P type-2 receptor by S1P strongly increases HIF-1 alpha protein levels, the active subunit of HIF-1. This is achieved through pVHL-independent stabilization of HIF-1 alpha. We demonstrate that the HIF-1 nuclear complex, formed on S1P stimulation, is transcriptionally active and specifically binds to a hypoxia-responsive elements. Moreover, S1P activates the expression of genes known to be closely regulated by HIF-1. Our results identify S1P as a novel and potent nonhypoxic activator of HIF-1. We believe that understanding the role played by HIF-1 in S1P gene regulation will have a strong impact on different aspects of vascular biology.

  7. Cytotoxic Necrotizing Factor-1 (CNF1) does not promote E. coli infection in a murine model of ascending pyelonephritis.

    PubMed

    Michaud, Jason E; Kim, Kwang Sik; Harty, William; Kasprenski, Matthew; Wang, Ming-Hsien

    2017-05-25

    Urinary tract infections (UTI) are among the most common and costly infections in both hospitalized and ambulatory patients. Uropathogenic E. coli (UPEC) represent the majority of UTI isolates and are a diverse group of bacteria that utilize a variety of virulence factors to establish infection of the genitourinary tract. The virulence factor cytotoxic necrotizing factor-1 (CNF1) is frequently expressed in clinical UPEC isolates. To date, there have been conflicting reports on the role of CNF1 in the pathogenesis of E. coli urinary tract infections. We examined the importance of CNF1 in a murine ascending kidney infection/ pyelonephritis model by performing comparative studies between a clinical UPEC isolate strain and a CNF1-deletion mutant. We found no alterations in bacterial burden with the loss of CNF1, whereas loss of the virulence factor fimH decreased bacterial burdens. In addition, we found no evidence that CNF1 contributed to the recruitment of inflammatory infiltrates in the kidney or bladder in vivo. While further examination of CNF-1 may reveal a role in UTI pathogenesis, our data casts doubt on the role of CNF-1 in the pathogenesis of UPEC UTI. As with other infections, different models and approaches are needed to elucidate the contribution of CNF1 to E. coli UTI.

  8. Interactome analysis of transcriptional coactivator multiprotein bridging factor 1 unveils a yeast AP-1-like transcription factor involved in oxidation tolerance of mycopathogen Beauveria bassiana.

    PubMed

    Chu, Xin-Ling; Dong, Wei-Xia; Ding, Jin-Li; Feng, Ming-Guang; Ying, Sheng-Hua

    2018-02-01

    Oxidation tolerance is an important determinant to predict the virulence and biocontrol potential of Beauveria bassiana, a well-known entomopathogenic fungus. As a transcriptional coactivator, multiprotein bridging factor 1 mediates the activity of transcription factor in diverse physiological processes, and its homolog in B. bassiana (BbMBF1) contributes to fungal oxidation tolerance. In this study, the BbMBF1-interactomes under oxidative stress and normal growth condition were deciphered by mass spectrometry integrated with the immunoprecipitation. BbMBF1p factor has a broad interaction with proteins that are involved in various cellular processes, and this interaction is dynamically regulated by oxidative stress. Importantly, a B. bassiana homolog of yeast AP-1-like transcription factor (BbAP-1) was specifically associated with the BbMBF1-interactome under oxidation and significantly contributed to fungal oxidation tolerance. In addition, qPCR analysis revealed that several antioxidant genes are jointly controlled by BbAP-1 and BbMBF1. Conclusively, it is proposed that BbMBF1p protein mediates BbAP-1p factor to transcribe the downstream antioxidant genes in B. bassiana under oxidative stress. This study demonstrates for the first time a proteomic view of the MBF1-interactome in fungi, and presents an initial framework to probe the transcriptional mechanism involved in fungal response to oxidation, which will provide a new strategy to improve the biocontrol efficacy of B. bassiana.

  9. Functional cloning of the proto-oncogene brain factor-1 (BF-1) as a Smad-binding antagonist of transforming growth factor-beta signaling.

    PubMed

    Rodriguez, C; Huang, L J; Son, J K; McKee, A; Xiao, Z; Lodish, H F

    2001-08-10

    Using the plasminogen activator inhibitor (PAI) promoter to drive the expression of a reporter gene (mouse CD2), we devised a system to clone negative regulators of the transforming growth factor-beta (TGF-beta) signaling pathway. We infected a TGF-beta-responsive cell line (MvLu1) with a retroviral cDNA library, selecting by fluorescence-activated cell sorter single cells displaying low PAI promoter activity in response to TGF-beta. Using this strategy we cloned the proto-oncogene brain factor-1 (BF-1). BF-1 represses the PAI promoter in part by associating with both unphosphorylated Smad3 (in the cytoplasm) and phosphorylated Smad3 (in the nucleus), thus preventing its binding to DNA. BF-1 also associates with Smad1, -2, and -4; the Smad MH2 domain binds to BF-1, and the C-terminal segment of BF-1 is uniquely and solely required for binding to Smads. Further, BF-1 represses another TGF-beta-induced promoter (p15), it up-regulates a TGF-beta-repressed promoter (Cyclin A), and it reverses the growth arrest caused by TGF-beta. Our results suggest that BF-1 is a general inhibitor of TGF-beta signaling and as such may play a key role during brain development.

  10. No Evidence for Disease History as a Risk Factor for Narcolepsy after A(H1N1)pdm09 Vaccination.

    PubMed

    Lamb, Favelle; Ploner, Alexander; Fink, Katharina; Maeurer, Markus; Bergman, Peter; Piehl, Fredrik; Weibel, Daniel; Sparén, Pär; Dahlström, Lisen Arnheim

    2016-01-01

    To investigate disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy. Case-control study in Sweden. Cases included persons referred for a Multiple Sleep Latency Test between 2009 and 2010, identified through diagnostic sleep centres and confirmed through independent review of medical charts. Controls, selected from the total population register, were matched to cases on age, gender, MSLT-referral date and county of residence. Disease history (prescriptions and diagnoses) and vaccination history was collected through telephone interviews and population-based healthcare registers. Conditional logistic regression was used to investigate disease history before A(H1N1)pdm09 vaccination as a risk-factor for narcolepsy. In total, 72 narcolepsy cases and 251 controls were included (range 3-69 years mean19-years). Risk of narcolepsy was increased in individuals with a disease history of nervous system disorders (OR range = 3.6-8.8) and mental and behavioural disorders (OR = 3.8, 95% CI 1.6-8.8) before referral. In a second analysis of vaccinated individuals only, nearly all initial associations were no longer statistically significant and effect sizes were smaller (OR range = 1.3-2.6). A significant effect for antibiotics (OR = 0.4, 95% CI 0.2-0.8) and a marginally significant effect for nervous system disorders was observed. In a third case-only analysis, comparing cases referred before vaccination to those referred after; prescriptions for nervous system disorders (OR = 26.0 95% CI 4.0-170.2) and ADHD (OR = 35.3 95% CI 3.4-369.9) were statistically significant during the vaccination period, suggesting initial associations were due to confounding by indication. The findings of this study do not support disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy.

  11. Factors influencing H1N1 vaccine behavior among Manitoba Metis in Canada: a qualitative study.

    PubMed

    Driedger, S Michelle; Maier, Ryan; Furgal, Chris; Jardine, Cindy

    2015-02-12

    During the first wave of the H1N1 influenza pandemic in 2009, Aboriginal populations in Canada experienced disproportionate rates of infection, particularly in the province of Manitoba. To protect those thought to be most at-risk, health authorities in Manitoba listed all Aboriginal people, including Metis, among those able to receive priority access to the novel vaccine when it first became available. Currently, no studies exist that have investigated the attitudes, influences, and vaccine behaviors among Aboriginal communities in Canada. This paper is the first to systematically connect vaccine behavior with the attitudes and beliefs that influenced Metis study participants' H1N1 vaccine decision-making. Researchers held focus groups (n = 17) with Metis participants in urban, rural, and remote locations of Manitoba following the conclusion of the H1N1 pandemic. Participants were asked about their vaccination decisions and about the factors that influenced their decisions. Following data collection, responses were coded into the broad categories of a social-ecological model, nuanced by categories stemming from earlier research. Responses were then quantified to show the most influential factors in positively or negatively affecting the vaccine decision. Media reporting, the influence of peer groups, and prioritization all had positive and negative influential effects on decision making. Whether vaccinated or not, the most negatively influential factors cited by participants were a lack of knowledge about the vaccine and the pandemic as well as concerns about vaccine safety. Risk of contracting H1N1 influenza was the biggest factor in positively influencing a vaccine decision, which in many cases trumped any co-existing negative influencers. Metis experiences of colonialism in Canada deeply affected their perceptions of the vaccine and pandemic, a context that health systems need to take into account when planning response activities in the future. Participants

  12. Tissue-specific deletion of c-Jun in the pancreas has limited effects on pancreas formation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yamamoto, Kaoru; Miyatsuka, Takeshi; Tanaka, Ayako

    2007-11-30

    It is well known that activating protein-1 (AP-1) is involved in a variety of cellular functions such as proliferation, differentiation, apoptosis, and oncogenesis. AP-1 is a dimer complex consisting of different subunits, and c-Jun is known to be one of its major components. In addition, it has been shown that mice lacking c-Jun are embryonic lethal and that c-Jun is essential for liver and heart development. However, the role of c-Jun in the pancreas is not well known. The aim of this study was to examine the possible role of c-Jun in the pancreas. First, c-Jun was strongly expressed inmore » pancreatic duct-like structures at an embryonic stage, while a lower level of expression was observed in some part of the adult pancreas, implying that c-Jun might play a role during pancreas development. Second, to address this point, we generated pancreas-specific c-Jun knock-out mice (Ptf1a-Cre; c-Jun{sup flox/flox} mice) by crossing Ptf1a-Cre knock-in mice with c-Jun floxed mice. Ptf1a is a pancreatic transcription factor and its expression is confined to pancreatic stem/progenitor cells, which give rise to all three types of pancreatic tissue: endocrine, exocrine, and duct. Contrary to our expectation, however, there was no morphological difference in the pancreas between Ptf1a-Cre; c-Jun{sup flox/flox} and control mice. In addition, there was no difference in body weight, pancreas weight, and the expression of various pancreas-related factors (insulin, glucagon, cytokeratin, and amylase) between the two groups. Furthermore, there was no difference in glucose tolerance between Ptf1a-Cre; c-Jun{sup flox/flox} and control mice. Taken together, although we cannot exclude the possibility that c-Jun ablation is compensated by some unknown factors, c-Jun appears to be dispensable for pancreas development at least after ptf1a gene promoter is activated.« less

  13. Soybean (Glycine max) WRINKLED1 transcription factor, GmWRI1a, positively regulates seed oil accumulation.

    PubMed

    Chen, Liang; Zheng, Yuhong; Dong, Zhimin; Meng, Fanfan; Sun, Xingmiao; Fan, Xuhong; Zhang, Yunfeng; Wang, Mingliang; Wang, Shuming

    2018-04-01

    Soybean is the world's most important leguminous crop producing high-quality protein and oil. Elevating oil accumulation in soybean seed is always many researchers' goal. WRINKLED1 (WRI1) encodes a transcription factor of the APETALA2/ethylene responsive element-binding protein (AP2/EREBP) family that plays important roles during plant seed oil accumulation. In this study, we isolated and characterized three distinct orthologues of WRI1 in soybean (Glycine max) that display different organ-specific expression patterns, among which GmWRI1a was highly expressed in maturing soybean seed. Electrophoretic mobility shift assays and yeast one-hybrid experiments demonstrated that the GmWRI1a protein was capable of binding to AW-box, a conserved sequence in the proximal upstream regions of many genes involved in various steps of oil biosynthesis. Transgenic soybean seeds overexpressing GmWRI1a under the control of the seed-specific napin promoter showed the increased total oil and fatty acid content and the changed fatty acid composition. Furthermore, basing on the activated expressions in transgenic soybean seeds and existence of AW-box element in the promoter regions, direct downstream genes of GmWRI1a were identified, and their products were responsible for fatty acid production, elongation, desaturation and export from plastid. We conclude that GmWRI1a transcription factor can positively regulate oil accumulation in soybean seed by a complex gene expression network related to fatty acid biosynthesis.

  14. Hypoxia-inducible factor-1β (HIF-1β) is upregulated in a HIF-1α-dependent manner in 518A2 human melanoma cells under hypoxic conditions

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mandl, Markus, E-mail: mmandl@mail.austria.com; Kapeller, Barbara; Lieber, Roman

    2013-04-26

    Highlights: •HIF-1β is a hypoxia-responsive protein in 518A2 human melanoma cells. •HIF-1β is upregulated in a HIF-1α-dependent manner under hypoxic conditions. •HIF-1β is not elevated due to heterodimerization with HIF-1α per se. •HIF-1β inducibility has a biological relevance as judged in Het-CAM model. -- Abstract: Solid tumors include hypoxic areas due to excessive cell proliferation. Adaptation to low oxygen levels is mediated by the hypoxia-inducible factor (HIF) pathway promoting invasion, metastasis, metabolic alterations, chemo-resistance and angiogenesis. The transcription factor HIF-1, the major player within this pathway consists of HIF-1α and HIF-1β. The alpha subunit is continuously degraded under normoxia andmore » becomes stabilized under reduced oxygen supply. In contrast, HIF-1β is generally regarded as constitutively expressed and being present in excess within the cell. However, there is evidence that the expression of this subunit is more complex. The aim of this study was to investigate the role of HIF-1β in human melanoma cells. Among a panel of five different cell lines, in 518A2 cells exposed to the hypoxia-mimetic cobalt chloride HIF-1β was rapidly elevated on protein level. Knockdown experiments performed under cobalt chloride-exposure and hypoxia revealed that this effect was mediated by HIF-1α. The non-canonical relationship between these subunits was further confirmed by pharmacologic inhibition of HIF-1α and by expression of a dominant-negative HIF mutant. Overexpression of HIF-1α showed a time delay in HIF-1β induction, thus arguing for HIF-1β de novo synthesis rather than protein stabilization by heterodimerization. A Hen’s egg test-chorioallantoic membrane model of angiogenesis and invasion indicated a local expression of HIF-1β and implies a biological relevance of these findings. In summary, this study demonstrates the HIF-1α-dependent regulation of HIF-1β under hypoxic conditions for the first time

  15. Insulin-like growth factor I (IGF-1) Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate.

    PubMed

    Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

    2013-01-01

    Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

  16. Fibulin-1 functions as a prognostic factor in lung adenocarcinoma.

    PubMed

    Cui, Yuan; Liu, Jian; Yin, Hai-Bing; Liu, Yi-Fei; Liu, Jun-Hua

    2015-09-01

    Fibulin-1 is a member of the fibulin gene family, characterized by tandem arrays of epidermal growth factor-like domains and a C-terminal fibulin-type module. Fibulin-1 plays important roles in a range of cellular functions including morphology, growth, adhesion and mobility. It acts as a tumor suppressor gene in cutaneous melanoma, prostate cancer and gastric cancer. However, whether fibulin-1 also acts as a tumor suppressor gene in lung adenocarcinoma remains unknown. We also determined the association of fibulin-1 expression with various clinical and pathological parameters, which would show its potential role in clinical prognosis. We investigated and followed up 140 lung adenocarcinoma patients who underwent lung resection without pre- and post-operative systemic chemotherapy at the Affiliated Hospital of Nantong University from 2009 to 2013. Western blot assay and immunohistochemistry were used to evaluate the expression of fibulin-1 in lung adenocarcinoma tissues. We then analyzed the correlations between fibulin-1 expression and clinicopathological variables as well as the patients' overall survival rate. Both western blot assay and immunohistochemistry demonstrated that the level of fibulin-1 was downregulated in human lung adenocarcinoma tissues compared with that of normal lung tissues. Fibulin-1 expression significantly correlated with histological differentiation (P = 0.046), clinical stage (P< 0.01), lymph node status (P = 0.038) and expression of Ki-67 (P = 0.013). More importantly, multivariate analysis revealed that fibulin-1 was an independent prognostic marker for lung adenocarcinoma, and high expression of fibulin-1 was significantly associated with better prognosis of lung adenocarcinoma patients. The results supported our hypothesis that fibulin-1 can act as a prognostic factor in lung adenocarcinoma progression. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: A review.

    PubMed

    Frater, Julanne; Lie, David; Bartlett, Perry; McGrath, John J

    2018-03-01

    Insulin-like Growth Factor 1 (IGF-1) and its signaling pathway play a primary role in normal growth and ageing, however serum IGF-1 is known to reduce with advancing age. Recent findings suggest IGF-1 is essential for neurogenesis in the adult brain, and this reduction of IGF-1 with ageing may contribute to age-related cognitive decline. Experimental studies have shown manipulation of the GH/GF-1 axis can slow rates of cognitive decline in animals, making IGF-1 a potential biomarker of cognition, and/or its signaling pathway a possible therapeutic target to prevent or slow age-related cognitive decline. A systematic literature review and qualitative narrative summary of current evidence for IGF-1 as a biomarker of cognitive decline in the ageing brain was undertaken. Results indicate IGF-1 concentrations do not confer additional diagnostic information for those with cognitive decline, and routine clinical measurement of IGF-1 is not currently justified. In cases of established cognitive impairment, it remains unclear whether increasing circulating or brain IGF-1 may reverse or slow down the rate of further decline. Advances in neuroimaging, genetics, neuroscience and the availability of large well characterized biobanks will facilitate research exploring the role of IGF-1 in both normal ageing and age-related cognitive decline. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. [Spatio-temporal process and the influencing factors on influenza A (H1N1) pandemic in Changsha].

    PubMed

    Xiao, Hong; Tian, Huai-yu; Zhao, Jian; Zhang, Xi-xing; Zhu, Pei-juan; Liu, Ru-chun; Chen, Tian-mu

    2011-06-01

    To analyze the spatio-temporal process on 2009 influenza A (H1N1) pandemic in Changsha and the influencing factors during the diffusion process. Data were from the following 5 sources, influenza A (H1N1) pandemic gathered in 2009, Geographic Information System (GIS) of Changsha, the broad range of theorems and techniques of hot spot analysis, spatio-temporal process analysis and Spearman correlation analysis. Hot spot areas appeared to be more in the economically developed areas, such as cities and townships. The cluster of spatial-temporal distribution of influenza A (H1N1) pandemic was most likely appearing in Liuyang city (RR = 22.70, P < 0.01). The secondary cluster would include districts as Yuelu (RR = 6.49, P < 0.01), Yuhua (RR = 81.63, P < 0.01). Xingsha township appeared as the center in the Changsha county (RR = 2.90, P < 0.01) while townships as Yutangping (RR = 19.31, P < 0.01), Chengjiao (RR = 73.14, P < 0.01) and Longtian appeared as the center in the west of Ningxiang county (RR = 14.43, P < 0.01) and Wushan as the center in the Wangcheng county (RR = 13.84, P < 0.01). As time went on, the epidemic moved towards the eastern and more developed regions. Regarding factor analysis, population, the amount of students, geographic relationship and business activities etc. appeared to be the key elements influencing the transmission of influenza A (H1N1) pandemic. At the beginning of the epidemic, population density served as the main factor (r = 0.477, P < 0.05) but during the initial and fast growing stages, it was replaced by the size of students to serve as the important indicator (r = 0.831, P < 0.01; r = 0.518, P < 0.01). However, during the peak of the epidemics, the business activities played an important role (r = -0.676, P < 0.01). Groups under high risk and districts with high incidence rates were shifting, along with the temporal process of influenza A (H1N1) pandemic, suggesting that the protection measures need to be adjusted, according to the

  19. Nuclear factor I-A represses expression of the cell adhesion molecule L1

    PubMed Central

    2009-01-01

    Background The neural cell adhesion molecule L1 plays a crucial role in development and plasticity of the nervous system. Neural cells thus require precise control of L1 expression. Results We identified a full binding site for nuclear factor I (NFI) transcription factors in the regulatory region of the mouse L1 gene. Electrophoretic mobility shift assay (EMSA) showed binding of nuclear factor I-A (NFI-A) to this site. Moreover, for a brain-specific isoform of NFI-A (NFI-A bs), we confirmed the interaction in vivo using chromatin immunoprecipitation (ChIP). Reporter gene assays showed that in neuroblastoma cells, overexpression of NFI-A bs repressed L1 expression threefold. Conclusion Our findings suggest that NFI-A, in particular its brain-specific isoform, represses L1 gene expression, and might act as a second silencer of L1 in addition to the neural restrictive silencer factor (NRSF). PMID:20003413

  20. Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer.

    PubMed

    Chan, Chien-Yi; Huang, Shih-Yi; Sheu, Jim Jinn-Chyuan; Roth, Mendel M; Chou, I-Tai; Lien, Chia-Hsien; Lee, Ming-Fen; Huang, Chun-Yin

    2017-02-28

    Either FOXO1 or HBP1 transcription factor is a downstream effector of the PI3K/Akt pathway and associated with tumorigenesis. However, the relationship between FOXO1 and HBP1 in oral cancer remains unclear. Analysis of 30 oral tumor specimens revealed that mean mRNA levels of both FOXO1 and HBP1 in non-invasive and invasive oral tumors were found to be significantly lower than that of the control tissues, and the status of low FOXO1 and HBP1 (< 0.3 fold of the control) was associated with invasiveness of oral tumors. To investigate if HBP1 is a direct transcription target of FOXO1, we searched potential FOXO1 binding sites in the HBP1 promoter using the MAPPER Search Engine, and two putative FOXO1 binding sites located in the HBP1 promoter -132 to -125 bp and -343 to -336 bp were predicted. These binding sites were then confirmed by both reporter gene assays and the in cellulo ChIP assay. In addition, Akt activity manipulated by PI3K inhibitor LY294002 or Akt mutants was shown to negatively affect FOXO1-mediated HBP1 promoter activation and gene expression. Last, the biological significance of the FOXO1-HBP1 axis in oral cancer malignancy was evaluated in cell growth, colony formation, and invasiveness. The results indicated that HBP1 knockdown potently promoted malignant phenotypes of oral cancer and the suppressive effect of FOXO1 on cell growth, colony formation, and invasion was alleviated upon HBP1 knockdown in invasive oral cancer cells. Taken together, our data provide evidence for HBP1 as a direct downstream target of FOXO1 in oral cancer malignancy.

  1. Transcription Factor Arabidopsis Activating Factor1 Integrates Carbon Starvation Responses with Trehalose Metabolism1[OPEN

    PubMed Central

    Garapati, Prashanth; Feil, Regina; Lunn, John Edward; Van Dijck, Patrick; Balazadeh, Salma; Mueller-Roeber, Bernd

    2015-01-01

    Plants respond to low carbon supply by massive reprogramming of the transcriptome and metabolome. We show here that the carbon starvation-induced NAC (for NO APICAL MERISTEM/ARABIDOPSIS TRANSCRIPTION ACTIVATION FACTOR/CUP-SHAPED COTYLEDON) transcription factor Arabidopsis (Arabidopsis thaliana) Transcription Activation Factor1 (ATAF1) plays an important role in this physiological process. We identified TREHALASE1, the only trehalase-encoding gene in Arabidopsis, as a direct downstream target of ATAF1. Overexpression of ATAF1 activates TREHALASE1 expression and leads to reduced trehalose-6-phosphate levels and a sugar starvation metabolome. In accordance with changes in expression of starch biosynthesis- and breakdown-related genes, starch levels are generally reduced in ATAF1 overexpressors but elevated in ataf1 knockout plants. At the global transcriptome level, genes affected by ATAF1 are broadly associated with energy and carbon starvation responses. Furthermore, transcriptional responses triggered by ATAF1 largely overlap with expression patterns observed in plants starved for carbon or energy supply. Collectively, our data highlight the existence of a positively acting feedforward loop between ATAF1 expression, which is induced by carbon starvation, and the depletion of cellular carbon/energy pools that is triggered by the transcriptional regulation of downstream gene regulatory networks by ATAF1. PMID:26149570

  2. AIP1 recruits phosphatase PP2A to ASK1 in tumor necrosis factor-induced ASK1-JNK activation.

    PubMed

    Min, Wang; Lin, Yan; Tang, Shibo; Yu, Luyang; Zhang, Haifeng; Wan, Ting; Luhn, Tricia; Fu, Haian; Chen, Hong

    2008-04-11

    Previously we have shown that AIP1 (apoptosis signal-regulating kinase [ASK]1-interacting protein 1), a novel member of the Ras-GAP protein family, facilitates dephosphorylation of ASK1 at pSer967 and subsequently 14-3-3 release from ASK1, leading to enhanced ASK1-JNK signaling. However, the phosphatase(s) responsible for ASK1 dephosphorylation at pSer967 has not been identified. In the present study, we identified protein phosphatase (PP)2A as a potential phosphatase in vascular endothelial cells (ECs). Tumor necrosis factor (TNF)-induced dephosphorylation of ASK1 pSer967 in ECs was blocked by PP2A inhibitor okadaic acid. Overexpression of PP2A catalytic subunit induced dephosphorylation of ASK1 pSer967 and activation of c-Jun N-terminal kinase (JNK). In contrast, a catalytic inactive form of PP2A or PP2A small interfering RNA blunted TNF-induced dephosphorylation of ASK1 pSer967 and activation of JNK without effects on NF-kappaB activation. Whereas AIP1, via its C2 domain, binds to ASK1, PP2A binds to the GAP domain of AIP1. Endogenous AIP1-PP2A complex can be detected in the resting state, and TNF induces a complex formation of AIP1-PP2A with ASK1. Furthermore, TNF-induced association of PP2A with ASK1 was diminished in AIP1-knockdown ECs, suggesting a critical role of AIP1 in recruiting PP2A to ASK1. TNF-signaling molecules TRAF2 and RIP1, known to be in complex with AIP1 and activate AIP1 by phosphorylating AIP1 at Ser604, are critical for TNF-induced ASK1 dephosphorylation. Finally, PP2A and AIP1 cooperatively induce activation of ASK1-JNK signaling and EC apoptosis, as demonstrated by both overexpression and small interfering RNA knockdown approaches. Taken together, our data support a critical role of PP2A-AIP1 complex in TNF-induced activation of ASK1-JNK apoptotic signaling.

  3. Suppressor of gamma response 1 (SOG1) encodes a putative transcription factor governing multiple responses to DNA damage

    PubMed Central

    Yoshiyama, Kaoru; Conklin, Phillip A.; Huefner, Neil D.; Britt, Anne B.

    2009-01-01

    The Arabidopsis sog1-1 (suppressor of gamma response) mutant was originally isolated as a second-site suppressor of the radiosensitive phenotype of seeds defective in the repair endonuclease XPF. Here, we report that SOG1 encodes a putative transcription factor. This gene is a member of the NAC domain [petunia NAM (no apical meristem) and Arabidopsis ATAF1, 2 and CUC2] family (a family of proteins unique to land plants). Hundreds of genes are normally up-regulated in Arabidopsis within an hour of treatment with ionizing radiation; the induction of these genes requires the damage response protein kinase ATM, but not the related kinase ATR. Here, we find that SOG1 is also required for this transcriptional up-regulation. In contrast, the SOG1-dependent checkpoint response observed in xpf mutant seeds requires ATR, but does not require ATM. Thus, phenotype of the sog1-1 mutant mimics aspects of the phenotypes of both atr and atm mutants in Arabidopsis, suggesting that SOG1 participates in pathways governed by both of these sensor kinases. We propose that, in plants, signals related to genomic stress are processed through a single, central transcription factor, SOG1. PMID:19549833

  4. No Major Host Genetic Risk Factor Contributed to A(H1N1)2009 Influenza Severity

    PubMed Central

    Garcia-Etxebarria, Koldo; Bracho, María Alma; Galán, Juan Carlos; Pumarola, Tomàs; Castilla, Jesús; Ortiz de Lejarazu, Raúl; Rodríguez-Dominguez, Mario; Quintela, Inés; Bonet, Núria; Garcia-Garcerà, Marc; Domínguez, Angela; González-Candelas, Fernando; Calafell, Francesc

    2015-01-01

    While most patients affected by the influenza A(H1N1) pandemic experienced mild symptoms, a small fraction required hospitalization, often without concomitant factors that could explain such a severe course. We hypothesize that host genetic factors could contribute to aggravate the disease. To test this hypothesis, we compared the allele frequencies of 547,296 genome-wide single nucleotide polymorphisms (SNPs) between 49 severe and 107 mild confirmed influenza A cases, as well as against a general population sample of 549 individuals. When comparing severe vs. mild influenza A cases, only one SNP was close to the conventional p = 5×10−8. This SNP, rs28454025, sits in an intron of the GSK233 gene, which is involved in a neural development, but seems not to have any connections with immunological or inflammatory functions. Indirectly, a previous association reported with CD55 was replicated. Although sample sizes are low, we show that the statistical power in our design was sufficient to detect highly-penetrant, quasi-Mendelian genetic factors. Hence, and assuming that rs28454025 is likely to be a false positive, no major genetic factor was detected that could explain poor influenza A course. PMID:26379185

  5. The Role of Nuclear Receptor Coactivator A1B1 in Growth Factor-Mediated Mammary Tumorigenesis

    DTIC Science & Technology

    2007-03-01

    study display dwarfism and the retardation of mammary gland growth [9]. At the 4-month time point, I similarly observed an overall decrease in mammary...Coactivator A1B1 in Growth Factor- Mediated Mammary Tumorigenesis PRINCIPAL INVESTIGATOR: Mark P Fereshteh (BS) CONTRACTING ORGANIZATION...U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION

  6. Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Hyung Gyun; Han, Eun Hee; Im, Ji Hye

    2015-09-25

    Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Takenmore » together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction. - Highlights: • CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. • CAPE inhibited 3-MC-induced CYP1A1 expression. • CAPE induced HIF-1α induction. • CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 expression.« less

  7. Insulin-Like Growth Factor I (IGF-1) Ec/Mechano Growth FactorA Splice Variant of IGF-1 within the Growth Plate

    PubMed Central

    Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

    2013-01-01

    Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation. PMID:24146828

  8. Hepatic expression of transcription factors affecting developmental regulation of UGT1A1 in the Han Chinese population.

    PubMed

    Nie, Ya-Li; He, Hang; Li, Jiang-Feng; Meng, Xiang-Guang; Yan, Liang; Wang, Pei; Wang, Shu-Jie; Bi, Hong-Zheng; Zhang, Li-Rong; Kan, Quan-Cheng

    2017-01-01

    Complete or partial inactivity of UGT1A1, the unique enzyme responsible for bilirubin glucuronidation, is commonly associated with hyperbilirubinemia. We investigated the dynamic expression of UGT1A1, and that of the transcription factors (TFs) involved in its developmental regulation, during human hepatic growth in Han Chinese individuals. Eighty-eight prenatal, pediatric, and adult liver samples were obtained from Han Chinese individuals. Quantitative real-time polymerase chain reaction was used to evaluate mRNA expression of UGT1A1 and TFs including PXR, CAR, HNF1A, HNF4A, PPARA, etc. UGT1A1 protein levels and metabolic activity were determined by western blotting and high-performance liquid chromatography. Direct sequencing was employed to genotype UGT1A1*6 (211G˃A) and UGT1A1*28 (TA6˃TA7) polymorphisms. UGT1A1 expression was minimal in prenatal samples, but significantly elevated during pediatric and adult stages. mRNA and protein levels and metabolic activity were prominently increased (120-, 20-, and 10-fold, respectively) in pediatric and adult livers compared to prenatal samples. Furthermore, expression did not differ appreciably between pediatric and adult periods. Dynamic expression of TFs, including PXR, CAR, HNF1A, HNF4A, and PPARA, was consistent with UGT1A1 levels at each developmental stage. A pronounced correlation between expression of these TFs and that of UGT1A1 (P < 0.001) was observed. Moreover, UGT1A1*6 and UGT1A1*28 polymorphisms reduced levels of UGT1A1 by up to 40-60 %. Hepatic expression of transcription factors is associated with developmental regulation of UGT1A1 in the Han Chinese population. Moreover, UGT1A1 polymorphisms are associated with reduced expression of UGT1A1 mRNA and protein, as well as enzyme activity.

  9. Finally, the Progenitor of the Type Ib iPTF13bvn

    NASA Astrophysics Data System (ADS)

    Van Dyk, Schulyer

    2017-08-01

    Supernovae (SNe) are among the most powerful events in the Universe and have a profound influence on galaxy evolution. Whereas we have been able to identify the luminous red supergiant progenitor stars of the most common core-collapse explosions, the hydrogen-rich Type II, the progenitors of hydrogen-poor Type Ib and Type Ic have been far more elusive. To strip away a SN Ib/c progenitor's outer layers, theoretical models with either (a) a highly-massive star with prodigious winds during the Wolf-Rayet phase or (b) a somewhat lower-mass star in a close, mass-exchange binary system have been proposed. One example exists so far of a progenitor identification, for the SN Ib iPTF13bvn in NGC 5806. Both models have been invoked to explain this event, although most evidence to date points toward the binary model. Our combined team observed this SN with WFC3 in Cycle 22, about 2 years after explosion, to investigate whether the progenitor had disappeared. As a result, we were able to report that indeed it had. We also attempted to better characterize the nature of the progenitor by subtracting our images from the pre-explosion HST data. Unfortunately, the old SN was apparently still conspicuously present. We therefore propose to reimage the SN site, when the SN should then be well below detectability, to produce high-quality templates of the host galaxy for subtraction. We can then finally fully reveal the progenitor and understand its true nature. iPTF13bvn is one of the most important historical SNe and will most probably be the best available case of a SN Ib progenitor for HST's remaining lifetime. It is imperative to understand the nature of this SN and its progenitor object.

  10. The Metastasis Efficiency Modifier Ribosomal RNA Processing 1 Homolog B (RRP1B) Is a Chromatin-associated Factor*

    PubMed Central

    Crawford, Nigel P. S.; Yang, Hailiu; Mattaini, Katherine R.; Hunter, Kent W.

    2009-01-01

    There is accumulating evidence for a role of germ line variation in breast cancer metastasis. We have recently identified a novel metastasis susceptibility gene, Rrp1b (ribosomal RNA processing 1 homolog B). Overexpression of Rrp1b in a mouse mammary tumor cell line induces a gene expression signature that predicts survival in breast cancer. Here we extend the analysis of RRP1B function by demonstrating that the Rrp1b activation gene expression signature accurately predicted the outcome in three of four publicly available breast carcinoma gene expression data sets. In addition, we provide insights into the mechanism of RRP1B. Tandem affinity purification demonstrated that RRP1B physically interacts with many nucleosome binding factors, including histone H1X, poly(ADP-ribose) polymerase 1, TRIM28 (tripartite motif-containing 28), and CSDA (cold shock domain protein A). Co-immunofluorescence and co-immunoprecipitation confirmed these interactions and also interactions with heterochromatin protein-1α and acetyl-histone H4 lysine 5. Finally, we investigated the effects of ectopic expression of an RRP1B allelic variant previously associated with improved survival in breast cancer. Gene expression analyses demonstrate that, compared with ectopic expression of wild type RRP1B in HeLa cells, the variant RRP1B differentially modulates various transcription factors controlled by TRIM28 and CSDA. These data suggest that RRP1B, a tumor progression and metastasis susceptibility candidate gene, is potentially a dynamic modulator of transcription and chromatin structure. PMID:19710015

  11. Factors Associated with Post-Seasonal Serological Titer and Risk Factors for Infection with the Pandemic A/H1N1 Virus in the French General Population

    PubMed Central

    Lapidus, Nathanael; de Lamballerie, Xavier; Salez, Nicolas; Setbon, Michel; Delabre, Rosemary M.; Ferrari, Pascal; Moyen, Nanikaly; Gougeon, Marie-Lise; Vely, Frédéric; Leruez-Ville, Marianne; Andreoletti, Laurent; Cauchemez, Simon; Boëlle, Pierre-Yves; Vivier, Éric; Abel, Laurent; Schwarzinger, Michaël; Legeas, Michèle; Le Cann, Pierre; Flahault, Antoine; Carrat, Fabrice

    2013-01-01

    The CoPanFlu-France cohort of households was set up in 2009 to study the risk factors for infection by the pandemic influenza virus (H1N1pdm) in the French general population. The authors developed an integrative data-driven approach to identify individual, collective and environmental factors associated with the post-seasonal serological H1N1pdm geometric mean titer, and derived a nested case-control analysis to identify risk factors for infection during the first season. This analysis included 1377 subjects (601 households). The GMT for the general population was 47.1 (95% confidence interval (CI): 45.1, 49.2). According to a multivariable analysis, pandemic vaccination, seasonal vaccination in 2009, recent history of influenza-like illness, asthma, chronic obstructive pulmonary disease, social contacts at school and use of public transports by the local population were associated with a higher GMT, whereas history of smoking was associated with a lower GMT. Additionally, young age at inclusion and risk perception of exposure to the virus at work were identified as possible risk factors, whereas presence of an air humidifier in the living room was a possible protective factor. These findings will be interpreted in light of the longitudinal analyses of this ongoing cohort. PMID:23613718

  12. A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation

    PubMed Central

    Hayes, Heather L.; Zhang, Lu; Becker, Thomas C.; Haldeman, Jonathan M.; Stephens, Samuel B.; Arlotto, Michelle; Moss, Larry G.; Newgard, Christopher B.

    2016-01-01

    The homeodomain transcription factor Pdx-1 has important roles in pancreas and islet development as well as in β-cell function and survival. We previously reported that Pdx-1 overexpression stimulates islet cell proliferation, but the mechanism remains unclear. Here, we demonstrate that overexpression of Pdx-1 triggers proliferation largely by a non-cell-autonomous mechanism mediated by soluble factors. Consistent with this idea, overexpression of Pdx-1 under the control of a β-cell-specific promoter (rat insulin promoter [RIP]) stimulates proliferation of both α and β cells, and overexpression of Pdx-1 in islets separated by a Transwell membrane from islets lacking Pdx-1 overexpression activates proliferation in the untreated islets. Microarray and gene ontology (GO) analysis identified inhibin beta-B (Inhbb), an activin subunit and member of the transforming growth factor β (TGF-β) superfamily, as a Pdx-1-responsive gene. Overexpression of Inhbb or addition of activin B stimulates rat islet cell and β-cell proliferation, and the activin receptors RIIA and RIIB are required for the full proliferative effects of Pdx-1 in rat islets. In human islets, Inhbb overexpression stimulates total islet cell proliferation and potentiates Pdx-1-stimulated proliferation of total islet cells and β cells. In sum, this study identifies a mechanism by which Pdx-1 induces a soluble factor that is sufficient to stimulate both rat and human islet cell proliferation. PMID:27620967

  13. Microtubule actin cross-linking factor 1, a novel target in glioblastoma.

    PubMed

    Afghani, Najlaa; Mehta, Toral; Wang, Jialiang; Tang, Nan; Skalli, Omar; Quick, Quincy A

    2017-01-01

    Genetic heterogeneity is recognized as a major contributing factor of glioblastoma resistance to clinical treatment modalities and consequently low overall survival rates. This genetic diversity results in variations in protein expression, both intratumorally and between individual glioblastoma patients. In this regard, the spectraplakin protein, microtubule actin cross-linking factor 1 (MACF1), was examined in glioblastoma. An expression analysis of MACF1 in various types of brain tumor tissue revealed that MACF1 was predominately present in grade III-IV astroctyomas and grade IV glioblastoma, but not in normal brain tissue, normal human astrocytes and lower grade brain tumors. Subsequent genetic inhibition experiments showed that suppression of MACF1 selectively inhibited glioblastoma cell proliferation and migration in cell lines established from patient derived xenograft mouse models and immortalized glioblastoma cell lines that were associated with downregulation of the Wnt-signaling mediators, Axin1 and β-catenin. Additionally, concomitant MACF1 silencing with the chemotherapeutic agent temozolomide (TMZ) used for the clinical treatment of glioblastomas cooperatively reduced the proliferative capacity of glioblastoma cells. In conclusion, the present study represents the first investigation on the functional role of MACF1 in tumor cell biology, as well as demonstrates its potential as a unique biomarker that can be targeted synergistically with TMZ as part of a combinatorial therapeutic approach for the treatment of genetically multifarious glioblastomas.

  14. Distribution and Risk Factors of 2009 Pandemic Influenza A (H1N1) in Mainland China

    PubMed Central

    Fang, Li-Qun; Wang, Li-Ping; de Vlas, Sake J.; Liang, Song; Tong, Shi-Lu; Li, Yan-Li; Li, Ya-Pin; Qian, Quan; Yang, Hong; Zhou, Mai-Geng; Wang, Xiao-Feng; Richardus, Jan Hendrik; Ma, Jia-Qi; Cao, Wu-Chun

    2012-01-01

    Data from all reported cases of 2009 pandemic influenza A (H1N1) were obtained from the China Information System for Disease Control and Prevention. The spatiotemporal distribution patterns of cases were characterized through spatial analysis. The impact of travel-related risk factors on invasion of the disease was analyzed using survival analysis, and climatic factors related to local transmission were identified using multilevel Poisson regression, both at the county level. The results showed that the epidemic spanned a large geographic area, with the most affected areas being in western China. Significant differences in incidence were found among age groups, with incidences peaking in school-age children. Overall, the epidemic spread from southeast to northwest. Proximity to airports and being intersected by national highways or freeways but not railways were variables associated with the presence of the disease in a county. Lower temperature and lower relative humidity were the climatic factors facilitating local transmission after correction for the effects of school summer vacation and public holidays, as well as population density and the density of medical facilities. These findings indicate that interventions focused on domestic travel, population density, and climatic factors could play a role in mitigating the public health impact of future influenza pandemics. PMID:22491083

  15. 26 CFR 1.846-1 - Application of discount factors.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (CONTINUED) INCOME TAXES (CONTINUED) Other Insurance Companies § 1.846-1 Application of discount factors. (a... losses based on their annual statement classification prior to the change. (2) Title insurance company reserves. A title insurance company may only take into account case reserves (relating to claims which have...

  16. 26 CFR 1.846-1 - Application of discount factors.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) INCOME TAXES Other Insurance Companies § 1.846-1 Application of discount factors. (a) In general... losses based on their annual statement classification prior to the change. (2) Title insurance company reserves. A title insurance company may only take into account case reserves (relating to claims which have...

  17. PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a)

    PubMed Central

    Emerling, Brooke M.; Weinberg, Frank; Liu, Juinn-Lin; Mak, Tak W.; Chandel, Navdeep S.

    2008-01-01

    The tumor suppressor PTEN is mutated or deleted in many tumors, causing the activation of the PI3K pathway. Here, we show that the loss of PTEN increases the transcriptional activity of hypoxia-inducible factor 1 (HIF-1) through the inactivation of Forkhead transcription factors (FOXO) in PTEN-null cells. Reintroduction of PTEN into the nucleus, overexpression of a nonphosphorylatable FOXO3a, which accumulates in the nucleus, or inhibition of nuclear export of FOXO3a by leptomycin B represses HIF-1 transcriptional activity in PTEN-null cells. HIF-1 transcriptional activity increases in PTEN-positive cells depleted of FOXO3a with siRNA. PTEN and FOXO3a regulate the transactivation domain of HIF-1α. Chromatin immunoprecipitation indicates that FOXO3a complexes with HIF-1α and p300 on the Glut-1 promoter, a HIF-1 target gene. Overexpression of p300 reverses FOXO3a-mediated repression of HIF-1 transcriptional activity. Coimmunoprecipitation and GAL4-HIF-1α transactivation assays reveal that FOXO3a interferes with p300-dependent HIF-1 transcriptional activity. Thus, FOXO3a negatively regulates HIF-1 transcriptional activity. PMID:18268343

  18. Subjects hospitalized with the 2009 pandemic influenza A (H1N1) virus in a respiratory infection unit: clinical factors correlating with ICU admission.

    PubMed

    Rovina, Nikoletta; Erifaki, Magdalini; Katsaounou, Paraskevi; Lyxi, Georgia; Koutsoukou, Antonia; Koulouris, Nikolaos G; Alchanatis, Manos

    2014-10-01

    The 2009 pandemic influenza A (H1N1) virus was accompanied by high morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with documented 2009 influenza A (H1N1) virus admitted to a reference chest hospital, the disease outcome, and risk factors associated with ICU admission. We assessed 109 subjects admitted to the respiratory infection unit of a hospital for chest disease with signs and symptoms of the 2009 influenza A (H1N1) virus between April 2009 and December 2010. Demographic data, comorbidities, clinical signs and symptoms, laboratory tests, radiographic findings, treatment, and final outcomes were all recorded. Factors associated with severe disease requiring ICU admission were determined. Ninety subjects (82.5%) had laboratory-confirmed 2009 influenza A (H1N1). Sixty-four percent of these subjects had pneumonia on admission, 26% had respiratory failure, and 11% required care in the ICU. Dyspnea and the presence of infiltrates on chest x-rays were the most common signs among the subjects with H1N1. All subjects were treated with antiviral therapy, and 75% received antibiotic treatment based on their clinical and laboratory findings. The predictive factors of ICU admission were severe hypoxemia and lymphocytosis. The outcome of subjects with influenza A (H1N1) virus infection was influenced by the severity of the disease on admission, the subjects' underlying conditions, and complications during hospitalization. Copyright © 2014 by Daedalus Enterprises.

  19. The translation elongation factor eEF1A1 couples transcription to translation during heat shock response

    PubMed Central

    Vera, Maria; Pani, Bibhusita; Griffiths, Lowri A; Muchardt, Christian; Abbott, Catherine M; Singer, Robert H; Nudler, Evgeny

    2014-01-01

    Translation elongation factor eEF1A has a well-defined role in protein synthesis. In this study, we demonstrate a new role for eEF1A: it participates in the entire process of the heat shock response (HSR) in mammalian cells from transcription through translation. Upon stress, isoform 1 of eEF1A rapidly activates transcription of HSP70 by recruiting the master regulator HSF1 to its promoter. eEF1A1 then associates with elongating RNA polymerase II and the 3′UTR of HSP70 mRNA, stabilizing it and facilitating its transport from the nucleus to active ribosomes. eEF1A1-depleted cells exhibit severely impaired HSR and compromised thermotolerance. In contrast, tissue-specific isoform 2 of eEF1A does not support HSR. By adjusting transcriptional yield to translational needs, eEF1A1 renders HSR rapid, robust, and highly selective; thus, representing an attractive therapeutic target for numerous conditions associated with disrupted protein homeostasis, ranging from neurodegeneration to cancer. DOI: http://dx.doi.org/10.7554/eLife.03164.001 PMID:25233275

  20. Low Insulin-Like Growth Factor-1 Level in Obesity Nephropathy: A New Risk Factor?

    PubMed Central

    Bancu, Ioana; Navarro Díaz, Maruja; Serra, Assumpta; Granada, Marisa; Lopez, Dolores; Romero, Ramon; Bonet, Josep

    2016-01-01

    Introduction IGF-1 (insulin-like growth factor-1) is a hormone involved in cell growth and other important processes. In the kidney, IGF-1 has a stimulating effect, increasing the blood flow and glomerular filtration rate. Although many experimental animal studies regarding the role of IGF-1 in the kidney have been conducted, few human studies are available in the literature. Obesity is a cause of renal failure, and several glomerular lesions associated with obesity have been described. However, no studies regarding the levels of IGF-1 in morbidly obese patients with renal injury associated with obesity have been conducted. Aim To determine the serum IGF-1 concentrations in morbidly obese patients with normal renal function but with different types of early obesity-related glomerular lesions and to evaluate the possible relationship between IGF-1 and the presence of renal lesions. Methods Eighty morbidly obese patients with renal biopsy, including 11 patients with no evidence of renal lesion, 17 patients with single glomerulomegaly, 21 patients with single podocyte hypertrophy, 10 patients with glomerulomegaly and podocyte hypertrophy, 5 patients with focal segmental hyalinosis, and 16 patients with increased mesangial matrix and/or mesangial proliferation, participated in this study. Biological parameters, including serum IGF-1 concentrations with the standard deviation score for age (SDS-IGF-1), were determined for all patients. Results Eighty patients (50 women and 30 men) with a mean BMI of 52.63 ± 8.71 and a mean age of 42.40 ± 9.45 years were included in this study. IGF-1, IGF-1 SDS and IGF-1BP3 levels according to the renal injury were compared (normal glomeruli: IGF-1 = 190.17 ± 72.46; glomerulomegaly: IGF-1 = 122.3 ± 50.05; podocyte hypertrophy: IGF-1 = 119.81 ± 60.34; focal segmental hyalinosis: IGF-1 170.98 ± 100.83, increased mesangial matrix and/or mesangial proliferation: IGF-1 117.73 ± 63.87). Statistically significant differences were

  1. Cross-Matching Source Observations from the Palomar Transient Factory (PTF)

    NASA Astrophysics Data System (ADS)

    Laher, Russ; Grillmair, C.; Surace, J.; Monkewitz, S.; Jackson, E.

    2009-01-01

    Over the four-year lifetime of the PTF project, approximately 40 billion instances of astronomical-source observations will be extracted from the image data. The instances will correspond to the same astronomical objects being observed at roughly 25-50 different times, and so a very large catalog containing important object-variability information will be the chief PTF product. Organizing astronomical-source catalogs is conventionally done by dividing the catalog into declination zones and sorting by right ascension within each zone (e.g., the USNOA star catalog), in order to facilitate catalog searches. This method was reincarnated as the "zones" algorithm in a SQL-Server database implementation (Szalay et al., MSR-TR-2004-32), with corrections given by Gray et al. (MSR-TR-2006-52). The primary advantage of this implementation is that all of the work is done entirely on the database server and client/server communication is eliminated. We implemented the methods outlined in Gray et al. for a PostgreSQL database. We programmed the methods as database functions in PL/pgSQL procedural language. The cross-matching is currently based on source positions, but we intend to extend it to use both positions and positional uncertainties to form a chi-square statistic for optimal thresholding. The database design includes three main tables, plus a handful of internal tables. The Sources table stores the SExtractor source extractions taken at various times; the MergedSources table stores statistics about the astronomical objects, which are the result of cross-matching records in the Sources table; and the Merges table, which associates cross-matched primary keys in the Sources table with primary keys in the MergedSoures table. Besides judicious database indexing, we have also internally partitioned the Sources table by declination zone, in order to speed up the population of Sources records and make the database more manageable. The catalog will be accessible to the public

  2. Steroidogenic Factor-1 and Human Disease

    PubMed Central

    El-Khairi, Ranna; Achermann, John C.

    2016-01-01

    Steroidogenic factor-1 (SF-1) (Ad4BP, NR5A1) is a nuclear receptor that plays a key role in adrenal and reproductive development and function. Deletion of the gene encoding Sf-1 (Nr5a1) in mice results in severe developmental defects of the adrenal gland and gonad. Consequently, initial work on the potential effects of SF-1 disruption in humans focused on individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis, and Müllerian structures. This is a rare phenotype, but has been reported on two occasions, because of alterations that affect key DNA-binding domains of SF-1. Attention then turned to a potential wider role of SF-1 in human adrenal and reproductive disorders. Although changes in SF-1 only very rarely cause isolated adrenal failure, it is emerging that variations in SF-1 are a surprisingly frequent cause of reproductive dysfunction in humans. In 46,XY disorders of sex development, a spectrum of phenotypes has been reported including severe and partial forms of gonadal (testicular) dysgenesis, hypospadias, anorchia with microphallus, and even male factor infertility. In 46,XX females, alterations in SF-1 are associated with primary ovarian insufficiency. Thus, SF-1 seems be a more significant factor in human reproductive health than was first envisioned, with implications for adults as well as children. PMID:23044873

  3. HIGHLY VARIABLE EXTINCTION AND ACCRETION IN THE JET-DRIVING CLASS I-TYPE YOUNG STAR PTF 10nvg (V2492 Cyg, IRAS 20496+4354)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hillenbrand, Lynne A.; Carpenter, John M.; Muirhead, Philip S.

    2013-03-15

    against the broad H{alpha} and Ca II triplet emission lines, similarly are formed in the outflow. CARMA maps resolve on larger scales a spatially extended outflow in millimeter-wavelength CO. We attribute the recently observed photometric and spectroscopic behavior to rotating circumstellar disk material located at separation a Almost-Equal-To 0.7(M{sub *}/M{sub Sun }){sup 1/3} AU from the continuum source, causing the semi-periodic dimming. Occultation of the central star as well as the bright inner disk and the accretion/outflow zones renders shocked gas in the inner part of the jet amenable to observation at the faint epochs. We discuss PTF 10nvg as a source exhibiting both accretion-driven (perhaps analogous to V1647 Ori) and extinction-driven (perhaps analogous to UX Ori or GM Cep) high-amplitude variability phenomena.« less

  4. SHORT HYPOCOTYL1 Encodes a SMARCA3-Like Chromatin Remodeling Factor Regulating Elongation1[OPEN

    PubMed Central

    Bo, Kailiang; Behera, Tusar K.; Pandey, Sudhakar; Wen, Changlong; Wang, Yuhui; Simon, Philipp W.; Li, Yuhong

    2016-01-01

    In Arabidopsis (Arabidopsis thaliana), the UVR8-mediated signaling pathway is employed to attain UVB protection and acclimation to deal with low-dosage UVB (LDUVB)-induced stresses. Here, we identified SHORT HYPOCOTYL1 (SH1) in cucumber (Cucumis sativus), which regulates LDUVB-dependent hypocotyl elongation by modulating the UVR8 signaling pathway. We showed that hypocotyl elongation in cucumbers carrying the recessive sh1 allele was LDUVB insensitive and that Sh1 encoded a human SMARCA3-like chromatin remodeling factor. The allele frequency and distribution pattern at this locus among natural populations supported the wild cucumber origin of sh1 for local adaptation, which was under selection during domestication. The cultivated cucumber carries predominantly the Sh1 allele; the sh1 allele is nearly fixed in the semiwild Xishuangbanna cucumber, and the wild cucumber population is largely at Hardy-Weinberg equilibrium for the two alleles. The SH1 protein sequence was highly conserved among eukaryotic organisms, but its regulation of hypocotyl elongation in cucumber seems to be a novel function. While Sh1 expression was inhibited by LDUVB, its transcript abundance was highly correlated with hypocotyl elongation rate and the expression level of cell-elongation-related genes. Expression profiling of key regulators in the UVR8 signaling pathway revealed significant differential expression of CsHY5 between two near isogenic lines of Sh1. Sh1 and CsHY5 acted antagonistically at transcriptional level. A working model was proposed in which Sh1 regulates LDUVB-dependent hypocotyl elongation in cucumber through changing the chromatin states and thus the accessibility of CsHY5 in the UVR8 signaling pathway to promoters of LDUVB-responsive genes for hypocotyl elongation. PMID:27559036

  5. Heat shock factor-1 knockout enhances cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter (MDR1) gene expressions to attenuate atherosclerosis

    PubMed Central

    Krishnamurthy, Karthikeyan; Glaser, Shannon; Alpini, Gianfranco D.; Cardounel, Arturo J.; Liu, Zhenguo; Ilangovan, Govindasamy

    2016-01-01

    Aims Stress response, in terms of activation of stress factors, is known to cause obesity and coronary heart disease such as atherosclerosis in human. However, the underlying mechanism(s) of these pathways are not known. Here, we investigated the effect of heat shock factor-1 (HSF-1) on atherosclerosis. Methods and results HSF-1 and low-density lipoprotein receptor (LDLr) double knockout (HSF-1−/−/LDLr−/−) and LDLr knockout (LDLr−/−) mice were fed with atherogenic western diet (WD) for 12 weeks. WD-induced weight gain and atherosclerotic lesion in aortic arch and carotid regions were reduced in HSF-1−/−/LDLr−/− mice, compared with LDLr−/− mice. Also, repression of PPAR-γ2 and AMPKα expression in adipose tissue, low hepatic steatosis, and lessened plasma adiponectins and lipoproteins were observed. In HSF-1−/−/LDLr−/− liver, higher cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter [MDR1/P-glycoprotein (P-gp)] gene expressions were observed, consistent with higher bile acid transport and larger hepatic bile ducts. Luciferase reporter gene assays with wild-type CYP7A1 and MDR1 promoters showed lesser luminescence than with mutant promoters (HSF-1 binding site deleted), indicating that HSF-1 binding is repressive of CYP7A1 and MDR1 gene expressions. Conclusion HSF-1 ablation not only eliminates heat shock response, but it also transcriptionally up-regulates CYP7A1 and MDR1/P-gp axis in WD-diet fed HSF-1−/−/LDLr−/− mice to reduce atherosclerosis. PMID:27131506

  6. The Arf-inducing Transcription Factor Dmp1 Encodes a Transcriptional Activator of Amphiregulin, Thrombospondin-1, JunB and Egr1

    PubMed Central

    Mallakin, Ali; Sugiyama, Takayuki; Kai, Fumitake; Taneja, Pankaj; Kendig, Robert D.; Frazier, Donna P.; Maglic, Dejan; Matise, Lauren A.; Willingham, Mark C.; Inoue, Kazushi

    2009-01-01

    Dmp1 (Dmtf1) encodes a Myb-like transcription factor implicated in tumor suppression through direct activation of the Arf-p53 pathway. The human DMP1 gene is frequently deleted in non-small cell lung cancers, especially those that retain wild-type INK4a/ARF and/or p53. To identify novel genes that are regulated by Dmp1, transcriptional profiles of lung tissue from Dmp1-null and wild-type mice were generated using the GeneChip Microarray. Comparative analysis of gene expression changes between the two groups resulted in identification of numerous genes that may be regulated by Dmp1. Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. These target genes were chosen for further analyses since they are involved in cell proliferation, transcription, angiogenesis/metastasis, apoptosis, or DNA methylation, and thus could account for the tumor suppressor phenotype of Dmp1. Dmp1 directly bound to the genomic loci of Areg, Tsp-1, JunB and Egr1. Significant upregulation or downregulation of the novel Dmp1 target genes was observed upon transient expression of Dmp1 in alveolar epithelial cells, an effect which was nullified by the inhibition of de novo mRNA synthesis. Interestingly, these genes and their protein products were significantly downregulated or upregulated in the lungs from Dmp1-heterozygous mice as well. Identification of novel Dmp1 target genes not only provides insights into the effects of Dmp1 on global gene expression, but also sheds light on the mechanism of haploid insufficiency of Dmp1 in tumor suppression. PMID:19816943

  7. Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study

    PubMed Central

    Bossini-Castillo, Lara; Martin, Jose Ezequiel; Broen, Jasper; Simeon, Carmen P; Beretta, Lorenzo; Gorlova, Olga Y; Vonk, Madelon C; Ortego-Centeno, Norberto; Espinosa, Gerard; Carreira, Patricia; García de la Peña, Paloma; Oreiro, Natividad; Román-Ivorra, José Andrés; Castillo, María Jesús; González-Gay, Miguel A; Sáez-Comet, Luis; Castellví, Ivan; Schuerwegh, Annemie J; Voskuyl, Alexandre E; Hoffmann-Vold, Anna-Maria; Hesselstrand, Roger; Nordin, Annika; Lunardi, Claudio; Scorza, Raffaella; van Laar, Jacob M; Shiels, Paul G; Herrick, Ariane; Worthington, Jane; Fonseca, Carmen; Denton, Christopher; Tan, Filemon K; Arnett, Frank C; Assassi, Shervin; Koeleman, Bobby P; Mayes, Maureen D; Radstake, Timothy R D J; Martin, Javier

    2013-01-01

    Introduction A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry. Methods 4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci. Results Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 pMH=1.94×10−4, OR 1.19; rs4958881 pMH=3.26×10−5, OR 1.19; rs3792783 pMH=2.16×10−4, OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets. Conclusions These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor. PMID:22896740

  8. Review of cardiometabolic risk factors in a cohort of paediatric type 1 diabetes mellitus patients.

    PubMed

    Donovan, A; Finner, N; O'Connor, C; Quinn, A; O'Gorman, C S

    2017-05-01

    Type 1 diabetes mellitus (T1DM) is a recognised risk factor for cardiometabolic disease. Other risk factors include age, gender, family history, glycaemic control, dyslipidaemia, weight, and activity levels. To estimate the point prevalence of cardiometabolic risk factors in a paediatric population with T1DM. Eighty-one patients with T1DM aged between 10 and 16 years attended during the study and 56 (69.1 %) patients agreed to participate. Mixed methods data collection included a questionnaire developed for this study, supplemented by retrospective and prospective data collected from the patient records. Of 56 subjects with T1DM, aged 12.7 ± 1.7 years (10-16 years) 26 were male and 30 were female. Mean HbA1c was 72 ± 14 mmol/mol. 53 subjects (94.6 %) had at least one additional cardiometabolic risk factor. Cardiometabolic risk factors are present in this population with T1DM. Identifying cardiometabolic risk factors in adolescent T1DM patients is the first step in prevention of future morbidity and mortality.

  9. Transforming growth factor β-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yang, Bin; Li, Wei; Zheng, Qichang

    Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein β (C/EBPβ) in an IκB kinase β (IKKβ) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPβ and SDF-1 was significantly potentiated by knockdown of transforming growth factor β-activated kinase 1 (TAK1), an upstream activator of IKKβ signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negativemore » effect on IL-1α-induced expression of C/EBPβ and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. - Highlights: • IL-1α induces IKKβ signaling-dependent SDF-1 expression by up-regulating C/EBPβ. • Activation of TAK1 by IL-1α negatively regulates C/EBPβ-dependent SDF-1 expression. • IL-1α-induced TAK1/p38 MAPK signaling counteracts ROS-dependent SDF-1 expression. • TAK1 counteracts IL-1α-induced SDF-1 expression by attenuating NRF2 up-regulation.« less

  10. Upregulation of Endogenous HMOX1 Expression by a Computer-Designed Artificial Transcription Factor

    PubMed Central

    Guo, Hongfeng; Tian, Yi; Lu, Hai; Wei, Yong; Ying, Dajun

    2010-01-01

    Heme oxygenase-1 (HO-1) is well known as a cytoprotective factor. Research has revealed that it is a promising therapeutic target for cardiovascular diseases. In the current study, an HMOX1 (HO-1 gene) enhancer-specific artificial zinc-finger protein (AZP) was designed using bioinformatical methods. Then, an artificial transcription factor (ATF) was constructed based on the AZP. In the ATF, the p65 functional domain was used as the effector domain (ED), and a nuclear localization sequence (NLS) was also included. We next analyzed the affinity of the ATF to the HMOX1 enhancer and the effect of the ATF on endogenous HMOX1 expression. The results suggest that the ATF could effectively upregulate endogenous HMOX1 expression in ECV304 cells. With further research, the ATF could be developed as a potential drug for cardiovascular diseases. PMID:20706680

  11. [Study on sensitivity of climatic factors on influenza A (H1N1) based on classification and regression tree and wavelet analysis].

    PubMed

    Xiao, Hong; Lin, Xiao-ling; Dai, Xiang-yu; Gao, Li-dong; Chen, Bi-yun; Zhang, Xi-xing; Zhu, Pei-juan; Tian, Huai-yu

    2012-05-01

    To analyze the periodicity of pandemic influenza A (H1N1) in Changsha in year 2009 and its correlation with sensitive climatic factors. The information of 5439 cases of influenza A (H1N1) and synchronous meteorological data during the period between May 22th and December 31st in year 2009 (223 days in total) in Changsha city were collected. The classification and regression tree (CART) was employed to screen the sensitive climatic factors on influenza A (H1N1); meanwhile, cross wavelet transform and wavelet coherence analysis were applied to assess and compare the periodicity of the pandemic disease and its association with the time-lag phase features of the sensitive climatic factors. The results of CART indicated that the daily minimum temperature and daily absolute humidity were the sensitive climatic factors for the popularity of influenza A (H1N1) in Changsha. The peak of the incidence of influenza A (H1N1) was in the period between October and December (Median (M) = 44.00 cases per day), simultaneously the daily minimum temperature (M = 13°C) and daily absolute humidity (M = 6.69 g/m(3)) were relatively low. The results of wavelet analysis demonstrated that a period of 16 days was found in the epidemic threshold in Changsha, while the daily minimum temperature and daily absolute humidity were the relatively sensitive climatic factors. The number of daily reported patients was statistically relevant to the daily minimum temperature and daily absolute humidity. The frequency domain was mostly in the period of (16 ± 2) days. In the initial stage of the disease (from August 9th and September 8th), a 6-day lag was found between the incidence and the daily minimum temperature. In the peak period of the disease, the daily minimum temperature and daily absolute humidity were negatively relevant to the incidence of the disease. In the pandemic period, the incidence of influenza A (H1N1) showed periodic features; and the sensitive climatic factors did have a "driving

  12. Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1).

    PubMed

    Laev, Sergey S; Salakhutdinov, Nariman F; Lavrik, Olga I

    2017-05-01

    Human apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein which is essential in the base excision repair (BER) pathway of DNA lesions caused by oxidation and alkylation. This protein hydrolyzes DNA adjacent to the 5'-end of an apurinic/apyrimidinic (AP) site to produce a nick with a 3'-hydroxyl group and a 5'-deoxyribose phosphate moiety or activates the DNA-binding activity of certain transcription factors through its redox function. Studies have indicated a role for APE1/Ref-1 in the pathogenesis of cancer and in resistance to DNA-interactive drugs. Thus, this protein has potential as a target in cancer treatment. As a result, major efforts have been directed to identify small molecule inhibitors against APE1/Ref-1 activities. These agents have the potential to become anticancer drugs. The aim of this review is to present recent progress in studies of all published small molecule APE1/Ref-1 inhibitors. The structures and activities of APE1/Ref-1 inhibitors, that target both DNA repair and redox activities, are presented and discussed. To date, there is an urgent need for further development of the design and synthesis of APE1/Ref-1 inhibitors due to high importance of this protein target. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Protective role of cytochrome P450 1A1 (CYP1A1) against benzo[a]pyrene-induced toxicity in mouse aorta.

    PubMed

    Uno, Shigeyuki; Sakurai, Kenichi; Nebert, Daniel W; Makishima, Makoto

    2014-02-28

    Benzo[a]pyrene (BaP) is an environmental pollutant produced by combustive processes, such as cigarette smoke and coke ovens, and is implicated in the pathogenesis of atherosclerosis. Cytochrome P450 1A1 (CYP1A1) plays a role in both metabolic activation and detoxication of BaP in a context-dependent manner. The role of CYP1A1 in BaP-induced toxicity in aorta remains unknown. First, we fed Apoe⁻/⁻ mice an atherogenic diet plus BaP and found that oral BaP-enhanced atherosclerosis is associated with increased reactive oxygen species (ROS) and inflammatory markers, such as plasma tumor necrosis factor levels and aortic mRNA expression of vascular endothelial growth factor A (Vegfa). We next examined the effect of an atherogenic diet plus BaP on ROS and inflammatory markers in Cyp1a1⁻/⁻ mice. Although this treatment was not sufficient to induce atherosclerotic lesions in Cyp1a1⁻/⁻ mice, plasma antioxidant levels were decreased in Cyp1a1⁻/⁻ mice even in the absence of BaP treatment. The atherogenic diet plus BaP effectively elevated plasma ROS levels and expression of atherosclerosis-related genes, specifically Vegfa, in Cyp1a1⁻/⁻ mice compared with wild-type mice. BaP treatment increased Vegfa mRNA levels in mouse embryonic fibroblasts from Cyp1a1⁻/⁻ mice but not from wild-type mice. BaP-induced DNA adduct formation was increased in the aorta of Cyp1a1⁻/⁻ mice, but not wild-type or Apoe⁻/⁻ mice, and the atherogenic diet decreased BaP-induced DNA adducts in Cyp1a1⁻/⁻ mice compared with mice on a control diet. These data suggest that ROS production contributes to BaP-exacerbated atherosclerosis and that CYP1A1 plays a protective role against oral BaP toxicity in aorta. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Factors Affecting Intention among Students to Be Vaccinated against A/H1N1 Influenza: A Health Belief Model Approach

    PubMed Central

    Teitler-Regev, Sharon; Shahrabani, Shosh; Benzion, Uri

    2011-01-01

    The outbreak of A/H1N1 influenza (henceforth, swine flu) in 2009 was characterized mainly by morbidity rates among young people. This study examined the factors affecting the intention to be vaccinated against the swine flu among students in Israel. Questionnaires were distributed in December 2009 among 387 students at higher-education institutions. The research questionnaire included sociodemographic characteristics and Health Belief Model principles. The results show that the factors positively affecting the intention to take the swine flu vaccine were past experience with seasonal flu shot and three HBM categories: higher levels of perceived susceptibility for catching the illness, perceived seriousness of illness, and lower levels of barriers. We conclude that offering the vaccine at workplaces may raise the intention to take the vaccine among young people in Israel. PMID:22229099

  15. Splicing factor SFRS1 recognizes a functionally diverse landscape of RNA transcripts.

    PubMed

    Sanford, Jeremy R; Wang, Xin; Mort, Matthew; Vanduyn, Natalia; Cooper, David N; Mooney, Sean D; Edenberg, Howard J; Liu, Yunlong

    2009-03-01

    Metazoan genes are encrypted with at least two superimposed codes: the genetic code to specify the primary structure of proteins and the splicing code to expand their proteomic output via alternative splicing. Here, we define the specificity of a central regulator of pre-mRNA splicing, the conserved, essential splicing factor SFRS1. Cross-linking immunoprecipitation and high-throughput sequencing (CLIP-seq) identified 23,632 binding sites for SFRS1 in the transcriptome of cultured human embryonic kidney cells. SFRS1 was found to engage many different classes of functionally distinct transcripts including mRNA, miRNA, snoRNAs, ncRNAs, and conserved intergenic transcripts of unknown function. The majority of these diverse transcripts share a purine-rich consensus motif corresponding to the canonical SFRS1 binding site. The consensus site was not only enriched in exons cross-linked to SFRS1 in vivo, but was also enriched in close proximity to splice sites. mRNAs encoding RNA processing factors were significantly overrepresented, suggesting that SFRS1 may broadly influence the post-transcriptional control of gene expression in vivo. Finally, a search for the SFRS1 consensus motif within the Human Gene Mutation Database identified 181 mutations in 82 different genes that disrupt predicted SFRS1 binding sites. This comprehensive analysis substantially expands the known roles of human SR proteins in the regulation of a diverse array of RNA transcripts.

  16. Phthalimide neovascular factor 1 (PNF1) modulates MT1-MMP activity in human microvascular endothelial cells

    PubMed Central

    Wieghaus, Kristen A.; Gianchandani, Erwin P.; Neal, Rebekah A.; Paige, Mikell A.; Brown, Milton L.; Papin, Jason A.; Botchwey, Edward A.

    2009-01-01

    We are creating synthetic pharmaceuticals with angiogenic activity and potential to promote vascular invasion. We previously demonstrated that one of these molecules, phthalimide neovascular factor 1 (PNF1), significantly expands microvascular networks in vivo following sustained release from poly(lactic-co-glycolic acid) (PLAGA) films. In addition, to probe PNF1 mode-of-action, we recently applied a novel pathway-based compendium analysis to a multi-timepoint, controlled microarray dataset of PNF1-treated (versus control) human microvascular endothelial cells (HMVECs), and we identified induction of tumor necrosis factor-alpha (TNF-α) and, subsequently, transforming growth factor-beta (TGF-β) signaling networks by PNF1. Here we validate this microarray data-set with quantitative real-time polymerase chain reaction (RT-PCR) analysis. Subsequently, we probe this dataset and identify three specific TGF-β-induced genes with regulation by PNF1 conserved over multiple timepoints—amyloid beta (A4) precursor protein (APP), early growth response 1 (EGR-1), and matrix metalloproteinase 14 (MMP14 or MT1-MMP)—that are also implicated in angiogenesis. We further focus on MMP14 given its unique role in angiogenesis, and we validate MT1-MMP modulation by PNF1 with an in vitro fluorescence assay that demonstrates the direct effects that PNF1 exerts on functional metalloproteinase activity. We also utilize endothelial cord formation in collagen gels to show that PNF1-induced stimulation of endothelial cord network formation in vitro is in some way MT1-MMP-dependent. Ultimately, this new network analysis of our transcriptional footprint characterizing PNF1 activity 1–48 h post-supplementation in HMVECs coupled with corresponding validating experiments suggests a key set of a few specific targets that are involved in PNF1 mode-of-action and important for successful promotion of the neovascularization that we have observed by the drug in vivo. PMID:19326468

  17. Phthalimide neovascular factor 1 (PNF1) modulates MT1-MMP activity in human microvascular endothelial cells.

    PubMed

    Wieghaus, Kristen A; Gianchandani, Erwin P; Neal, Rebekah A; Paige, Mikell A; Brown, Milton L; Papin, Jason A; Botchwey, Edward A

    2009-07-01

    We are creating synthetic pharmaceuticals with angiogenic activity and potential to promote vascular invasion. We previously demonstrated that one of these molecules, phthalimide neovascular factor 1 (PNF1), significantly expands microvascular networks in vivo following sustained release from poly(lactic-co-glycolic acid) (PLAGA) films. In addition, to probe PNF1 mode of action, we recently applied a novel pathway-based compendium analysis to a multi-timepoint, controlled microarray data set of PNF1-treated (vs. control) human microvascular endothelial cells (HMVECs), and we identified induction of tumor necrosis factor-alpha (TNF-alpha) and, subsequently, transforming growth factor-beta (TGF-beta) signaling networks by PNF1. Here we validate this microarray data set with quantitative real-time polymerase chain reaction (RT-PCR) analysis. Subsequently, we probe this data set and identify three specific TGF-beta-induced genes with regulation by PNF1 conserved over multiple timepoints-amyloid beta (A4) precursor protein (APP), early growth response 1 (EGR-1), and matrix metalloproteinase 14 (MMP14 or MT1-MMP)-that are also implicated in angiogenesis. We further focus on MMP14 given its unique role in angiogenesis, and we validate MT1-MMP modulation by PNF1 with an in vitro fluorescence assay that demonstrates the direct effects that PNF1 exerts on functional metalloproteinase activity. We also utilize endothelial cord formation in collagen gels to show that PNF1-induced stimulation of endothelial cord network formation in vitro is in some way MT1-MMP-dependent. Ultimately, this new network analysis of our transcriptional footprint characterizing PNF1 activity 1-48 h post-supplementation in HMVECs coupled with corresponding validating experiments suggests a key set of a few specific targets that are involved in PNF1 mode of action and important for successful promotion of the neovascularization that we have observed by the drug in vivo.

  18. TCL1A, a Novel Transcription Factor and a Coregulator of Nuclear Factor κB p65: Single Nucleotide Polymorphism and Estrogen Dependence.

    PubMed

    Ho, Ming-Fen; Lummertz da Rocha, Edroaldo; Zhang, Cheng; Ingle, James N; Goss, Paul E; Shepherd, Lois E; Kubo, Michiaki; Wang, Liewei; Li, Hu; Weinshilboum, Richard M

    2018-06-01

    T-cell leukemia 1A ( TCL1A ) single-nucleotide polymorphisms (SNPs) have been associated with aromatase inhibitor-induced musculoskeletal adverse events. We previously demonstrated that TCL1A is inducible by estradiol (E 2 ) and plays a critical role in the regulation of cytokines, chemokines, and Toll-like receptors in a TCL1A SNP genotype and estrogen-dependent fashion. Furthermore, TCLIA SNP-dependent expression phenotypes can be "reversed" by exposure to selective estrogen receptor modulators such as 4-hydroxytamoxifen (4OH-TAM). The present study was designed to comprehensively characterize the role of TCL1A in transcriptional regulation across the genome by performing RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) assays with lymphoblastoid cell lines. RNA-seq identified 357 genes that were regulated in a TCL1A SNP- and E 2 -dependent fashion with expression patterns that were 4OH-TAM reversible. ChIP-seq for the same cells identified 57 TCL1A binding sites that could be regulated by E 2 in a SNP-dependent fashion. Even more striking, nuclear factor- κ B (NF- κ B) p65 bound to those same DNA regions. In summary, TCL1A is a novel transcription factor with expression that is regulated in a SNP- and E 2 -dependent fashion-a pattern of expression that can be reversed by 4OH-TAM. Integrated RNA-seq and ChIP-seq results suggest that TCL1A also acts as a transcriptional coregulator with NF- κ B p65, an important immune system transcription factor. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Overexpression of Annexin A1 Suppresses Pro-Inflammatory Factors in PC12 Cells Induced by 1-Methyl-4-Phenylpyridinium

    PubMed Central

    Kiani-Esfahani, Abbas; Kazemi Sheykhshabani, Sedigheh; Peymani, Maryam; Hashemi, Motahare-Sadat; Ghaedi, Kamran; Nasr-Esfahani, Mohammad Hossein

    2016-01-01

    Objective Annexin A1 (ANXA1) is suggested to have anti-inflammatory function. However, the precise function of ANXA1 has remained unclear. In this study, we therefore examined the potency of ANXA1 in regulating reactive oxygen species (ROS) production and suppressing pro-inflammatory responses in PC12 cells induced by 1-methyl-4-phenylpyridinium (MPP+). Materials and Methods In this experimental study, cDNA of ANXA1 was cloned and inserted to the PGL268 pEpi-FGM18F vector to produce a recombinant PGL/ANXA1 vector for transfection into the PC12 cells. ANXA1 transfected cells were then treated with MPP+. Apoptosis and the content of pro-inflammatory factors including ROS, Interlukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were assessed by flow-cytometry, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot in ANXA1-transfected cells and the data were compared with those obtained from mock and control cells. Results Data revealed that overexpression of ANXA1 is associated with decreased levels of ROS and expression level of IL-6 and iNOS transcripts, and NF-κB protein in MPP+ treated PC12 cells. Conclusion ANXA1 may be considered as an agent for prevention of neurodegenerative or inflammatory conditions. PMID:27540524

  20. Overexpression of Annexin A1 Suppresses Pro-Inflammatory Factors in PC12 Cells Induced by 1-Methyl-4-Phenylpyridinium.

    PubMed

    Kiani-Esfahani, Abbas; Kazemi Sheykhshabani, Sedigheh; Peymani, Maryam; Hashemi, Motahare-Sadat; Ghaedi, Kamran; Nasr-Esfahani, Mohammad Hossein

    2016-01-01

    Annexin A1 (ANXA1) is suggested to have anti-inflammatory function. However, the precise function of ANXA1 has remained unclear. In this study, we therefore examined the potency of ANXA1 in regulating reactive oxygen species (ROS) production and suppressing pro-inflammatory responses in PC12 cells induced by 1-methyl-4-phenylpyridinium (MPP+). In this experimental study, cDNA of ANXA1 was cloned and inserted to the PGL268 pEpi-FGM18F vector to produce a recombinant PGL/ANXA1 vector for transfection into the PC12 cells. ANXA1 transfected cells were then treated with MPP+. Apoptosis and the content of pro-inflammatory factors including ROS, Interlukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were assessed by flow-cytometry, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot in ANXA1-transfected cells and the data were compared with those obtained from mock and control cells. Data revealed that overexpression of ANXA1 is associated with decreased levels of ROS and expression level of IL-6 and iNOS transcripts, and NF-κB protein in MPP+ treated PC12 cells. ANXA1 may be considered as an agent for prevention of neurodegenerative or inflammatory conditions.

  1. Interferon regulatory factor 1 and a variant of heterogeneous nuclear ribonucleoprotein L coordinately silence the gene for adhesion protein CEACAM1.

    PubMed

    Dery, Kenneth J; Silver, Craig; Yang, Lu; Shively, John E

    2018-06-15

    The adhesion protein carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is widely expressed in epithelial cells as a short cytoplasmic isoform (S-iso) and in leukocytes as a long cytoplasmic isoform (L-iso) and is frequently silenced in cancer by unknown mechanisms. Previously, we reported that interferon response factor 1 (IRF1) biases alternative splicing (AS) to include the variable exon 7 (E7) in CEACAM1, generating long cytoplasmic isoforms. We now show that IRF1 and a variant of heterogeneous nuclear ribonucleoprotein L (Lv1) coordinately silence the CEACAM1 gene. RNAi-mediated Lv1 depletion in IRF1-treated HeLa and melanoma cells induced significant CEACAM1 protein expression, reversed by ectopic Lv1 expression. The Lv1-mediated CEACAM1 repression resided in residues Gly 71 -Gly 89 and Ala 38 -Gly 89 in Lv1's N-terminal extension. ChIP analysis of IRF1- and FLAG-tagged Lv1-treated HeLa cells and global treatment with the global epigenetic modifiers 5-aza-2'-deoxycytidine and trichostatin A indicated that IRF1 and Lv1 together induce chromatin remodeling, restricting IRF1 access to the CEACAM1 promoter. In interferon γ-treated HeLa cells, the transcription factor SP1 did not associate with the CEACAM1 promoter, but binding by upstream transcription factor 1 (USF1), a known CEACAM1 regulator, was greatly enhanced. ChIP-sequencing revealed that Lv1 overexpression in IRF1-treated cells induces transcriptional silencing across many genes, including DCC ( d eleted in c olorectal c arcinoma), associated with CEACAM5 in colon cancer. Notably, IRF1, but not IRF3 and IRF7, affected CEACAM1 expression via translational repression. We conclude that IRF1 and Lv1 coordinately regulate CEACAM1 transcription, alternative splicing, and translation and may significantly contribute to CEACAM1 silencing in cancer. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Identification of the collagen type 1 alpha 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma

    PubMed Central

    2014-01-01

    Background Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death especially among Asian and African populations. It is urgent that we identify carcinogenesis-related genes to establish an innovative treatment strategy for this disease. Methods Triple-combination array analysis was performed using one pair each of HCC and noncancerous liver samples from a 68-year-old woman. This analysis consists of expression array, single nucleotide polymorphism array and methylation array. The gene encoding collagen type 1 alpha 1 (COL1A1) was identified and verified using HCC cell lines and 48 tissues from patients with primary HCC. Results Expression array revealed that COL1A1 gene expression was markedly decreased in tumor tissues (log2 ratio –1.1). The single nucleotide polymorphism array showed no chromosomal deletion in the locus of COL1A1. Importantly, the methylation value in the tumor tissue was higher (0.557) than that of the adjacent liver tissue (0.008). We verified that expression of this gene was suppressed by promoter methylation. Reactivation of COL1A1 expression by 5-aza-2′-deoxycytidine treatment was seen in HCC cell lines, and sequence analysis identified methylated CpG sites in the COL1A1 promoter region. Among 48 pairs of surgical specimens, 13 (27.1%) showed decreased COL1A1 mRNA expression in tumor sites. Among these 13 cases, 10 had promoter methylation at the tumor site. The log-rank test indicated that mRNA down-regulated tumors were significantly correlated with a poor overall survival rate (P = 0.013). Conclusions Triple-combination array analysis successfully identified COL1A1 as a candidate survival-related gene in HCCs. Epigenetic down-regulation of COL1A1 mRNA expression might have a role as a prognostic biomarker of HCC. PMID:24552139

  3. Histone H1 functions as a stimulatory factor in backup pathways of NHEJ

    PubMed Central

    Rosidi, Bustanur; Wang, Minli; Wu, Wenqi; Sharma, Aparna; Wang, Huichen; Iliakis, George

    2008-01-01

    DNA double-strand breaks (DSBs) induced in the genome of higher eukaryotes by ionizing radiation (IR) are predominantly removed by two pathways of non-homologous end-joining (NHEJ) termed D-NHEJ and B-NHEJ. While D-NHEJ depends on the activities of the DNA-dependent protein kinase (DNA-PK) and DNA ligase IV/XRCC4/XLF, B-NHEJ utilizes, at least partly, DNA ligase III/XRCC1 and PARP-1. Using in vitro end-joining assays and protein fractionation protocols similar to those previously applied for the characterization of DNA ligase III as an end-joining factor, we identify here histone H1 as an additional putative NHEJ factor. H1 strongly enhances DNA-end joining and shifts the product spectrum from circles to multimers. While H1 enhances the DNA-end-joining activities of both DNA Ligase IV and DNA Ligase III, the effect on ligase III is significantly stronger. Histone H1 also enhances the activity of PARP-1. Since histone H1 has been shown to counteract D-NHEJ, these observations and the known functions of the protein identify it as a putative alignment factor operating preferentially within B-NHEJ. PMID:18250087

  4. Structural and calorimetric studies demonstrate that the hepatocyte nuclear factor 1β (HNF1β) transcription factor is imported into the nucleus via a monopartite NLS sequence.

    PubMed

    Wiedmann, Mareike M; Aibara, Shintaro; Spring, David R; Stewart, Murray; Brenton, James D

    2016-09-01

    The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in ovarian clear cell carcinoma (CCC) and is a potential therapeutic target. To explore potential approaches that block HNF1β transcription we have identified and characterised extensively the nuclear localisation signal (NLS) for HNF1β and its interactions with the nuclear protein import receptor, Importin-α. Pull-down assays demonstrated that the DNA binding domain of HNF1β interacted with a spectrum of Importin-α isoforms and deletion constructs tagged with eGFP confirmed that the HNF1β (229)KKMRRNR(235) sequence was essential for nuclear localisation. We further characterised the interaction between the NLS and Importin-α using complementary biophysical techniques and have determined the 2.4Å resolution crystal structure of the HNF1β NLS peptide bound to Importin-α. The functional, biochemical, and structural characterisation of the nuclear localisation signal present on HNF1β and its interaction with the nuclear import protein Importin-α provide the basis for the development of compounds targeting transcription factor HNF1β via its nuclear import pathway. Copyright © 2016. Published by Elsevier Inc.

  5. Risk Factors for premature birth in a hospital 1

    PubMed Central

    Ahumada-Barrios, Margarita E.; Alvarado, German F.

    2016-01-01

    Abstract Objective: to determine the risk factors for premature birth. Methods: retrospective case-control study of 600 pregnant women assisted in a hospital, with 298 pregnant women in the case group (who gave birth prematurely <37 weeks) and 302 pregnant women who gave birth to a full-term newborn in the control group. Stata software version 12.2 was used. The Chi-square test was used in bivariate analysis and logistic regression was used in multivariate analysis, from which Odds Ratios (OR) and Confidence Intervals (CI) of 95% were derived. Results: risk factors associated with premature birth were current twin pregnancy (adjusted OR= 2.4; p= 0.02), inadequate prenatal care (< 6 controls) (adjusted OR= 3.2; p <0.001), absent prenatal care (adjusted OR= 3.0; p <0.001), history of premature birth (adjusted OR= 3.7; p <0.001) and preeclampsia (adjusted OR= 1.9; p= 0.005). Conclusion: history of premature birth, preeclampsia, not receiving prenatal care and receiving inadequate prenatal care were risk factors for premature birth. PMID:27463110

  6. A stable transcription factor complex nucleated by oligomeric AML1–ETO controls leukaemogenesis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sun, Xiao-Jian; Wang, Zhanxin; Wang, Lan

    2013-06-30

    Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression. AML1–ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia, is a transcription factor implicated in both gene repression and activation. AML1–ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis, making it important to identify co-regulatory factors that ‘read’ the NHR2 oligomerization and contribute to leukaemogenesis. Here we show that, in human leukaemic cells, AML1–ETO resides in and functions through a stable AML1–ETO-containing transcription factor complex (AETFC) that contains several haematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalentmore » interactions, provide multiple DNA-binding domains for diverse target genes, co-localize genome wide, cooperatively regulate gene expression, and contribute to leukaemogenesis. Within the AETFC complex, AML1–ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis of the NHR2–N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1–ETO-induced haematopoietic stem/progenitor cell self-renewal and leukaemogenesis. These results reveal new mechanisms of action of AML1–ETO, and provide a potential therapeutic target in t(8;21)-positive acute myeloid leukaemia.« less

  7. [Detection of factor VIII intron 1 inversion in severe haemophilia A].

    PubMed

    Liang, Yan; Yan, Zhen-yu; Yan, Mei; Hua, Bao-lai; Xiao, Bai; Zhao, Yong-qiang; Liu, Jing-zhong

    2009-06-01

    Screening the intron 1 inversion of factor VIII (FVIII) in the population of severe haemophilia A(HA) in China and performing carrier detection and prenatal diagnosis. Using LD-PCR to detect intron 22 inversions and multiple-PCR within two tubes to intron 1 inversions in severe HA patients. Carrier detection and prenatal diagnosis were performed in affected families. Linkage analysis and DNA sequencing were used to verify these tests. One hundred and eighteen patients were seven diagnosed as intron 22 inversions and 7 were intron 1 inversions out of 247 severe HA patients. The prevalence of the intron 1 inversion in Chinese severe haemophilia A patients was 2.8% (7/247). Six women from family A and 2 from family B were diagnosed as carriers. One fetus from family A was affected fetus. Intron 1 inversion could be detected directly by multiple-PCR within two tubes. This method made the strategy more perfective in carrier and prenatal diagnosis of haemophilia A.

  8. Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor

    PubMed Central

    Sainz, Bruno; Barretto, Naina; Martin, Danyelle N.; Hiraga, Nobuhiko; Imamura, Michio; Hussain, Snawar; Marsh, Katherine A.; Yu, Xuemei; Chayama, Kazuaki; Alrefai, Waddah A.; Uprichard, Susan L.

    2011-01-01

    Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ~170 million individuals infected and current interferon-based treatment having toxic side-effects and marginal efficacy, more effective antivirals are critically needed1. Although HCV protease inhibitors were just FDA approved, analogous to HIV therapy, optimal HCV therapy likely will require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a promising multi-faceted target for antiviral intervention; however, to date FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-Like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection as silencing or antibody-mediated blocking of NPC1L1 impairs cell-cultured-derived HCV (HCVcc) infection initiation. In addition, the clinically-available FDA-approved NPC1L1 antagonist ezetimibe2,3 potently blocks HCV uptake in vitro via a virion cholesterol-dependent step prior to virion-cell membrane fusion. Importantly, ezetimibe inhibits infection of all major HCV genotypes in vitro, and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor, but also discovered a new antiviral target and potential therapeutic agent. PMID:22231557

  9. Tumor necrosis factor receptor-1 can function through a G alpha q/11-beta-arrestin-1 signaling complex.

    PubMed

    Kawamata, Yuji; Imamura, Takeshi; Babendure, Jennie L; Lu, Juu-Chin; Yoshizaki, Takeshi; Olefsky, Jerrold M

    2007-09-28

    Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine secreted from macrophages and adipocytes. It is well known that chronic TNFalpha exposure can lead to insulin resistance both in vitro and in vivo and that elevated blood levels of TNFalpha are observed in obese and/or diabetic individuals. TNFalpha has many acute biologic effects, mediated by a complex intracellular signaling pathway. In these studies we have identified new G-protein signaling components to this pathway in 3T3-L1 adipocytes. We found that beta-arrestin-1 is associated with TRAF2 (TNF receptor-associated factor 2), an adaptor protein of TNF receptors, and that TNFalpha acutely stimulates tyrosine phosphorylation of G alpha(q/11) with an increase in G alpha(q/11) activity. Small interfering RNA-mediated knockdown of beta-arrestin-1 inhibits TNFalpha-induced tyrosine phosphorylation of G alpha(q/11) by interruption of Src kinase activation. TNFalpha stimulates lipolysis in 3T3-L1 adipocytes, and beta-arrestin-1 knockdown blocks the effects of TNFalpha to stimulate ERK activation and glycerol release. TNFalpha also led to activation of JNK with increased expression of the proinflammatory gene, monocyte chemoattractant protein-1 and matrix metalloproteinase 3, and beta-arrestin-1 knockdown inhibited both of these effects. Taken together these results reveal novel elements of TNFalpha action; 1) the trimeric G-protein component G alpha(q/11) and the adapter protein beta-arrestin-1 can function as signaling molecules in the TNFalpha action cascade; 2) beta-arrestin-1 can couple TNFalpha stimulation to ERK activation and lipolysis; 3) beta-arrestin-1 and G alpha(q/11) can mediate TNFalpha-induced phosphatidylinositol 3-kinase activation and inflammatory gene expression.

  10. Improvement of enzymatic saccharification yield in Arabidopsis thaliana by ectopic expression of the rice SUB1A-1 transcription factor

    PubMed Central

    Núñez-López, Lizeth; Aguirre-Cruz, Andrés

    2015-01-01

    Saccharification of polysaccharides releases monosaccharides that can be used by ethanol-producing microorganisms in biofuel production. To improve plant biomass as a raw material for saccharification, factors controlling the accumulation and structure of carbohydrates must be identified. Rice SUB1A-1 is a transcription factor that represses the turnover of starch and postpones energy-consuming growth processes under submergence stress. Arabidopsis was employed to test if heterologous expression of SUB1A-1 or SUB1C-1 (a related gene) can be used to improve saccharification. Cellulolytic and amylolytic enzymatic treatments confirmed that SUB1A-1 transgenics had better saccharification yield than wild-type (Col-0), mainly from accumulated starch. This improved saccharification yield was developmentally controlled; when compared to Col-0, young transgenic vegetative plants yielded 200–300% more glucose, adult vegetative plants yielded 40–90% more glucose and plants in reproductive stage had no difference in yield. We measured photosynthetic parameters, starch granule microstructure, and transcript abundance of genes involved in starch degradation (SEX4, GWD1), juvenile transition (SPL3-5) and meristematic identity (FUL, SOC1) but found no differences to Col-0, indicating that starch accumulation may be controlled by down-regulation of CONSTANS and FLOWERING LOCUS T by SUB1A-1 as previously reported. SUB1A-1 transgenics also offered less resistance to deformation than wild-type concomitant to up-regulation of AtEXP2 expansin and BGL2 glucan-1,3,-beta-glucosidase. We conclude that heterologous SUB1A-1 expression can improve saccharification yield and softness, two traits needed in bioethanol production. PMID:25780769

  11. Polymorphism of Cyp1a1 (T6235C) is not a significant risk factor of osteoporosis in postmenopausal Indonesian woman

    NASA Astrophysics Data System (ADS)

    Auerkari, EI; Budhy, LW; Kiranahayu, R.; Djamal, NZ; Kusdhany, LS; Rahardjo, TBW; Talbot, Christopher

    2018-05-01

    Osteoporosis is an increasingly common disease resulting in reduced bone mineral density (BMD) and elevated likelihood of bone fracture, and particularly affected are postmenopausal women with additional risk factors including genetic predisposition. The CYP1A1, is one of the candidate genes that have been suggested to be associated with the pathogenesis of osteoporosis. This work aimed to evaluate the distribution of a selected polymorphism of this gene (T6235C) with respect to the BMD status in postmenopausal Indonesian women. The results show that osteoporosis is associated with age and menopause, as expected, but not with the tested polymorphism of CYP1A1 in the Indonesian sample population. It is suggested that other P450 cytochrome enzymes and their polymorphisms could provide more significant indicators of the future health of postmenopausal women.

  12. Isolation and molecular characterization of a novel WIN1/SHN1 ethylene-responsive transcription factor TdSHN1 from durum wheat (Triticum turgidum. L. subsp. durum).

    PubMed

    Djemal, Rania; Khoudi, Habib

    2015-11-01

    Over the last decade, APETALA2/Ethylene Responsive Factor (AP2/ERF) proteins have become the subject of intensive research activity due to their involvement in a variety of biological processes. This research led to the identification of AP2/ERF genes in many species; however, little is known about these genes in durum wheat, one of the most important cereal crops in the world. In this study, a new member of the AP2/ERF transcription factor family, designated TdSHN1, was isolated from durum wheat using thermal asymetric interlaced PCR (TAIL-PCR) method. Protein sequence analysis showed that TdSHN1 contained an AP2/ERF domain of 63 amino acids and a putative nuclear localization signal (NLS). Phylogenetic analysis showed that TdSHN1 belongs to a group Va protein in the ERF subfamily which contains the Arabidopsis ERF proteins (SHN1, SHN2, and SHN3). Expression of TdSHN1 was strongly induced by salt, drought, abscisic acid (ABA), and cold. In planta, TdSHN1 protein was able to activate the transcription of GUS reporter gene driven by the GCC box and DRE element sequences. In addition, TdSHN1 was targeted to the nucleus when transiently expressed in tobacco epidermal cells. In transgenic yeast, overexpression of TdSHN1 increased tolerance to multiple abiotic stresses. Taken together, the results showed that TdSHN1 encodes an abiotic stress-inducible, transcription factor which confers abiotic stress tolerance in yeast. TdSHN1 is therefore a promising candidate for improvement of biotic and abiotic stress tolerance in wheat as well as other crops.

  13. Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) and inhibits pro-survival function of Nrf1

    PubMed Central

    Biswas, Madhurima; Kwong, Erick K.; Park, Eujean; Nagra, Parminder; Chan, Jefferson Y.

    2013-01-01

    Nuclear factor E2-related factor-1 (Nrf1) is a basic leucine zipper transcription factor that is known to regulate antioxidant and cytoprotective gene expression. It was recently shown that Nrf1 is regulated by SCF-Fbw7 ubiquitin ligase. However our knowledge of upstream signals that targets Nrf1 for degradation by the UPS is not known. We report here that Nrf1 expression is negatively regulated by glycogen synthase kinase 3 (GSK3) in Fbw7-dependent manner. We show that GSK3 interacts with Nrf1 and phosphorylates the Cdc4 phosphodegron domain (CPD) in Nrf1. Mutation of serine residue in the CPD of Nrf1 to alanine (S350A), blocks Nrf1 from phosphorylation by GSK3, and stabilizes Nrf1. Knockdown of Nrf1 and expression of a constitutively active form of GSK3 results in increased apoptosis in neuronal cells in response to ER stress, while expression of the GSK3 phosphorylation resistant S350A–Nrfl attenuates apoptotic cell death. Together these data suggest that GSK3 regulates Nrf1 expression and cell survival function in response to stress activation. PMID:23623971

  14. Rescue of the colony-stimulating factor 1 (CSF-1)-nullizygous mouse (Csf1(op)/Csf1(op)) phenotype with a CSF-1 transgene and identification of sites of local CSF-1 synthesis.

    PubMed

    Ryan, G R; Dai, X M; Dominguez, M G; Tong, W; Chuan, F; Chisholm, O; Russell, R G; Pollard, J W; Stanley, E R

    2001-07-01

    Colony-stimulating factor 1 (CSF-1) regulates the survival, proliferation, and differentiation of mononuclear phagocytes. It is expressed as a secreted glycoprotein or proteoglycan found in the circulation or as a biologically active cell-surface glycoprotein. To investigate tissue CSF-1 regulation, CSF-1-null Csf1(op)/Csf1(op) mice expressing transgenes encoding the full-length membrane-spanning CSF-1 precursor driven by 3.13 kilobases of the mouse CSF-1 promoter and first intron were characterized. Transgene expression corrected the gross osteopetrotic, neurologic, weight, tooth, and reproductive defects of Csf1(op)/Csf1(op) mice. Detailed analysis of one transgenic line revealed that circulating CSF-1, tissue macrophage numbers, hematopoietic tissue cellularity, and hematopoietic parameters were normalized. Tissue CSF-1 levels were normal except for elevations in 4 secretory tissues. Skin fibroblasts from the transgenic mice secreted normal amounts of CSF-1 but also expressed some cell-surface CSF-1. Also, lacZ driven by the same promoter/first intron revealed beta-galactosidase expression in hematopoietic, reproductive, and other tissue locations proximal to CSF-1 cellular targets, consistent with local regulation by CSF-1 at these sites. These studies indicate that the 3.13-kilobase promoter/first intron confers essentially normal CSF-1 expression. They also pinpoint new cellular sites of CSF-1 expression, including ovarian granulosa cells, mammary ductal epithelium, testicular Leydig cells, serous acinar cells of salivary gland, Paneth cells of the small intestine, as well as local sites in several other tissues.

  15. Myeloid leukemia factor 1 associates with a novel heterogeneous nuclear ribonucleoprotein U-like molecule.

    PubMed

    Winteringham, Louise N; Endersby, Raelene; Kobelke, Simon; McCulloch, Ross K; Williams, James H; Stillitano, Justin; Cornwall, Scott M; Ingley, Evan; Klinken, S Peter

    2006-12-15

    Myeloid leukemia factor 1 (MLF1) is an oncoprotein associated with hemopoietic lineage commitment and acute myeloid leukemia. Here we show that Mlf1 associated with a novel binding partner, Mlf1-associated nuclear protein (Manp), a new heterogeneous nuclear ribonucleoprotein (hnRNP) family member, related to hnRNP-U. Manp localized exclusively in the nucleus and could redirect Mlf1 from the cytoplasm into the nucleus. The nuclear content of Mlf1 was also regulated by 14-3-3 binding to a canonical 14-3-3 binding motif within the N terminus of Mlf1. Significantly Mlf1 contains a functional nuclear export signal and localized primarily to the nuclei of hemopoietic cells. Mlf1 was capable of binding DNA, and microarray analysis revealed that it affected the expression of several genes, including transcription factors. In summary, this study reveals that Mlf1 translocates between nucleus and cytoplasm, associates with a novel hnRNP, and influences gene expression.

  16. The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation.

    PubMed

    Maurus, K; Hufnagel, A; Geiger, F; Graf, S; Berking, C; Heinemann, A; Paschen, A; Kneitz, S; Stigloher, C; Geissinger, E; Otto, C; Bosserhoff, A; Schartl, M; Meierjohann, S

    2017-09-07

    The MAPK pathway is activated in the majority of melanomas and is the target of therapeutic approaches. Under normal conditions, it initiates the so-called immediate early response, which encompasses the transient transcription of several genes belonging to the AP-1 transcription factor family. Under pathological conditions, such as continuous MAPK pathway overactivation due to oncogenic alterations occurring in melanoma, these genes are constitutively expressed. The consequences of a permanent expression of these genes are largely unknown. Here, we show that FOSL1 is the main immediate early AP-1 member induced by melanoma oncogenes. We first examined its role in established melanoma cells. We found that FOSL1 is involved in melanoma cell migration as well as cell proliferation and anoikis-independent growth, which is mediated by the gene product of its target gene HMGA1, encoding a multipotent chromatin modifier. As FOSL1 expression is increased in patient melanoma samples compared to nevi, we investigated the effect of enhanced FOSL1 expression on melanocytes. Intriguingly, we found that FOSL1 acts oncogenic and transforms melanocytes, enabling subcutaneous tumor growth in vivo. During the process of transformation, FOSL1 reprogrammed the melanocytes and downregulated MITF in a HMGA1-dependent manner. At the same time, AXL was upregulated, leading to a shift in the MITF/AXL balance. Furthermore, FOSL1 re-enforced pro-tumorigenic transcription factors MYC, E2F3 and AP-1. Together, this led to the enhancement of several growth-promoting processes, such as ribosome biogenesis, cellular detachment and pyrimidine metabolism. Overall, we demonstrate that FOSL1 is a novel reprogramming factor for melanocytes with potent tumor transformation potential.

  17. The Potyviral P3 Protein Targets Eukaryotic Elongation Factor 1A to Promote the Unfolded Protein Response and Viral Pathogenesis1[OPEN

    PubMed Central

    Shine, M.B.; Cui, Xiaoyan; Chen, Xin; Ma, Na; Kachroo, Pradeep; Zhi, Haijan; Kachroo, Aardra

    2016-01-01

    The biochemical function of the potyviral P3 protein is not known, although it is known to regulate virus replication, movement, and pathogenesis. We show that P3, the putative virulence determinant of soybean mosaic virus (SMV), targets a component of the translation elongation complex in soybean. Eukaryotic elongation factor 1A (eEF1A), a well-known host factor in viral pathogenesis, is essential for SMV virulence and the associated unfolded protein response (UPR). Silencing GmEF1A inhibits accumulation of SMV and another ER-associated virus in soybean. Conversely, endoplasmic reticulum (ER) stress-inducing chemicals promote SMV accumulation in wild-type, but not GmEF1A-knockdown, plants. Knockdown of genes encoding the eEF1B isoform, which is important for eEF1A function in translation elongation, has similar effects on UPR and SMV resistance, suggesting a link to translation elongation. P3 and GmEF1A promote each other’s nuclear localization, similar to the nuclear-cytoplasmic transport of eEF1A by the Human immunodeficiency virus 1 Nef protein. Our results suggest that P3 targets host elongation factors resulting in UPR, which in turn facilitates SMV replication and place eEF1A upstream of BiP in the ER stress response during pathogen infection. PMID:27356973

  18. A pentapeptide monocyte locomotion inhibitory factor protects brain ischemia injury by targeting the eEF1A1/endothelial nitric oxide synthase pathway.

    PubMed

    Zhang, Yuefan; Chen, Jun; Li, Fan; Li, Dong; Xiong, Qinhui; Lin, Yang; Zhang, Dazhi; Wang, Xiao-Fan; Yang, Pengyuan; Rui, Yao-Cheng

    2012-10-01

    Ischemic stroke is a major cause of death worldwide but lacks viable treatment or treatment targets. Monocyte locomotion inhibitory factor (MLIF) is a small heat-stable pentapeptide produced by Entamoeba histolytica in axenic culture, which is supposed to protect the brain from ischemic injury; the mechanism, however, remains unknown. In this study, we further investigated the mechanism underlying the protective role of MLIF in brain ischemia. A middle cerebral artery occlusion model in rats was used for detecting the effect of MLIF in the brain ischemia in vivo. To identify targets of MLIF in brain endothelial cells, we performed immunoprecipitation of biotin-conjugated MLIF and mass spectrometry. MLIF can protect the brain from ischemic injury in vivo, yielding decreased ischemic volume, prolonged survival, and improved neurological outcome. In vitro studies showed that MLIF displayed protective effects through inhibition of expression of pathological inflammatory adhesion molecules and enhancing endothelial nitric oxide synthase expression and nitric oxide release in the cerebrovascular endothelium. The target screening experiments demonstrated binding of MLIF to the ribosomal protein translation elongation factor eEF1A1. MLIF enhanced endothelial nitric oxide synthase expression through stabilization of endothelial nitric oxide synthase mRNA, and eEF1A1 was shown to be necessary for this enhanced expression. Knockdown of eEF1A1 or inhibition of endothelial nitric oxide synthase attenuated MLIF-mediated inhibition of adhesion molecule expression. In this study, we identified a new potential pharmacologically targetable mechanism underlying MLIF's protective effects in brain ischemia through the eEF1A1/endothelial nitric oxide synthase pathway.

  19. Environmental Factors Associated with Type 1 Diabetes Development: A Case Control Study in Egypt.

    PubMed

    Awadalla, Nabil J; Hegazy, Amal A; Abd El-Salam, Manal; Elhady, Marwa

    2017-06-07

    Uncertainty still exists regarding the role of some environmental risk in the development of type 1 diabetes mellitus (T1DM) both globally and in Egypt. The objective here was to explore the potential environmental risk factors associated with the development of T1DM among children in Egypt. A case-controlled study of 204 T1DM children and an equal number of age and sex-matched controls was conducted in Assiut, Egypt. Data regarding the parental, gestational, neonatal, and childhood possible risk factors for T1DM were evaluated. The final sex adjusted multivariable logistic regression model revealed that the risk for T1DM was significantly higher among rural residents (aOR = 2.03, 95% CI: 1.30-4.25), those with parental history of T1DM (aOR = 9.03, 95% CI: 1.02-83.32), birth through cesarean section (aOR = 2.13, 95% CI: 1.09-5.03), and having history of early introduction of cow milk in the first year of life (aOR = 19.49, 95% CI: 8.73-45.53). On the other hand, a protective effect was observed between at least six months' breastfeeding, vitamin D supplementation in the first year of life, high physical activity, and the development of T1DM. Educational programs should be adopted to improve awareness and knowledge of the parents to avoid the increased risk factors and encourage protective practices.

  20. A specific colorimetric assay for measuring transglutaminase 1 and factor XIII activities.

    PubMed

    Hitomi, Kiyotaka; Kitamura, Miyako; Alea, Mileidys Perez; Ceylan, Ismail; Thomas, Vincent; El Alaoui, Saïd

    2009-11-15

    Transglutaminase (TGase) is an enzyme that catalyzes both isopeptide cross-linking and incorporation of primary amines into proteins. Eight TGases have been identified in humans, and each of these TGases has a unique tissue distribution and physiological significance. Although several assays for TGase enzymatic activity have been reported, it has been difficult to establish an assay for discriminating each of these different TGase activities. Using a random peptide library, we recently identified the preferred substrate sequences for three major TGases: TGase 1, TGase 2, and factor XIII. In this study, we use these substrates in specific tests for measuring the activities of TGase 1 and factor XIII.

  1. TGF-β1 (Transforming Growth Factor1) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity.

    PubMed

    Salvarani, Nicolò; Maguy, Ange; De Simone, Stefano A; Miragoli, Michele; Jousset, Florian; Rohr, Stephan

    2017-05-01

    TGF-β 1 (transforming growth factor1 ) importantly contributes to cardiac fibrosis by controlling differentiation, migration, and collagen secretion of cardiac myofibroblasts. It is still elusive, however, to which extent TGF-β 1 alters the electrophysiological phenotype of myofibroblasts and cardiomyocytes and whether it affects proarrhythmic myofibroblast-cardiomyocyte crosstalk observed in vitro. Patch-clamp recordings of cultured neonatal rat ventricular myofibroblasts revealed that TGF-β 1 , applied for 24 to 48 hours at clinically relevant concentrations (≤2.5 ng/mL), causes substantial membrane depolarization concomitant with a several-fold increase of transmembrane currents. Transcriptome analysis revealed TGF-β 1 -dependent changes in 29 of 63 ion channel/pump/connexin transcripts, indicating a pleiotropic effect on the electrical phenotype of myofibroblasts. Whereas not affecting cardiomyocyte membrane potentials and cardiomyocyte-cardiomyocyte gap junctional coupling, TGF-β 1 depolarized cardiomyocytes coupled to myofibroblasts by ≈20 mV and increased gap junctional coupling between myofibroblasts and cardiomyocytes >5-fold as reflected by elevated connexin 43 and consortin transcripts. TGF-β 1 -dependent cardiomyocyte depolarization resulted from electrotonic crosstalk with myofibroblasts as demonstrated by immediate normalization of cardiomyocyte electrophysiology after targeted disruption of coupled myofibroblasts and by cessation of ectopic activity of cardiomyocytes coupled to myofibroblasts during pharmacological gap junctional uncoupling. In cardiac fibrosis models exhibiting slow conduction and ectopic activity, block of TGF-β 1 signaling completely abolished both arrhythmogenic conditions. TGF-β 1 profoundly alters the electrophysiological phenotype of cardiac myofibroblasts. Apart from possibly contributing to the control of cell function in general, the changes proved to be pivotal for proarrhythmic myofibroblast

  2. The nuclear matrix protein NMP-1 is the transcription factor YY1.

    PubMed Central

    Guo, B; Odgren, P R; van Wijnen, A J; Last, T J; Nickerson, J; Penman, S; Lian, J B; Stein, J L; Stein, G S

    1995-01-01

    NMP-1 was initially identified as a nuclear matrix-associated DNA-binding factor that exhibits sequence-specific recognition for the site IV regulatory element of a histone H4 gene. This distal promoter domain is a nuclear matrix interaction site. In the present study, we show that NMP-1 is the multifunctional transcription factor YY1. Gel-shift and Western blot analyses demonstrate that NMP-1 is immunoreactive with YY1 antibody. Furthermore, purified YY1 protein specifically recognizes site IV and reconstitutes the NMP-1 complex. Western blot and gel-shift analyses indicate that YY1 is present within the nuclear matrix. In situ immunofluorescence studies show that a significant fraction of YY1 is localized in the nuclear matrix, principally but not exclusively associated with residual nucleoli. Our results confirm that NMP-1/YY1 is a ubiquitous protein that is present in both human cells and in rat osteosarcoma ROS 17/2.8 cells. The finding that NMP-1 is identical to YY1 suggests that this transcriptional regulator may mediate gene-matrix interactions. Our results are consistent with the concept that the nuclear matrix may functionally compartmentalize the eukaryotic nucleus to support regulation of gene expression. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:7479833

  3. Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties.

    PubMed

    Krastel, Philipp; Roggo, Silvio; Schirle, Markus; Ross, Nathan T; Perruccio, Francesca; Aspesi, Peter; Aust, Thomas; Buntin, Kathrin; Estoppey, David; Liechty, Brigitta; Mapa, Felipa; Memmert, Klaus; Miller, Howard; Pan, Xuewen; Riedl, Ralph; Thibaut, Christian; Thomas, Jason; Wagner, Trixie; Weber, Eric; Xie, Xiaobing; Schmitt, Esther K; Hoepfner, Dominic

    2015-08-24

    Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF-1α) as the primary target for this compound class. Nannocystin A (1) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti-cancer compound didemnin B on EF-1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Stimulation of Transforming Growth Factor1-Induced Endothelial-To-Mesenchymal Transition and Tissue Fibrosis by Endothelin-1 (ET-1): A Novel Profibrotic Effect of ET-1.

    PubMed

    Wermuth, Peter J; Li, Zhaodong; Mendoza, Fabian A; Jimenez, Sergio A

    2016-01-01

    TGF-β-induced endothelial-to-mesenchymal transition (EndoMT) is a newly recognized source of profibrotic activated myofibroblasts and has been suggested to play a role in the pathogenesis of various fibrotic processes. Endothelin-1 (ET-1) has been implicated in the development of tissue fibrosis but its participation in TGF-β-induced EndoMT has not been studied. Here we evaluated the role of ET-1 on TGF-β1-induced EndoMT in immunopurified CD31+/CD102+ murine lung microvascular endothelial cells. The expression levels of α-smooth muscle actin (α-SMA), of relevant profibrotic genes, and of various transcription factors involved in the EndoMT process were assessed employing quantitative RT-PCR, immunofluorescence histology and Western blot analysis. TGF-β1 caused potent induction of EndoMT whereas ET-1 alone had a minimal effect. However, ET-1 potentiated TGF-β1-induced EndoMT and TGF-β1-stimulated expression of mesenchymal cell specific and profibrotic genes and proteins. ET-1 also induced expression of the TGF-β receptor 1 and 2 genes, suggesting a plausible autocrine mechanism to potentiate TGF-β-mediated EndoMT and fibrosis. Stimulation of TGF-β1-induced skin and lung fibrosis by ET-1 was confirmed in vivo in an animal model of TGF-β1-induced tissue fibrosis. These results suggest a novel role for ET-1 in the establishment and progression of tissue fibrosis.

  5. Socioeconomic Factors Influencing Hospitalized Patients with Pneumonia Due to Influenza A(H1N1)pdm09 in Mexico

    PubMed Central

    Manabe, Toshie; Higuera Iglesias, Anjarath Lorena; Vazquez Manriquez, Maria Eugenia; Martinez Valadez, Eduarda Leticia; Ramos, Leticia Alfaro; Izumi, Shinyu; Takasaki, Jin; Kudo, Koichiro

    2012-01-01

    Background In addition to clinical aspects and pathogen characteristics, people's health-related behavior and socioeconomic conditions can affect the occurrence and severity of diseases including influenza A(H1N1)pdm09. Methodology and Principal Findings A face-to-face interview survey was conducted in a hospital in Mexico City at the time of follow-up consultation for hospitalized patients with pneumonia due to influenza virus infection. In all, 302 subjects were enrolled and divided into two groups based on the period of hospitalization. Among them, 211 tested positive for influenza A(H1N1)pdm09 virus by real-time reverse-transcriptase-polymerase-chain-reaction during the pandemic period (Group-pdm) and 91 tested positive for influenza A virus in the post-pandemic period (Group-post). All subjects were treated with oseltamivir. Data on the demographic characteristics, socioeconomic status, living environment, and information relating to A(H1N1)pdm09, and related clinical data were compared between subjects in Group-pdm and those in Group-post. The ability of household income to pay for utilities, food, and health care services as well as housing quality in terms of construction materials and number of rooms revealed a significant difference: Group-post had lower socioeconomic status than Group-pdm. Group-post had lower availability of information regarding H1N1 influenza than Group-pdm. These results indicate that subjects in Group-post had difficulty receiving necessary information relating to influenza and were more likely to be impoverished than those in Group-pdm. Possible factors influencing time to seeking health care were number of household rooms, having received information on the necessity of quick access to health care, and house construction materials. Conclusions Health-care-seeking behavior, poverty level, and the distribution of information affect the occurrence and severity of pneumonia due to H1N1 virus from a socioeconomic point of view. These

  6. Risk factors for 2009 pandemic influenza A (H1N1)-related hospitalization and death among racial/ethnic groups in New Mexico.

    PubMed

    Thompson, Deborah L; Jungk, Jessica; Hancock, Emily; Smelser, Chad; Landen, Michael; Nichols, Megin; Selvage, David; Baumbach, Joan; Sewell, Mack

    2011-09-01

    We assessed risk factors for 2009 pandemic influenza A (H1N1)-related hospitalization, mechanical ventilation, and death among New Mexico residents. We calculated population rate ratios using Poisson regression to analyze risk factors for H1N1-related hospitalization. We performed a cross-sectional analysis of hospitalizations during September 14, 2009 through January 13, 2010, using logistic regression to assess risk factors for mechanical ventilation and death among those hospitalized. During the study period, 926 laboratory-confirmed H1N1-related hospitalizations were identified. H1N1-related hospitalization was significantly higher among American Indians (risk ratio [RR] = 2.6; 95% confidence interval [CI] = 2.2, 3.2), Blacks (RR = 1.7; 95% CI = 1.2, 2.4), and Hispanics (RR = 1.8; 95% CI = 1.5, 2.0) than it was among non-Hispanic Whites, and also was higher among persons of younger age and lower household income. Mechanical ventilation was significantly associated with age 25 years and older, obesity, and lack of or delayed antiviral treatment. Death was significantly associated with male gender, cancer during the previous 12 months, and liver disorder. This analysis supports recent national efforts to include American Indian/Alaska Native race as a group at high risk for complications of influenza with respect to vaccination and antiviral treatment recommendations.

  7. Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) and inhibits pro-survival function of Nrf1

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Biswas, Madhurima; Kwong, Erick K.; Park, Eujean

    2013-08-01

    Nuclear factor E2-related factor-1 (Nrf1) is a basic leucine zipper transcription factor that is known to regulate antioxidant and cytoprotective gene expression. It was recently shown that Nrf1 is regulated by SCF–Fbw7 ubiquitin ligase. However our knowledge of upstream signals that targets Nrf1 for degradation by the UPS is not known. We report here that Nrf1 expression is negatively regulated by glycogen synthase kinase 3 (GSK3) in Fbw7-dependent manner. We show that GSK3 interacts with Nrf1 and phosphorylates the Cdc4 phosphodegron domain (CPD) in Nrf1. Mutation of serine residue in the CPD of Nrf1 to alanine (S350A), blocks Nrf1 frommore » phosphorylation by GSK3, and stabilizes Nrf1. Knockdown of Nrf1 and expression of a constitutively active form of GSK3 results in increased apoptosis in neuronal cells in response to ER stress, while expression of the GSK3 phosphorylation resistant S350A–Nrf1 attenuates apoptotic cell death. Together these data suggest that GSK3 regulates Nrf1 expression and cell survival function in response to stress activation. Highlights: • The effect of GSK3 on Nrf1 expression was examined. • GSK3 destabilizes Nrf1 protein via Fbw7 ubiquitin ligase. • GSK3 binds and phosphorylates Nrf1. • Protection from stress-induced apoptosis by Nrf1 is inhibited by GSK3.« less

  8. Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline.

    PubMed

    Huffman, Derek M; Farias Quipildor, Gabriela; Mao, Kai; Zhang, Xueying; Wan, Junxiang; Apontes, Pasha; Cohen, Pinchas; Barzilai, Nir

    2016-02-01

    Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole-body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P < 0.05). Furthermore, central IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P < 0.05). Taken together, IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  9. Estimation of Gust Response Factor for a Tall Building Model with 1:1.5 Plan Ratios

    NASA Astrophysics Data System (ADS)

    Sarath Kumar, H.; Selvi Rajan, S.

    2017-08-01

    The purpose of structural analysis and design of structures as per the building codes and its corresponding standers is to ensure the safety of structure under maximum loads and remains functional under service load. The structure which is designed under consideration of codes should also satisfy the durability, economy and aesthetics. The primary purpose of this work is to understand and compare design wind loads according with the Gust Response Factor as per codes of practices. The paper is concerned with the calculation of design wind loads on a rectangular building model (1:300gemetric scale) of size 10cm x 15cm x 70cm with an aspect ratio of 1:1.5:7 at eight different levels over the height under sub-urban terrain category for 00 angle and 900 angle wind incidence. The experiment id conducted in an atmospheric boundary layer wind tunnel facility of CSIR-Structural engineering Research centre, Chennai. The measured pressures are integrated to evaluate mean and RMS (Root, Mean, Square). Further the variation of above mentioned loads and response factor along the heights of the building with respect to sub-urban terrain condition are discussed and summarized in addition, the codal values of various international standards [IS-875 part-3 1987, IS-875 part-3 draft, ASCE-07] have also considered for comparison.

  10. Prolonged neutropenia after irinotecan-based chemotherapy in a child with polymorphisms of UGT1A1 and SLCO1B1.

    PubMed

    Sakaguchi, S; Garcia-Bournissen, F; Kim, R; Schwarz, U I; Nathan, P C; Ito, S

    2009-12-01

    Genetic polymorphisms of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and SLCO1B1 coding organic anion-transporter polypeptide 1B1, are independent risk factors known to increase irinotecan toxicity in adults. Although combined occurrence of polymorphisms in these 2 genes is likely to influence susceptibility to irinotecan toxicity, data are scarce, especially in children. We report an 11-year-old female with severe and prolonged neutropenia after irinotecan-based chemotherapy. The patient's genotyping revealed polymorphisms in both UGT1A1 and SLCO1B1. To our knowledge, this is the first case report of combined genotyping of both UGT1A1 and SLCO1B1 in a child with severe irinotecan toxicity.

  11. Histone Deacetylase-1 Is Enriched at the Platelet-derived Growth Factor-D Promoter in Response to Interleukin-1β and Forms a Cytokine-inducible Gene-silencing Complex with NF-κB p65 and Interferon Regulatory Factor-1*

    PubMed Central

    Liu, Mary Y.; Khachigian, Levon M.

    2009-01-01

    Understanding the mechanisms governing cytokine control of growth factor expression in smooth muscle cells would provide invaluable insight into the molecular regulation of vascular phenotypes and create future opportunities for therapeutic intervention. Here, we report that the proinflammatory cytokine interleukin (IL)-1β suppresses platelet-derived growth factor (PDGF)-D promoter activity and mRNA and protein expression in smooth muscle cells. NF-κB p65, induced by IL-1β, interacts with a novel element in the PDGF-D promoter and inhibits PDGF-D transcription. Interferon regulatory factor-1 (IRF-1) is also induced by IL-1β and binds to a different element upstream in the promoter. Immunoprecipitation and chromatin immunoprecipitation experiments showed that IL-1β stimulates p65 interaction with IRF-1 and the accumulation of both factors at the PDGF-D promoter. Mutation of the IRF-1 and p65 DNA-binding elements relieved the promoter from IL-1β-mediated repression. PDGF-D repression by IL-1β involves histone deacetylation and interaction of HDAC-1 with IRF-1 and p65. HDAC-1 small interfering RNA ablates complex formation with IRF-1 and p65 and abrogates IRF-1 and p65 occupancy of the PDGF-D promoter. Thus, HDAC-1 is enriched at the PDGF-D promoter in cells exposed to IL-1β and forms a cytokine-inducible gene-silencing complex with p65 and IRF-1. PMID:19843519

  12. Structure of a highly stable mutant of human fibroblast growth factor 1.

    PubMed

    Szlachcic, Anna; Zakrzewska, Małgorzata; Krowarsch, Daniel; Os, Vibeke; Helland, Ronny; Smalås, Arne O; Otlewski, Jacek

    2009-01-01

    Fibroblast growth factors (FGFs) are involved in diverse cellular processes such as cell migration, angiogenesis, osteogenesis, wound healing and embryonic and foetal development. Human acidic fibroblast growth factor (FGF-1) is the only member of the FGF family that binds with high affinity to all four FGF receptors and thus is considered to be the human mitogen with the broadest specificity. However, pharmacological applications of FGF-1 are limited owing to its low stability. It has previously been reported that the introduction of single mutations can significantly improve the stability of FGF-1 and its resistance to proteolytic degradation. Here, the structure of the Q40P/S47I/H93G triple mutant of FGF-1, which exhibits much higher stability, a prolonged half-life and enhanced mitogenic activity, is presented. Compared with the wild-type structure, three localized conformational changes in the stable triple mutant were observed, which is in agreement with the perfect energetic additivity of the single mutations described in a previous study. The huge change in FGF-1 stability (the denaturation temperature increased by 21.5 K, equivalent to DeltaDeltaG(den) = 24.3 kJ mol(-1)) seems to result from the formation of a short 3(10)-helix (position 40), an improvement in the propensity of amino acids to form beta-sheets (position 47) and the rearrangement of a local hydrogen-bond network (positions 47 and 93).

  13. Cholangiocyte Endothelin 1 and Transforming Growth Factor β1 Production in Rat Experimental Hepatopulmonary Syndrome

    PubMed Central

    LUO, BAO; TANG, LIPING; WANG, ZHISHAN; ZHANG, JUNLAN; LING, YIQUN; FENG, WENGUANG; SUN, JU-ZHONG; STOCKARD, CECIL R.; FROST, ANDRA R.; CHEN, YIU-FAI; GRIZZLE, WILLIAM E.; FALLON, MICHAEL B.

    2010-01-01

    Background & Aims Hepatic production and release of endothelin 1 plays a central role in experimental hepatopulmonary syndrome after common bile duct ligation by stimulating pulmonary endothelial nitric oxide production. In thioacetamide-induced nonbiliary cirrhosis, hepatic endothelin 1 production and release do not occur, and hepatopulmonary syndrome does not develop. However, the source and regulation of hepatic endothelin 1 after common bile duct ligation are not fully characterized. We evaluated the sources of hepatic endothelin 1 production after common bile duct ligation in relation to thioacetamide cirrhosis and assessed whether transforming growth factor β1 regulates endothelin 1 production. Methods Hepatopulmonary syndrome and hepatic and plasma endothelin 1 levels were evaluated after common bile duct ligation or thioacetamide administration. Cellular sources of endothelin 1 were assessed by immunohistochemistry and laser capture microdissection of cholangiocytes. Transforming growth factor β1 expression and signaling were assessed by using immunohistochemistry and Western blotting and by evaluating normal rat cholangiocytes. Results Hepatic and plasma endothelin 1 levels increased and hepatopulmonary syndrome developed only after common bile duct ligation. Hepatic endothelin 1 and transforming growth factor β1 levels increased over a similar time frame, and cholangiocytes were a major source of each peptide. Transforming growth factor β1 signaling in cholangiocytes in vivo was evident by increased phosphorylation and nuclear localization of Smad2, and hepatic endothelin 1 levels correlated directly with liver transforming growth factor β1 and phosphorylated Smad2 levels. Transforming growth factor β1 also stimulated endothelin 1 promoter activity, expression, and production in normal rat cholangiocytes. Conclusions Cholangiocytes are a major source of hepatic endothelin 1 production during the development of hepatopulmonary syndrome after common

  14. Time-of-flight neutron powder diffraction study on the third row transition metal hexafluorides WF6, OsF6, and PtF6

    NASA Astrophysics Data System (ADS)

    Marx, R.; Seppelt, K.; Ibberson, R. M.

    1996-05-01

    A neutron diffraction study on the third-row transition metal hexafluorides MF6 (M≡W, Os, Pt) has been performed using the high resolution neutron powder diffractometer (HRPD) at the spallation source ISIS, England. The previously unknown structures of the low-temperature phases of OsF6 and PtF6 are reported. WF6, OsF6, and PtF6, which exhibit a (5dt2g)0, (5dt2g)2, and (5dt2g)4 electronic configuration, respectively, are found to be isostructural and crystallize in the UF6 structure, space group Pmnb, (No. 62). The geometry of the MF6 molecules is to good approximation octahedral for each compound, the mean M-F bond length increasing only slightly from 182.5 (W) to 185.0 (Pt). For WF6 deviations from ideal octahedral geometry are only marginally significant [181.8(2) to 183.2(2) pm] and may be interpreted on the basis of packing effects. Deviations for the d2 complex OsF6 are somewhat larger [181.5(2) to 184.4(3) pm] and may be assumed to be caused by packing effects essentially the same as for WF6, in addition to a first-order Jahn-Teller effect arising from the (5dt2g)2 electronic configuration. While eliminating the effects of packing by a comparison of individual M-F bond lengths for WF6 and OsF6, the OsF6 molecule shows to have D4h symmetry with two apical M-F bonds about 1.8 pm longer than the four equatorial bonds as a result of the Jahn-Teller distortion. Only small deviations from ideal octahedral geometry [184.4(3) to 185.8(3) pm] are found for the d4 complex PtF6. Within the series W to Pt a substantial shortening of the F...F van der Waals contact distances is observed. This shortening more than compensates for the increase in the M-F bond lengths and leads to unit cell volumes and cell parameters decreasing continuously from W to Pt. The variation of F...F contact distances and M-F bond lengths may be rationalized in terms of polarization of the F-ligands in the field of the highly charged nuclei of the central atoms which are only incompletely

  15. Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in mice.

    PubMed

    Hayashi, Hiromitsu; Sakai, Keiko; Baba, Hideo; Sakai, Takao

    2012-05-01

    The matricellular protein, thrombospondin-1 (TSP-1), is prominently expressed during tissue repair. TSP-1 binds to matrix components, proteases, cytokines, and growth factors and activates intracellular signals through its multiple domains. TSP-1 converts latent transforming growth factor-beta1 (TGF-β1) complexes into their biologically active form. TGF-β plays significant roles in cell-cycle regulation, modulation of differentiation, and induction of apoptosis. Although TGF-β1 is a major inhibitor of proliferation in cultured hepatocytes, the functional requirement of TGF-β1 during liver regeneration remains to be defined in vivo. We generated a TSP-1-deficient mouse model of a partial hepatectomy (PH) and explored TSP-1 induction, progression of liver regeneration, and TGF-β-mediated signaling during the repair process after hepatectomy. We show here that TSP-1-mediated TGF-β1 activation plays an important role in suppressing hepatocyte proliferation. TSP-1 expression was induced in endothelial cells (ECs) as an immediate early gene in response to PH. TSP-1 deficiency resulted in significantly reduced TGF-β/Smad signaling and accelerated hepatocyte proliferation through down-regulation of p21 protein expression. TSP-1 induced in ECs by reactive oxygen species (ROS) modulated TGF-β/Smad signaling and proliferation in hepatocytes in vitro, suggesting that the immediately and transiently produced ROS in the regenerating liver were the responsible factor for TSP-1 induction. We have identified TSP-1 as an inhibitory element in regulating liver regeneration by TGF-β1 activation. Our work defines TSP-1 as a novel immediate early gene that could be a potential therapeutic target to accelerate liver regeneration. Copyright © 2011 American Association for the Study of Liver Diseases.

  16. Transcriptional regulation of the cytosolic chaperonin theta subunit gene, Cctq, by Ets domain transcription factors Elk-1, Sap-1a, and Net in the absence of serum response factor.

    PubMed

    Yamazaki, Yuji; Kubota, Hiroshi; Nozaki, Masami; Nagata, Kazuhiro

    2003-08-15

    The chaperonin-containing t-complex polypeptide 1 (CCT) is a molecular chaperone that facilitates protein folding in eukaryotic cytosol, and the expression of CCT is highly dependent on cell growth. We show here that transcription of the gene encoding the theta subunit of mouse CCT, Cctq, is regulated by the ternary complex factors (TCFs), Elk-1, Sap-1a, and Net (Sap-2). Reporter gene assay using HeLa cells indicated that the Cctq gene promoter contains a cis-acting element of the CCGGAAGT sequence (CQE1) at -36 bp. The major CQE1-binding proteins in HeLa cell nuclear extract was recognized by anti-Elk-1 or anti-Sap-1a antibodies in electrophoretic mobility shift assay, and recombinant Elk-1, Sap-1a, or Net specifically recognized CQE1. The CQE1-dependent transcriptional activity in HeLa cells was virtually abolished by overexpression of the DNA binding domains of TCFs. Overexpression of full-length TCFs with Ras indicated that exogenous TCFs can regulate the CQE1-dependent transcription in a Ras-dependent manner. PD98059, an inhibitor of MAPK, significantly repressed the CQE1-dependent transcription. However, no serum response factor was detected by electrophoretic mobility shift assay using the CQE1 element. These results indicate that transcription of the Cctq gene is regulated by TCFs under the control of the Ras/MAPK pathway, probably independently of serum response factor.

  17. [Rbf1 (RPG-box binding factor), a transcription factor involved in yeast-hyphal transition of Candida albicans].

    PubMed

    Aoki, Y; Ishii, N; Watanabe, M; Yoshihara, F; Arisawa, M

    1998-01-01

    The major fungal pathogen for fungal diseases which have become a major medical problem in the last few years is Candida albicans, which can grow both in yeast and hyphae forms. This ability of C. albicans is thought to contribute to its colonization and dissemination within host tissues. In a recent few years, accompanying the introduction of molecular biological tools into C. albicans organism, several factors involved in the signal transduction pathway for yeast-hyphal transition have been identified. One MAP kinase pathway in C. albicans, similar to that leading to STE12 activation in Saccharomyces cerevisiae, has been reported. C. albicans strains mutant in these genes show retarded filamentous growth on a solid media but no impairment of filamentous growth in mice. These results suggest two scenarios that a kinase signaling cascade plays a part in stimulating the morphological transition in C. albicans, and that there would be another signaling pathway effective in animals. In this latter true hyphal pathway, although some candidate proteins, such as Efg1 (transcription factor), Int1 (integrin-like membrane protein), or Phr1 (pH-regulated membrane protein), have been identified, it is still too early to say that we understand the whole picture of that cascade. We have cloned a C. albicans gene encoding a novel DNA binding protein, Rbf1, that predominantly localizes in the nucleus, and shows transcriptional activation capability. Disruption of the functional RBF1 genes of C. albicans induced the filamentous growth on all solid and liquid media tested, suggesting that Rbf1 might be another candidate for the true hyphal pathway. Relationships with other factors described above, and the target (regulated) genes of Rbf1 is under investigation.

  18. Cloning and expression of porcine Colony Stimulating Factor-1 (CSF-1) and Colony Stimulating Factor-1 Receptor (CSF-1R) and analysis of the species specificity of stimulation by CSF-1 and Interleukin 34

    PubMed Central

    Gow, Deborah J.; Garceau, Valerie; Kapetanovic, Ronan; Sester, David P.; Fici, Greg J.; Shelly, John A.; Wilson, Thomas L.; Hume, David A.

    2012-01-01

    Macrophage Colony Stimulating Factor (CSF-1) controls the survival, differentiation and proliferation of cells of the mononuclear phagocyte system. A second ligand for the CSF-1R, Interleukin 34 (IL-34), has been described, but its physiological role is not yet known. The domestic pig provides an alternative to traditional rodent models for evaluating potential therapeutic applications of CSF-1R agonists and antagonists. To enable such studies, we cloned and expressed active pig CSF-1. To provide a bioassay, pig CSF-1R was expressed in the factor-dependent Ba/F3 cell line. On this transfected cell line, recombinant porcine CSF-1 and human CSF-1 had identical activity. Mouse CSF-1 does not interact with the human CSF-1 receptor but was active on pig. By contrast, porcine CSF-1 was active on mouse, human, cat and dog cells. IL-34 was previously shown to be species-specific, with mouse and human proteins demonstrating limited cross-species activity. The pig CSF-1R was equally responsive to both mouse and human IL-34. Based upon the published crystal structures of CSF-1/CSF-1R and IL34/CSF-1R complexes, we discuss the molecular basis for the species specificity. PMID:22974529

  19. Higher atypical enteropathogenic Escherichia coli (a-EPEC) bacterial loads in children with diarrhea are associated with PCR detection of the EHEC factor for adherence 1/lymphocyte inhibitory factor A (efa1/lifa) gene.

    PubMed

    Slinger, Robert; Lau, Kimberley; Slinger, Michael; Moldovan, Ioana; Chan, Francis

    2017-03-23

    Typical enteropathogenic Escherichia coli (t-EPEC) are known to cause diarrhea in children but it is uncertain whether atypical EPEC (a-EPEC) do, since a-EPEC lack the bundle-forming pilus (bfp) gene that encodes a key adherence factor in t-EPEC. In culture-based studies of a-EPEC, the presence of another adherence factor, called EHEC factor for adherence/lymphocyte activation inhibitor (efa1/lifA), was strongly associated with diarrhea. Since a-EPEC culture is not feasible in clinical laboratories, we designed an efa1/lifA quantitative PCR assay and examined whether the presence of efa1/lifA was associated with higher a-EPEC bacterial loads in pediatric diarrheal stool samples. Fecal samples from children with diarrhea were tested by qPCR for EPEC (presence of eae gene) and for shiga toxin genes to exclude enterohemorrhagic E. coli, which also contain the eae gene. EPEC containing samples were then tested for the bundle-forming pilus gene found in t-EPEC and efa1/lifA. The eae gene quantity in efa1/lifA-positive and negative samples was compared. Thirty-nine of 320 (12%) fecal samples tested positive for EPEC and 38/39 (97%) contained a-EPEC. The efa1/lifA gene was detected in 16/38 (42%) a-EPEC samples. The median eae concentration for efa1/lifA positive samples was significantly higher than for efa1/lifA negative samples (median 16,745 vs. 1183 copies/µL, respectively, p = 0.006). Atypical enteropathogenic E. coli-positive diarrheal stool samples containing the efa1/lifA gene had significantly higher bacterial loads than samples lacking this gene. This supports the idea that efa1/lifA contributes to diarrheal pathogenesis and suggests that, in EPEC-positive samples, efa/lifA may be a useful additional molecular biomarker.

  20. The role of IL-1 gene polymorphisms (IL1A, IL1B, and IL1RN) as a risk factor in unsuccessful implants retaining overdentures.

    PubMed

    Sampaio Fernandes, Margarida; Vaz, Paula; Braga, Ana Cristina; Sampaio Fernandes, João Carlos; Figueiral, Maria Helena

    2017-10-01

    Implant-supported overdentures are an alternative predictable rehabilitation method that has a high impact on improving the patient's quality of life. However, some biological complications may interfere with the maintenance and survival of these overdenture implants. The goal of this article was to assess the factors that affect peri-implant success, through a hypothetical prediction model for biological complications of implant overdentures. A retrospective observational, prevalence study was conducted in 58 edentulous Caucasian patients rehabilitated with implant overdentures. A total of 229 implants were included in the study. Anamnestic, clinical, and implant-related parameters were collected and recorded in a single database. "Patient" was chosen as the unit of analysis, and a complete screening protocol was established. The data analytical study included assessing the odds ratio, concerning the presence or absence of a particular risk factor, by using binary logistic regression modeling. Probability values (p values) inferior to 0.05 were considered as representing statistically significant evidence. The performed prediction model included the following variables: mean probing depth, metal exposure, IL1B_allele2, maxillary edentulousness, and Fusobacterium nucleatum. The F. nucleatum showed significant association with the outcome. Introducing a negative coefficient appeared to prevent complications or even boost the biological defense when associated with other factors. The prediction model developed in this study could serve as a basis for further improved models that would assist clinicians in the daily diagnosis and treatment planning practice of oral rehabilitation with implant overdentures. Copyright © 2017 Japan Prosthodontic Society. Published by Elsevier Ltd. All rights reserved.

  1. Metabolic syndrome as an independent risk factor of hypoxaemia in influenza A (H1N1) 2009 pandemic.

    PubMed

    Bijani, Behzad; Pahlevan, Ali Asghar; Qasemi-Barqi, Reza; Jahanihashemi, Hassan

    2016-06-01

    A swine-origin influenza A (H1N1) emerged as a pandemic in 2009. We investigated the association between the overweight, metabolic syndrome and the severity of disease in the confirmed cases in Qazvin province, Iran. The study sample included all patients over 12 years old with confirmed influenza A (H1N1) in the province of Qazvin, Iran, in the 2009 pandemic, excluding pregnant women. To define overweight, sex and age-specific body mass index (BMI) cutoffs recommended by the International Obesity Task Force were used. Metabolic syndrome was defined by ATP III criteria. Multiple logistic regression analysis was performed to identify statistically independent predictors of hypoxaemia. Out of 55 confirmed cases, 28 (50.9%) were overweight and 24 (45.3%) were identified as having metabolic syndrome by ATP III criteria. Twenty four patients had hypoxaemia (arterial oxygen saturation below 90%) during the course of the disease. In multivariate logistic regression analysis, pulmonary co-morbidity (OR=9.54; 95% CI, 1.36 to 66.88; p= 0.023) and the metabolic syndrome (OR=18.66; 95% CI, 1.60 to 217.47; p= 0.019) were revealed to be independent risk factors for hypoxaemia in influenza A (H1N1) pdm09. The results of the present study reveal the role of the metabolic syndrome on the severity of influenza A (H1N1) pdm09 infection.

  2. Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent Manner*

    PubMed Central

    Chen, Rui; Dioum, Elhadji M.; Hogg, Richard T.; Gerard, Robert D.; Garcia, Joseph A.

    2011-01-01

    Hypoxia-inducible factors (HIFs) are stress-responsive transcriptional regulators of cellular and physiological processes involved in oxygen metabolism. Although much is understood about the molecular machinery that confers HIF responsiveness to oxygen, far less is known about HIF isoform-specific mechanisms of regulation, despite the fact that HIF-1 and HIF-2 exhibit distinct biological roles. We recently determined that the stress-responsive genetic regulator sirtuin 1 (Sirt1) selectively augments HIF-2 signaling during hypoxia. However, the mechanism by which Sirt1 maintains activity during hypoxia is unknown. In this report, we demonstrate that Sirt1 gene expression increases in a HIF-dependent manner during hypoxia in Hep3B and in HT1080 cells. Impairment of HIF signaling affects Sirt1 deacetylase activity as decreased HIF-1 signaling results in the appearance of acetylated HIF-2α, which is detected without pharmacological inhibition of Sirt1. We also find that Sirt1 augments HIF-2 mediated, but not HIF-1 mediated, transcriptional activation of the isolated Sirt1 promoter. These data in summary reveal a bidirectional link of HIF and Sirt1 signaling during hypoxia. PMID:21345792

  3. Somatomedin-1 binding protein-3: insulin-like growth factor-1 binding protein-3, insulin-like growth factor-1 carrier protein.

    PubMed

    2003-01-01

    Somatomedin-1 binding protein-3 [insulin-like growth factor-1 binding protein-3, SomatoKine] is a recombinant complex of insulin-like growth factor-1 (rhIGF-1) and binding protein-3 (IGFBP-3), which is the major circulating somatomedin (insulin-like growth factor) binding protein; binding protein-3 regulates the delivery of somatomedin-1 to target tissues. Somatomedin-1 binding protein-3 has potential as replacement therapy for somatomedin-1 which may become depleted in indications such as major surgery, organ damage/failure and traumatic injury, resulting in catabolism. It also has potential for the treatment of osteoporosis; diseases associated with protein wasting including chronic renal failure, cachexia and severe trauma; and to attenuate cardiac dysfunction in a variety of disease states, including after severe burn trauma. Combined therapy with somatomedin-1 and somatomedin-1 binding protein-3 would prolong the duration of action of somatomedin-1 and would reduce or eliminate some of the undesirable effects associated with somatomedin-1 monotherapy. Somatomedin-1 is usually linked to binding protein-3 in the normal state of the body, and particular proteases clip them apart in response to stresses and release somatomedin-1 as needed. Therefore, somatomedin-1 binding protein-3 is a self-dosing system and SomatoKine would augment the natural supply of these linked compounds. Somatomedin-1 binding protein-3 was developed by Celtrix using its proprietary recombinant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on June 1 2000. Insmed and Avecia, UK, have signed an agreement for the manufacturing of SomatoKine and its components, IGF-1 and binding protein-3. CGMP clinical production of SomatoKine and its components will be done in Avecia's Advanced Biologics Centre, Billingham, UK, which manufactures recombinant-based medicines and vaccines with a capacity of up to 1000 litres. In 2003, manufacturing of SomatoKine is

  4. The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2alpha.

    PubMed

    Gort, E H; van Haaften, G; Verlaan, I; Groot, A J; Plasterk, R H A; Shvarts, A; Suijkerbuijk, K P M; van Laar, T; van der Wall, E; Raman, V; van Diest, P J; Tijsterman, M; Vooijs, M

    2008-03-06

    Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that play a crucial role in oxygen homeostasis. Intratumoral hypoxia and genetic alterations lead to HIF activity, which is a hallmark of solid cancer and is associated with poor clinical outcome. HIF activity is regulated by an evolutionary conserved mechanism involving oxygen-dependent HIFalpha protein degradation. To identify novel components of the HIF pathway, we performed a genome-wide RNA interference screen in Caenorhabditis elegans, to suppress HIF-dependent phenotypes, like egg-laying defects and hypoxia survival. In addition to hif-1 (HIFalpha) and aha-1 (HIFbeta), we identified hlh-8, gska-3 and spe-8. The hlh-8 gene is homologous to the human oncogene TWIST1. We show that TWIST1 expression in human cancer cells is enhanced by hypoxia in a HIF-2alpha-dependent manner. Furthermore, intronic hypoxia response elements of TWIST1 are regulated by HIF-2alpha, but not HIF-1alpha. These results identify TWIST1 as a direct target gene of HIF-2alpha, which may provide insight into the acquired metastatic capacity of hypoxic tumors.

  5. Krüppel-Like Factor 1 (KLF1), KLF2, and Myc Control a Regulatory Network Essential for Embryonic Erythropoiesis

    PubMed Central

    Pang, Christopher J.; Lemsaddek, Wafaa; Alhashem, Yousef N.; Bondzi, Cornelius; Redmond, Latasha C.; Ah-Son, Nicolas; Dumur, Catherine I.; Archer, Kellie J.; Haar, Jack L.

    2012-01-01

    The Krüppel-like factor 1 (KLF1) and KLF2 positively regulate embryonic β-globin expression and have additional overlapping roles in embryonic (primitive) erythropoiesis. KLF1−/− KLF2−/− double knockout mice are anemic at embryonic day 10.5 (E10.5) and die by E11.5, in contrast to single knockouts. To investigate the combined roles of KLF1 and KLF2 in primitive erythropoiesis, expression profiling of E9.5 erythroid cells was performed. A limited number of genes had a significantly decreasing trend of expression in wild-type, KLF1−/−, and KLF1−/− KLF2−/− mice. Among these, the gene for Myc (c-Myc) emerged as a central node in the most significant gene network. The expression of the Myc gene is synergistically regulated by KLF1 and KLF2, and both factors bind the Myc promoters. To characterize the role of Myc in primitive erythropoiesis, ablation was performed specifically in mouse embryonic proerythroblast cells. After E9.5, these embryos exhibit an arrest in the normal expansion of circulating red cells and develop anemia, analogous to KLF1−/− KLF2−/− embryos. In the absence of Myc, circulating erythroid cells do not show the normal increase in α- and β-like globin gene expression but, interestingly, have accelerated erythroid cell maturation between E9.5 and E11.5. This study reveals a novel regulatory network by which KLF1 and KLF2 regulate Myc to control the primitive erythropoietic program. PMID:22566683

  6. A zinc finger transcription factor ART1 regulates multiple genes implicated in aluminum tolerance in rice.

    PubMed

    Yamaji, Naoki; Huang, Chao Feng; Nagao, Sakiko; Yano, Masahiro; Sato, Yutaka; Nagamura, Yoshiaki; Ma, Jian Feng

    2009-10-01

    Aluminum (Al) toxicity is the major limiting factor of crop production on acid soils, but some plant species have evolved ways of detoxifying Al. Here, we report a C2H2-type zinc finger transcription factor ART1 (for Al resistance transcription factor 1), which specifically regulates the expression of genes related to Al tolerance in rice (Oryza sativa). ART1 is constitutively expressed in the root, and the expression level is not affected by Al treatment. ART1 is localized in the nucleus of all root cells. A yeast one-hybrid assay showed that ART1 has a transcriptional activation potential and interacts with the promoter region of STAR1, an important factor in rice Al tolerance. Microarray analysis revealed 31 downstream transcripts regulated by ART1, including STAR1 and 2 and a couple of homologs of Al tolerance genes in other plants. Some of these genes were implicated in both internal and external detoxification of Al at different cellular levels. Our findings shed light on comprehensively understanding how plants detoxify aluminum to survive in an acidic environment.

  7. ADP-Ribosylation Factor 6 and a Functional PIX/p95-APP1 Complex Are Required for Rac1B-mediated Neurite Outgrowth

    PubMed Central

    Albertinazzi, Chiara; Za, Lorena; Paris, Simona; de Curtis, Ivan

    2003-01-01

    The mechanisms coordinating adhesion, actin organization, and membrane traffic during growth cone migration are poorly understood. Neuritogenesis and branching from retinal neurons are regulated by the Rac1B/Rac3 GTPase. We have identified a functional connection between ADP-ribosylation factor (Arf) 6 and p95-APP1 during the regulation of Rac1B-mediated neuritogenesis. P95-APP1 is an ADP-ribosylation factor GTPase-activating protein (ArfGAP) of the GIT family expressed in the developing nervous system. We show that Arf6 has a predominant role in neurite extension compared with Arf1 and Arf5. Cotransfection experiments indicate a specific and cooperative potentiation of neurite extension by Arf6 and the carboxy-terminal portion of p95-APP1. Localization studies in neurons expressing different p95-derived constructs show a codistribution of p95-APP1 with Arf6, but not Arf1. Moreover, p95-APP1–derived proteins with a mutated or deleted ArfGAP domain prevent Rac1B-induced neuritogenesis, leading to PIX-mediated accumulation at large Rab11-positive endocytic vesicles. Our data support a role of p95-APP1 as a specific regulator of Arf6 in the control of membrane trafficking during neuritogenesis. PMID:12686588

  8. Insulin-like Growth Factor 1 Regulates the Expression of ATP-Binding Cassette Transporter A1 in Pancreatic Beta Cells.

    PubMed

    Lyu, J; Imachi, H; Iwama, H; Zhang, H; Murao, K

    2016-05-01

    ATP-binding cassette transporter A1 (ABCA1) in pancreatic beta cells influences insulin secretion and cholesterol homeostasis. The present study investigates whether insulin-like growth factor 1 (IGF-1), which mediates stimulation of ABCA1 gene expression, could also interfere with the phosphatidylinositol 3-kinase (PI3-K) cascade.ABCA1 expression was examined by real-time polymerase chain reaction (PCR), Western blot analysis, and a reporter gene assay in rat insulin-secreting INS-1 cells incubated with IGF-1. The binding of forkhead box O1 (FoxO1) protein to the ABCA1 promoter was assessed by a chromatin immunoprecipitation (ChIP) assay. ABCA1 protein levels increased in response to rising concentrations of IGF-1. Real-time PCR analysis showed a significant increase in ABCA1 mRNA expression. However, both effects were suppressed after silencing the IGF-1 receptor. In parallel with its effect on endogenous ABCA1 mRNA levels, IGF-1 induced the activity of a reporter construct containing the ABCA1 promoter, while it was abrogated by LY294002, a specific inhibitor of PI3-K. Constitutively active Akt stimulated activity of the ABCA1 promoter, and a dominant-negative mutant of Akt or mutagenesis of the FoxO1 response element in the ABCA1 promoter abolished the ability of IGF-1 to stimulate promoter activity. A ChIP assay showed that FoxO1 mediated its transcriptional activity by directly binding to the ABCA1 promoter region. The knockdown of FoxO1 disrupted the effect of IGF-1 on ABCA1 expression. Furthermore, IGF-1 promoted cholesterol efflux and reduced the pancreatic lipotoxicity. These results demonstrate that the PI3-K/Akt/FoxO1 pathway contributes to the regulation of ABCA1 expression in response to IGF-1 stimulation. © Georg Thieme Verlag KG Stuttgart · New York.

  9. A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection.

    PubMed

    Okumura, Cheryl Y M; Hollands, Andrew; Tran, Dan N; Olson, Joshua; Dahesh, Samira; von Köckritz-Blickwede, Maren; Thienphrapa, Wdee; Corle, Courtney; Jeung, Seung Nam; Kotsakis, Anna; Shalwitz, Robert A; Johnson, Randall S; Nizet, Victor

    2012-09-01

    Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. HIF-1 is also activated in response to bacterial pathogens and supports the innate immune response of both phagocytes and keratinocytes. In this work, we show that a new pharmacological compound AKB-4924 increases HIF-1 levels and enhances the antibacterial activity of phagocytes and keratinocytes against both methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus in vitro. AKB-4924 is also effective in stimulating the killing capacity of keratinocytes against the important opportunistic skin pathogens Pseudomonas aeruginosa and Acinetobacter baumanii. The effect of AKB-4924 is mediated through the activity of host cells, as the compound exerts no direct antimicrobial activity. Administered locally as a single agent, AKB-4924 limits S. aureus proliferation and lesion formation in a mouse skin abscess model. This approach to pharmacologically boost the innate immune response via HIF-1 stabilization may serve as a useful adjunctive treatment for antibiotic-resistant bacterial infections.

  10. Transcription Factor Foxo1 Is a Negative Regulator of NK Cell Maturation and Function

    PubMed Central

    Deng, Youcai; Kerdiles, Yann; Chu, Jianhong; Yuan, Shunzong; Wang, Youwei; Chen, Xilin; Mao, Hsiaoyin; Zhang, Lingling; Zhang, Jianying; Hughes, Tiffany; Deng, Yafei; Zhang, Qi; Wang, Fangjie; Zou, Xianghong; Liu, Chang-Gong; Freud, Aharon G.; Li, Xiaohui; Caligiuri, Michael A; Vivier, Eric; Yu, Jianhua

    2015-01-01

    SUMMARY Little is known about the role of negative regulators in controlling natural killer (NK) cell development and effector functions. Foxo1 is a multifunctional transcription factor of the forkhead family. Using a mouse model of conditional deletion in NK cells, we found that Foxo1 negatively controlled NK cell differentiation and function. Immature NK cells expressed abundant Foxo1 and little Tbx21 relative to mature NK cells, but these two transcription factors reversed their expression as NK cells proceeded through development. Foxo1 promoted NK cell homing to lymph nodes through upregulating CD62L expression, and impaired late-stage maturation and effector functions by repressing Tbx21 expression. Loss of Foxo1 rescued the defect in late-stage NK cell maturation in heterozygous Tbx21+/− mice. Collectively, our data reveal a regulatory pathway by which the negative regulator Foxo1 and the positive regulator Tbx21 play opposing roles in controlling NK cell development and effector functions. PMID:25769609

  11. Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms: 211G>A (G71R) mutation becomes a risk factor under inadequate feeding.

    PubMed

    Sato, Hiroko; Uchida, Toshihiko; Toyota, Kentaro; Kanno, Miyako; Hashimoto, Taeko; Watanabe, Masashi; Nakamura, Tomohiro; Tamiya, Gen; Aoki, Kuraaki; Hayasaka, Kiyoshi

    2013-01-01

    Breastfeeding jaundice is a well-known phenomenon, but its pathogenesis is still unclear. Increased production of bilirubin, impaired hepatic uptake and metabolism of bilirubin, and increased enterohepatic circulation of bilirubin account for most cases of pathological neonatal hyperbilirubinemia. We previously reported that 211G>A (G71R) mutation of the UGT1A1 gene is prevalent in East Asians and is associated with the development of neonatal hyperbilirubinemia. Recently, significant association of G71R mutation with hyperbilirubinemia in breast-fed neonates was reported. We enrolled 401 full-term Japanese infants, who were exclusively breast-fed without supplementation of formula before developing hyperbilirubinemia, and classified them into two groups based on the degree of maximal body weight loss during the neonatal period. We analyzed the sex, gestational age, delivery mode, body weight at birth, maximal body weight loss and genotypes of G71R and (TA)(7) polymorphic mutations of UGT1A1. Statistical analysis revealed that maximal body weight loss during the neonatal period is the only independent risk factor for the development of neonatal hyperbilirubinemia. The effect of G71R mutation on neonatal hyperbilirubinemia is significant in neonates with 5% or greater maximal body weight loss and its influence increases in parallel with the degree of maximal body weight loss. Our study indicates that G71R mutation is a risk factor for neonatal hyperbilirubinemia only in infants with inadequate breastfeeding and suggests that adequate breastfeeding may overcome the genetic predisposing factor, G71R mutation, for the development of neonatal hyperbilirubinemia.

  12. Risk Factors for Death from Influenza A(H1N1)pdm09, State of São Paulo, Brazil, 2009

    PubMed Central

    Ribeiro, Ana Freitas; Pellini, Alessandra Cristina Guedes; Kitagawa, Beatriz Yuko; Marques, Daniel; Madalosso, Geraldine; de Cassia Nogueira Figueira, Gerrita; Fred, João; Albernaz, Ricardo Kerti Mangabeira; Carvalhanas, Telma Regina Marques Pinto; Zanetta, Dirce Maria Trevisan

    2015-01-01

    This case-control study aimed to assess the risk factors for death from influenza A(H1N1)pdm09 in patients with laboratory confirmation, who had severe acute respiratory illness-SARI and were hospitalized between June 28th and August 29th 2009, in the metropolitan regions of São Paulo and Campinas, Brazil. Medical charts of all the 193 patients who died (cases) and the 386 randomly selected patients who recovered (controls) were investigated in 177 hospitals. Household interviews were conducted with those who had survived and the closest relative of those who had died. 73.6% of cases and 38.1% of controls were at risk of developing influenza-related complications. The 18-to-59-year age group (OR = 2.31, 95%CI: 1.31–4.10 (reference up to 18 years of age)), presence of risk conditions for severity of influenza (OR = 1.99, 95%CI: 1.11–3.57, if one or OR = 6.05, 95%CI: 2.76–13.28, if more than one), obesity (OR = 2.73, 95%CI: 1.28–5.83), immunosuppression (OR = 3.43, 95%CI: 1.28–9.19), and search for previous care associated with the hospitalization (OR = 3.35, 95%CI: 1.75–6.40) were risk factors for death. Antiviral treatment performed within 72 hours of the onset of symptoms (OR = 0.17, 95%CI: 0.08–0.37, if within 48hours, and OR = 0.30, 95%CI: 0.11–0.81, if between 48 and 72 hours) was protective against death. The identification of high-risk patients and early treatment are important factors for reducing morbi-mortality from influenza. PMID:25774804

  13. Dexamethasone impairs hypoxia-inducible factor-1 function

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wagner, A.E.; Huck, G.; Stiehl, D.P.

    2008-07-25

    Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription-factor composed of {alpha}- and {beta}-subunits. HIF-1 is not only necessary for the cellular adaptation to hypoxia, but it is also involved in inflammatory processes and wound healing. Glucocorticoids (GC) are therapeutically used to suppress inflammatory responses. Herein, we investigated whether GC modulate HIF-1 function using GC receptor (GR) possessing (HepG2) and GR deficient (Hep3B) human hepatoma cell cultures as model systems. Dexamethasone (DEX) treatment increased HIF-1{alpha} levels in the cytosol of HepG2 cells, while nuclear HIF-1{alpha} levels and HIF-1 DNA-binding was reduced. In addition, DEX dose-dependently lowered the hypoxia-induced luciferase activity in amore » reporter gene system. DEX suppressed the hypoxic stimulation of the expression of the HIF-1 target gene VEGF (vascular endothelial growth factor) in HepG2 cultures. DEX did not reduce hypoxically induced luciferase activity in HRB5 cells, a Hep3B derivative lacking GR. Transient expression of the GR in HRB5 cells restored the susceptibility to DEX. Our study discloses the inhibitory action of GC on HIF-1 dependent gene expression, which may be important with respect to the impaired wound healing in DEX-treated patients.« less

  14. Reassessment of murine APOBEC1 as a retrovirus restriction factor in vivo.

    PubMed

    Barrett, Bradley S; Guo, Kejun; Harper, Michael S; Li, Sam X; Heilman, Karl J; Davidson, Nicholas O; Santiago, Mario L

    2014-11-01

    APOBEC1 is a cytidine deaminase involved in cholesterol metabolism that has been linked to retrovirus restriction, analogous to the evolutionarily-related APOBEC3 proteins. In particular, murine APOBEC1 was shown to inhibit Friend retrovirus (FV) in vitro, generating high levels of C-to-T and G-to-A mutations. These observations raised the possibility that FV infection might be altered in APOBEC1-null mice. To examine this question directly, we infected wild-type and APOBEC1-null mice with FV complex and evaluated acute infection levels. Surprisingly, APOBEC1-null mice exhibited similar cellular infection levels and plasma viremia relative to wild-type mice. Moreover, next-generation sequencing analyses revealed that in contrast to APOBEC3, APOBEC1 did not enhance retroviral C-to-T and G-to-A mutational frequencies in genomic DNA. Thus, APOBEC1 neither inhibited nor significantly drove the molecular evolution of FV in vivo. Our findings reinforce that not all retrovirus restriction factors characterized as potent in vitro may be functionally relevant in vivo. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Metformin is a novel suppressor for transforming growth factor (TGF)-β1

    NASA Astrophysics Data System (ADS)

    Xiao, Han; Zhang, Jianshu; Xu, Zhonghe; Feng, Yenan; Zhang, Mingliang; Liu, Jianli; Chen, Ruifei; Shen, Jing; Wu, Jimin; Lu, Zhizhen; Fang, Xiaohong; Li, Jingyuan; Zhang, Youyi

    2016-06-01

    Metformin is a widely used first-line antidiabetic drug that has been shown to protect against a variety of specific diseases in addition to diabetes, including cardiovascular disorders, polycystic ovary syndrome, and cancer. However, the precise mechanisms underlying the diverse therapeutic effects of metformin remain elusive. Here, we report that transforming growth factor1 (TGF-β1), which is involved in the pathogenesis of numerous diseases, is a novel target of metformin. Using a surface plasmon resonance-based assay, we identified the direct binding of metformin to TGF-β1 and found that metformin inhibits [125I]-TGF-β1 binding to its receptor. Furthermore, based on molecular docking and molecular dynamics simulations, metformin was predicted to interact with TGF-β1 at its receptor-binding domain. Single-molecule force spectroscopy revealed that metformin reduces the binding probability but not the binding force of TGF-β1 to its type II receptor. Consequently, metformin suppresses type II TGF-β1 receptor dimerization upon exposure to TGF-β1, which is essential for downstream signal transduction. Thus, our results indicate that metformin is a novel TGF-β suppressor with therapeutic potential for numerous diseases in which TGF-β1 hyperfunction is indicated.

  16. Prognostic value of the stromal cell-derived factor 1 3'A mutation in pediatric human immunodeficiency virus type 1 infection.

    PubMed

    Tresoldi, Eleonora; Romiti, Maria Luisa; Boniotto, Michele; Crovella, Sergio; Salvatori, Francesca; Palomba, Elvia; Pastore, Angela; Cancrini, Caterina; de Martino, Maurizio; Plebani, Anna; Castelli, Guido; Rossi, Paolo; Tovo, Pier Angelo; Amoroso, Antonio; Scarlatti, Gabriella

    2002-03-01

    A mutation of the stromal cell-derived factor 1 gene (SDF-1 3'A) was shown to protect adults exposed to human immunodeficiency virus type 1 (HIV-1) from infection and to affect HIV disease progression in adults. The presence of this mutation in HIV-1-infected Kenyan children did not predict mother-to-child virus transmission. The SDF-1 3'A polymorphism was studied in 256 HIV-1-infected, 118 HIV-1-exposed but uninfected, and 170 unexposed and uninfected children of Italian origin, and the frequency of SDF-1 3'A heterozygosity and homozygosity in each of the 3 groups was similar. Of the 256 HIV-1-infected children, 194 were regularly followed up and were assigned to groups according to disease progression. The frequency of the SDF-1 3'A allele was substantially lower among children with long-term nonprogression than among children with rapid (P =.0329) or delayed (P =.0375) progression. We show that the presence of the SDF-1 3'A gene correlates with accelerated disease progression in HIV-1-infected children born to seropositive mothers but does not protect against mother-to-child HIV-1 transmission.

  17. Growth factor independence-1 (Gfi-1) plays a role in mediating specific granule deficiency (SGD) in a patient lacking a gene-inactivating mutation in the C/EBPϵ gene

    PubMed Central

    Khanna-Gupta, Arati; Sun, Hong; Zibello, Theresa; Lee, Han Myung; Dahl, Richard; Boxer, Laurence A.

    2007-01-01

    Neutrophil-specific granule deficiency (SGD) is a rare congenital disorder marked by recurrent bacterial infections. Neutrophils from SGD patients lack secondary and tertiary granules and their content proteins and lack normal neutrophil functions. Gene-inactivating mutations in the C/EBPϵ gene have been identified in 2 SGD patients. Our studies on a third SGD patient revealed a heterozygous mutation in the C/EBPϵ gene. However, we demonstrate elevated levels of C/EBPϵ and PU.1 proteins in the patient's peripheral blood neutrophils. The expression of the transcription factor growth factor independence-1 (Gfi-1), however, was found to be markedly reduced in our SGD patient despite the absence of an obvious mutation in this gene. This may explain the elevated levels of both C/EBPϵ and PU.1, which are targets of Gfi-1 transcriptional repression. We have generated a growth factor–dependent EML cell line from the bone marrow of Gfi-1+/− and Gfi-1+/+ mice as a model for Gfi-1–deficient SGD, and demonstrate that lower levels of Gfi-1 expression in the Gfi-1+/− EML cells is associated with reduced levels of secondary granule protein (SGP) gene expression. Furthermore, we demonstrate a positive role for Gfi-1 in SGP expression, in that Gfi-1 binds to and up-regulates the promoter of neutrophil collagenase (an SGP gene), in cooperation with wild-type but not with mutant C/EBPϵ. We hypothesize that decreased Gfi-1 levels in our SGD patient, together with the mutant C/EBPϵ, block SGP expression, thereby contributing to the underlying etiology of the disease in our patient. PMID:17244686

  18. Opposite effects of dihydrosphingosine 1-phosphate and sphingosine 1-phosphate on transforming growth factor-beta/Smad signaling are mediated through the PTEN/PPM1A-dependent pathway.

    PubMed

    Bu, Shizhong; Kapanadze, Bagrat; Hsu, Tien; Trojanowska, Maria

    2008-07-11

    Transforming growth factor-beta (TGF-beta) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-beta through cross-activation of Smad signaling. Here we report that another product of sphingosine kinase, dihydrosphingosine 1-phosphate (dhS1P), has an opposite role in the regulation of TGF-beta signaling. In contrast to S1P, dhS1P inhibits TGF-beta-induced Smad2/3 phosphorylation and up-regulation of collagen synthesis. The effects of dhS1P require a lipid phosphatase, PTEN, a key modulator of cell growth and survival. dhS1P stimulates phosphorylation of the C-terminal domain of PTEN and its subsequent translocation into the nucleus. We demonstrate a novel function of nuclear PTEN as a co-factor of the Smad2/3 phosphatase, PPM1A. Complex formation of PTEN with PPM1A does not require the lipid phosphatase activity but depends on phosphorylation of the serine/threonine residues located in the C-terminal domain of PTEN. Upon complex formation with PTEN, PPM1A is protected from degradation induced by the TGF-beta signaling. Consequently, overexpression of PTEN abrogates TGF-beta-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. PTEN-mediated cross-talk between the sphingolipid and TGF-beta signaling pathways may play an important role in physiological and pathological TGF-beta signaling.

  19. Predicting soil water content at - 33 kPa by pedotransfer functions in stoniness 1 soils in northeast Venezuela.

    PubMed

    Pineda, M C; Viloria, J; Martínez-Casasnovas, J A; Valera, A; Lobo, D; Timm, L C; Pires, L F; Gabriels, D

    2018-02-22

    Soil water content is a key property in the study of water available for plants, infiltration, drainage, hydraulic conductivity, irrigation, plant water stress and solute movement. However, its measurement consumes time and, in the case of stony soils, the presence of stones difficult to determinate the water content. An alternative is the use of pedotransfer functions (PTFs), as models to predict these properties from readily available data. The present work shows a comparison of different widely used PTFs to estimate water content at-33 kPa (WR -33kPa ) in high stoniness soils. The work was carried out in the Caramacate River, an area of high interest because the frequent landslides worsen the quality of drinking water. The performance of all evaluated PTFs was compared with a PTF generated for the study area. Results showed that the Urach's PTF presented the best performance in relation to the others and could be used to estimate WR -33kPa in soils of Caramacate River basin. The calculated PTFs had a R 2 of 0.65. This was slightly higher than the R 2 of the Urach's PTF. The inclusion of the rock fragment volume could have the better results. The weak performance of the other PTFs could be related to the fact that the mountain soils of the basin are rich in 2:1 clay and high stoniness, which were not used as independent variables for PTFs to estimate the WR -33kPa .

  20. Expression of a transmembrane phosphotyrosine phosphatase inhibits cellular response to platelet-derived growth factor and insulin-like growth factor-1.

    PubMed

    Mooney, R A; Freund, G G; Way, B A; Bordwell, K L

    1992-11-25

    Tyrosine phosphorylation is a mechanism of signal transduction shared by many growth factor receptors and oncogene products. Phosphotyrosine phosphatases (PTPases) potentially modulate or counter-regulate these signaling pathways. To test this hypothesis, the transmembrane PTPase CD45 (leukocyte common antigen) was expressed in the murine cell line C127. Hormone-dependent autophosphorylation of the platelet-derived growth factor (PDGF) and insulin-like growth factor-1 (IGF-1) receptors was markedly reduced in cells expressing the transmembrane PTPase. Tyrosine phosphorylation of other PDGF-dependent phosphoproteins (160, 140, and 55 kDa) and IGF-1-dependent phosphoproteins (145 kDa) was similarly decreased. Interestingly, the pattern of growth factor-independent tyrosine phosphorylations was comparable in cells expressing the PTPase and control cells. This suggests a selectivity or accessibility of the PTPase limited to a subset of cellular phosphotyrosyl proteins. The maximum mitogenic response to PDGF and IGF-1 in cells expressing the PTPase was decreased by 67 and 71%, respectively. These results demonstrate that a transmembrane PTPase can both affect the tyrosine phosphorylation state of growth factor receptors and modulate proximal and distal cellular responses to the growth factors.

  1. A second cistron in the CACNA1A gene encodes a transcription factor that mediates cerebellar development and SCA6

    PubMed Central

    Du, Xiaofei; Wang, Jun; Zhu, Haipeng; Rinaldo, Lorenzo; Lamar, Kay-Marie; Palmenberg, Ann C.; Hansel, Christian; Gomez, Christopher M.

    2014-01-01

    SUMMARY The CACNA1A gene, encoding the voltage-gated calcium channel subunit α1A, is involved in pre- and postsynaptic Ca2+ signaling, gene expression, and several genetic neurological disorders. We found that CACNA1A employs a novel strategy to directly coordinate a gene expression program, using a bicistronic mRNA bearing a cryptic internal ribosomal entry site (IRES). The first cistron encodes the well-characterized α1A subunit. The second expresses a newly-recognized transcription factor, α1ACT, that coordinates expression of a program of genes involved in neural and Purkinje cell development. α1ACT also contains the polyglutamine (polyQ) tract that, when expanded, causes spinocerebellar ataxia type 6 (SCA6). When expressed as an independent polypeptide, α1ACT, bearing an expanded polyQ tract, lacks transcription factor function and neurite outgrowth properties, causes cell death in culture, and leads to ataxia and cerebellar atrophy in transgenic mice. Suppression of CACNA1A IRES function in SCA6 may be a potential therapeutic strategy. PMID:23827678

  2. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis.

    PubMed

    Welsh, Sarah J; Bellamy, William T; Briehl, Margaret M; Powis, Garth

    2002-09-01

    Hypoxia-inducible factor 1 (HIF-1), a heterodimer of HIF-1alpha and HIF-1beta subunits, is a transcriptional activator central to the cellular response to low oxygen that includes metabolic adaptation, angiogenesis, metastasis, and inhibited apoptosis. Thioredoxin-1 (Trx-1) is a small redox protein overexpressed in a number of human primary tumors. We have examined the effects of Trx-1 on HIF activity and the activation of downstream genes. Stable transfection of human breast carcinoma MCF-7 cells with human Trx-1 caused a significant increase in HIF-1alpha protein levels under both normoxic (20% oxygen) and hypoxic (1% oxygen) conditions. Trx-1 increased hypoxia-induced HIF-1 transactivation activity measured using a luciferase reporter under the control of the hypoxia response element. Changes in HIF-1alpha mRNA levels did not account for the changes observed at the protein level, and HIF-1beta protein levels did not change. Trx-1 transfection also caused a significant increase in the protein products of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF) and nitric oxide synthase 2 in a number of different cell lines (MCF-7 human breast and HT29 human colon carcinomas and WEHI7.2 mouse lymphoma cells) under both normoxic and hypoxic conditions. The pattern of expression of the different isoforms of VEGF was not changed by Trx-1. Transfection of a redox-inactive Trx-1 (C32S/C35S) markedly decreased levels of HIF-1alpha protein, HIF-1 transactivating activity, and VEGF protein in MCF-7 cells compared with empty vector controls. In vivo studies using WEHI7.2 cells transfected with Trx-1 showed significantly increased tumor VEGF and angiogenesis. The results suggest that Trx-1 increases HIF-1alpha protein levels in cancer cells and increases VEGF production and tumor angiogenesis.

  3. Pediatric diabetes consortium type 1 diabetes new onset (NeOn) study: Factors associated with HbA1c levels one year after diagnosis

    USDA-ARS?s Scientific Manuscript database

    To identify determinants of hemoglobin A1c (HbA1c) levels 1 yr after the diagnosis of type 1 diabetes (T1D) in participants in the Pediatric Diabetes Consortium (PDC) T1D New Onset (NeOn) Study. Diabetes-specific as well as socioeconomic factors during the first year following diagnosis were analyze...

  4. EBP1 is a novel E2F target gene regulated by transforming growth factor-β.

    PubMed

    Judah, David; Chang, Wing Y; Dagnino, Lina

    2010-11-10

    Regulation of gene expression requires transcription factor binding to specific DNA elements, and a large body of work has focused on the identification of such sequences. However, it is becoming increasingly clear that eukaryotic transcription factors can exhibit widespread, nonfunctional binding to genomic DNA sites. Conversely, some of these proteins, such as E2F, can also modulate gene expression by binding to non-consensus elements. E2F comprises a family of transcription factors that play key roles in a wide variety of cellular functions, including survival, differentiation, activation during tissue regeneration, metabolism, and proliferation. E2F factors bind to the Erb3-binding protein 1 (EBP1) promoter in live cells. We now show that E2F binding to the EBP1 promoter occurs through two tandem DNA elements that do not conform to typical consensus E2F motifs. Exogenously expressed E2F1 activates EBP1 reporters lacking one, but not both sites, suggesting a degree of redundancy under certain conditions. E2F1 increases the levels of endogenous EBP1 mRNA in breast carcinoma and other transformed cell lines. In contrast, in non-transformed primary epidermal keratinocytes, E2F, together with the retinoblastoma family of proteins, appears to be involved in decreasing EBP1 mRNA abundance in response to growth inhibition by transforming growth factor1. Thus, E2F is likely a central coordinator of multiple responses that culminate in regulation of EBP1 gene expression, and which may vary depending on cell type and context.

  5. Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection.

    PubMed

    Rondina, Matthew T; Tatsumi, Kohei; Bastarache, Julie A; Mackman, Nigel

    2016-07-01

    To identify plasma biomarkers that can be early predictors of mortality in critically ill patients with primary influenza A/H1N1. A prospective, multicenter, case-cohort pilot study. Three academic ICUs. Fifteen patients with primary influenza A/H1N1 that included seven survivors and eight nonsurvivors. For comparison, age- and gender-matched healthy controls (n = 27) were also studied. Plasma was prepared from whole blood drawn on ICU admission in patients with influenza (ICU day 1). Microvesicle tissue factor activity, thrombin-antithrombin complexes, and D-dimers were measured as procoagulant markers and markers of activation of coagulation. Plasma cytokine levels were measured on the same blood samples in a subset of 12 patients with influenza using the Luminex Multi-Analyte Profiling system (Luminex Corporation, DeSoto, TX). Patients were followed up for the primary outcome of 28-day mortality. The average admission Acute Physiology and Chronic Health Evaluation II score of the patients was 25.5 ± 9.3, 60% of patients had shock, and the 28-day mortality rate was 53.3% (n = 8/15). Patients with influenza had dysregulated indices of coagulation and inflammation compared with controls. Among the markers of activation of coagulation measured on ICU day 1, only increased microvesicle tissue factor activity was significantly associated with subsequent influenza-related mortality (5.6 ± 1.2 pg/mL in nonsurvivors vs 1.8 ± 0.8 pg/mL in survivors; p < 0.05). Interleukin-8 was significantly higher in nonsurvivors compared with survivors (71.8 ± 29.1 pg/mL, n = 5 vs 17.3 ± 3.7 pg/mL, n = 7; p < 0.05). In addition, microvesicle tissue factor activity and interleukin-8 levels were significantly and positively correlated (r = 0.60; p = 0.003). Other cytokines, thrombin-antithrombin complexes, and D-dimer were not different between nonsurvivors and survivors and did not correlate with illness severity or mortality. This study identifies an association

  6. Risk Factors for 2009 Pandemic Influenza A (H1N1)–Related Hospitalization and Death Among Racial/Ethnic Groups in New Mexico

    PubMed Central

    Jungk, Jessica; Hancock, Emily; Smelser, Chad; Landen, Michael; Nichols, Megin; Selvage, David; Baumbach, Joan; Sewell, Mack

    2011-01-01

    Objectives. We assessed risk factors for 2009 pandemic influenza A (H1N1)–related hospitalization, mechanical ventilation, and death among New Mexico residents. Methods. We calculated population rate ratios using Poisson regression to analyze risk factors for H1N1-related hospitalization. We performed a cross-sectional analysis of hospitalizations during September 14, 2009 through January 13, 2010, using logistic regression to assess risk factors for mechanical ventilation and death among those hospitalized. Results. During the study period, 926 laboratory-confirmed H1N1-related hospitalizations were identified. H1N1-related hospitalization was significantly higher among American Indians (risk ratio [RR] = 2.6; 95% confidence interval [CI] = 2.2, 3.2), Blacks (RR = 1.7; 95% CI = 1.2, 2.4), and Hispanics (RR = 1.8; 95% CI = 1.5, 2.0) than it was among non-Hispanic Whites, and also was higher among persons of younger age and lower household income. Mechanical ventilation was significantly associated with age 25 years and older, obesity, and lack of or delayed antiviral treatment. Death was significantly associated with male gender, cancer during the previous 12 months, and liver disorder. Conclusions. This analysis supports recent national efforts to include American Indian/Alaska Native race as a group at high risk for complications of influenza with respect to vaccination and antiviral treatment recommendations. PMID:21778495

  7. Clinical and Virological Factors Associated with Viremia in Pandemic Influenza A/H1N1/2009 Virus Infection

    PubMed Central

    Tse, Herman; To, Kelvin K. W.; Wen, Xi; Chen, Honglin; Chan, Kwok-Hung; Tsoi, Hoi-Wah; Li, Iris W. S.; Yuen, Kwok-Yung

    2011-01-01

    Background Positive detection of viral RNA in blood and other non-respiratory specimens occurs in severe human influenza A/H5N1 viral infection but is not known to occur commonly in seasonal human influenza infection. Recently, viral RNA was detected in the blood of patients suffering from severe pandemic influenza A/H1N1/2009 viral infection, although the significance of viremia had not been previously studied. Our study aims to explore the clinical and virological factors associated with pandemic influenza A/H1N1/2009 viremia and to determine its clinical significance. Methodology/Principal Findings Clinical data of patients admitted to hospitals in Hong Kong between May 2009 and April 2010 and tested positive for pandemic influenza A/H1N1/2009 was collected. Viral RNA was detected by reverse-transcription polymerase chain reactions (RT-PCR) targeting the matrix (M) and HA genes of pandemic influenza A/H1N1/2009 virus from the following specimens: nasopharyngeal aspirate (NPA), endotracheal aspirate (ETA), blood, stool and rectal swab. Stool and/ or rectal swab was obtained only if the patient complained of any gastrointestinal symptoms. A total of 139 patients were included in the study, with viral RNA being detected in the blood of 14 patients by RT-PCR. The occurrence of viremia was strongly associated with a severe clinical presentation and a higher mortality rate, although the latter association was not statistically significant. D222G/N quasispecies were observed in 90% of the blood samples. Conclusion Presence of pandemic influenza A/H1N1/2009 viremia is an indicator of disease severity and strongly associated with D222G/N mutation in the viral hemagglutinin protein. PMID:21980333

  8. Predicting refeeding hypophosphataemia: insulin growth factor 1 (IGF-1) as a diagnostic biochemical marker for clinical practice.

    PubMed

    Goyale, Atul; Ashley, Sarah L; Taylor, David R; Elnenaei, Manal O; Alaghband-Zadeh, Jamshid; Sherwood, Roy A; le Roux, Carel W; Vincent, Royce P

    2015-01-01

    Refeeding syndrome (RS) is a potentially fatal condition that can occur following the re-introduction of nutrition after a period of starvation. Hypophosphataemia following the reintroduction of nutrition is often the only reliable biochemical marker of RS. Refeeding index (RI) generated from baseline insulin-like growth factor-1 (IGF-1) and leptin has been proposed as a useful biochemical marker for the identification of patients at risk of developing refeeding hypophosphataemia (RH). A prospective study included 52 patients referred for parenteral nutrition (PN). The sensitivity and specificity of IGF-1 measured using a sensitive assay was compared to the RI in predicting the development of RH (a ≥ 30% drop in PO4 during the first 36-h of PN administration). Leptin and IGF-1 were analysed on baseline samples using a quantitative enzyme-linked immunoassay. Daily blood samples were collected from all patients for routine biochemistry for the full duration of PN administration. High sensitivity IGF-1 measurement alone was comparable with the RI, using receiver-operating characteristic (ROC) curve analysis, with areas under the curve being 0.79 and 0.80, respectively, and superior to leptin alone (0.72) for predicting ≥ 30% drop in PO4. The cut-off value for IGF-1 that gave best sensitivity (91% [95% CI 75-98%]) and specificity (65% [95% CI 41-85%]) was 63.7 µg/L, with a likelihood ratio of 2.59. Baseline IGF-1 is an objective, sensitive and specific biochemical marker in identifying patients who are at high risk of developing RH prior to PN administration and therefore may have a role in clinical practice. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  9. Characterisation of Translation Elongation Factor eEF1B Subunit Expression in Mammalian Cells and Tissues and Co-Localisation with eEF1A2

    PubMed Central

    Janikiewicz, Justyna; Doig, Jennifer; Abbott, Catherine M.

    2014-01-01

    Translation elongation is the stage of protein synthesis in which the translation factor eEF1A plays a pivotal role that is dependent on GTP exchange. In vertebrates, eEF1A can exist as two separately encoded tissue-specific isoforms, eEF1A1, which is almost ubiquitously expressed, and eEF1A2, which is confined to neurons and muscle. The GTP exchange factor for eEF1A1 is a complex called eEF1B made up of subunits eEF1Bα, eEF1Bδ and eEF1Bγ. Previous studies have cast doubt on the ability of eEF1B to interact with eEF1A2, suggesting that this isoform might use a different GTP exchange factor. We show that eEF1B subunits are all widely expressed to varying degrees in different cell lines and tissues, and at different stages of development. We show that ablation of any of the subunits in human cell lines has a small but significant impact on cell viability and cycling. Finally, we show that both eEF1A1 and eEF1A2 colocalise with all eEF1B subunits, in such close proximity that they are highly likely to be in a complex. PMID:25436608

  10. The processivity factor complex of feline herpes virus-1 is a new drug target.

    PubMed

    Zhukovskaya, Natalia L; Guan, Hancheng; Saw, Yih Ling; Nuth, Manunya; Ricciardi, Robert P

    2015-03-01

    Feline herpes virus-1 (FHV-1) is ubiquitous in the cat population and is a major cause of blindness for which antiviral drugs, including acyclovir, are not completely effective. Recurrent infections, due to reactivation of latent FHV-1 residing in the trigeminal ganglia, can lead to epithelial keratitis and stromal keratitis and eventually loss of sight. This has prompted the medical need for an antiviral drug that will specifically inhibit FHV-1 infection. A new antiviral target is the DNA polymerase and its associated processivity factor, which forms a complex that is essential for extended DNA strand synthesis. In this study we have cloned and expressed the FHV-1 DNA polymerase (f-UL30) and processivity factor (f-UL42) and demonstrated that both proteins are required to completely synthesize the 7249 nucleotide full-length DNA from the M13 primed-DNA template in vitro. Significantly, a known inhibitor of human herpes simplex virus-1 (HSV-1) processivity complex was shown to inhibit FHV-1 processive DNA synthesis in vitro and block infection of cells. This validates using f-UL42/f-UL30 as a new antiviral drug target to treat feline ocular herpes infection. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Evaluation of aldehyde dehydrogenase 1 and transcription factors in both primary breast cancer and axillary lymph node metastases as a prognostic factor.

    PubMed

    Ito, Maiko; Shien, Tadahiko; Omori, Masako; Mizoo, Taeko; Iwamoto, Takayuki; Nogami, Tomohiro; Motoki, Takayuki; Taira, Naruto; Doihara, Hiroyoshi; Miyoshi, Shinichiro

    2016-05-01

    Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells, and the expression of ALDH1 may be a prognostic factor of poor clinical outcome. The epithelial-mesenchymal transition may produce cells with stem-cell-like properties promoted by transcription factors. We investigated the expression of ALDH1 and transcription factors in both primary and metastatic lesions, and prognostic value of them in breast cancer patients with axillary lymph node metastasis (ALNM). Forty-seven breast cancer patients with ALNM who underwent surgery at Okayama University Hospital from 2002 to 2008 were enrolled. We retrospectively evaluated the levels of ALDH1 and transcription factors, such as Snail, Slug and Twist, in both primary and metastatic lesions by immunohistochemistry. In primary lesions, the positive rate of ALDH1, Snail, Slug and Twist was 19, 49, 40 and 26%, respectively. In lymph nodes, that of ALDH1, Snail, Slug and Twist was 21, 32, 13 and 23%, respectively. The expression of ALDH1 or transcription factors alone was not significantly associated with a poor prognosis. However, co-expression of ALDH1 and Slug in primary lesions was associated with a shorter DFS (P = 0.009). The evaluation of the co-expression of ALDH1 and transcription factors in primary lesions may be useful in prognosis of node-positive breast cancers.

  12. Microtubule actin cross-linking factor 1, a novel potential target in cancer.

    PubMed

    Miao, Zhiping; Ali, Arshad; Hu, Lifang; Zhao, Fan; Yin, Chong; Chen, Chu; Yang, Tuanmin; Qian, Airong

    2017-10-01

    Cancer is a polygenic disease characterized by uncontrolled growth of normal body cells, deregulation of the cell cycle as well as resistance to apoptosis. The spectraplakin protein microtubule actin cross-linking factor 1 (MACF1) plays an essential function in various cellular processes, including cell proliferation, migration, signaling transduction and embryo development. MACF1 is also involved in processes such as metastatic invasion in which cytoskeleton organization is a critical element that contributes to tumor progression in various human cancers. Aberrant expression of MACF1 initiates the tumor cell proliferation, and migration and metastasis in numerous cancers, such as breast cancer, colon cancer, lung cancer and glioblastoma. In this review, we summarized the current knowledge of MACF1 and its critical role in different human cancers. This will be helpful for researchers to investigate the novel functional role of MACF1 in human cancers and as a potential target to enhance the efficacy of therapeutic treatment modalities. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  13. Asymptomatic Carotid T1-High-Intense Plaque as a Risk Factor for a Subsequent Cerebrovascular Ischemic Event.

    PubMed

    Kurosaki, Yoshitaka; Yoshida, Kazumichi; Fukuda, Hitoshi; Handa, Akira; Chin, Masaki; Yamagata, Sen

    2017-01-01

    Intraplaque hemorrhage, detected as a high-signal intensity on carotid MRI, is also strongly associated with ischemic events in symptomatic patients. However, in asymptomatic patients, the relationship of the T1-high intense plaque and the subsequent stroke is not clear. The aim of this study is to test the hypothesis that asymptomatic carotid T1-high intense plaque is a risk factor for a subsequent cerebrovascular ischemic event. Of the 1,353 consecutive patients, who underwent head and carotid MRI as part of their annual medical check-up, the imaging quality of 13 was poor and 150 did not present for follow-up examination, thus leaving 1,190 subjects for evaluation. Of the 1,190 patients, 96 patients had findings of high-signal intensity on carotid MRI and 1,094 patients did not. Cerebrovascular events were retrospectively evaluated. During a mean follow-up period of 53 months, 4 patients with high-signal intensities on carotid MRI (4%) and 3 with no findings (0.3%) had a cerebrovascular ischemic event, with the occurrences significantly higher in the high-signal-intensity group. (p < 0.01) Cox regression analysis indicated that the presence of the high-intense plaque on carotid MRI (hazard ratio [HR] 4.2; 95% CI 1.0-17.1; p = 0.04), age (HR 1.1; 95% CI 1.0-1.2; p = 0.003), and diabetes mellitus (HR 7.2; 95% CI 1.8-27.4; p = 0.004) were associated with the occurrence of subsequent ischemic cerebrovascular events. Asymptomatic carotid T1-high-intense plaque might be a potential high-risk factor for a subsequent cerebrovascular ischemic event. © 2017 S. Karger AG, Basel.

  14. [Insulin-like growth factor-binding protein-1: a new biochemical marker of nonalcoholic fatty liver disease?].

    PubMed

    Graffigna, Mabel Nora; Belli, Susana H; de Larrañaga, Gabriela; Fainboim, Hugo; Estepo, Claudio; Peres, Silvia; García, Natalia; Levalle, Oscar

    2009-03-01

    to assess the presence of nonalcoholic fatty liver disease in patients with risk factors for this pathology (obesity, dyslipidemia, metabolic syndrome and diabetes type 2) and to determine the role of insulin, HOMA index, insulin-like growth factor-binding protein-1, sex hormone-binding globulin and plasminogen activator inhibitor type 1, as biochemical markers. Ninety-one patients with risk factors for nonalcoholic fatty liver disease were evaluated. Serum transaminases, insulin, sex hormone-binding globulin, insulin-like growth factor-binding protein-1 and plasminogen activator inhibitor type 1 were measured. The diagnosis of fatty liver was performed by ultrasonography and liver biopsies were performed to 31 subjects who had steatosis by ultrasonography and high alanine aminotransferase. Nonalcoholic fatty liver disease was present in 65 out of 91 patients (71,4%). Liver biopsy performed to 31 subjects confirmed nonalcoholic steatohepatitis. Twenty-five patients had different degrees of fibrosis. Those individuals with fatty liver had higher waist circumference, serum levels of triglycerides, insulin and HOMA index, and lower serum insulin-like growth factor-binding protein-1 concentration. The degree ofhepatic steatosis by ultrasonography was positively correlated to waist circumference, triglycerides, insulin and HOMA index (p<0,003; p<0,003; p<0,002 and p<0,001, respectively), and was negatively correlated to HDL-cholesterol and insulin-like growth factor-binding protein-1 (p<0,025 and p<0,018, respectively). We found a high prevalence of NAFLD in patients with risk factors, most of them overweight or obese. Although SHBG and PAI-1 have a closely relationship to insulin resistance, they did not show to be markers of NAFLD. Regardless of low IGFBP-1 levels associated with NAFLD, serum IGFBP-1 measure is less accessible than insulin and triglycerides levels, HOMA index and waist circumference. Moreover, it is not a better marker for NAFLD than the above

  15. Factors Mediating Seasonal and Influenza A (H1N1) Vaccine Acceptance among Ethnically Diverse Populations in the Urban South

    PubMed Central

    Frew, Paula M.; Painter, Julia E.; Hixson, Brooke; Kulb, Carolyn; Moore, Kathryn; del Rio, Carlos; Esteves-Jaramillo, Alejandra; Omer, Saad B.

    2012-01-01

    Objective We examined the acceptability of the influenza A (H1N1) and seasonal vaccinations immediately following government manufacture approval to gauge potential product uptake in minority communities. We studied correlates of vaccine acceptance including attitudes, beliefs, perceptions, and influenza immunization experiences, and sought to identify communication approaches to increase influenza vaccine coverage in community settings. Methods Adults ≥ 18 years participated in a cross-sectional survey from September through December 2009. Venue-based sampling was used to recruit participants of racial and ethnic minorities. Results The sample (N=503) included mostly lower income (81.9%, n=412) participants and African Americans (79.3%, n=399). Respondents expressed greater acceptability of the H1N1 vaccination compared to seasonal flu immunization (t=2.86, p=0.005) although H1N1 vaccine acceptability was moderately low (38%, n=191). Factors associated with acceptance of the H1N1 vaccine included positive attitudes about immunizations [OR=0.23, CI (0.16, 0.33)], community perceptions of H1N1 [OR=2.15, CI (1.57, 2.95)], and having had a flu shot in the past 5 years [OR=2.50, CI (1.52, 4.10). The factors associated with acceptance of the seasonal flu vaccine included positive attitudes about immunization [OR=0.43, CI (0.32, 0.59)], community perceptions of H1N1 [OR=1.53, CI (1.16, 2.01)], and having had the flu shot in the past 5 years [OR=3.53, CI (2.16, 5.78)]. Participants were most likely to be influenced to take a flu shot by physicians [OR=1.94, CI (1.31, 2.86)]. Persons who obtained influenza vaccinations indicated that Facebook (χ2=11.7, p=.02) and Twitter (χ2=18.1, p=.001) could be useful vaccine communication channels and that churches (χ2=21.5, p<.001) and grocery stores (χ2=21.5, p<.001) would be effective “flu shot stops” in their communities. Conclusions In this population, positive vaccine attitudes and community perceptions, along with

  16. CYP1A1, GSTM1, GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

    PubMed Central

    Hamachi, Tadamichi; Tajima, Osamu; Uezono, Kousaku; Tabata, Shinji; Abe, Hiroshi; Ohnaka, Keizo; Kono, Suminori

    2013-01-01

    AIM: To investigate the role of functional genetic polymorphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied were CYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other lifestyle factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1. A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual

  17. A Low-Voltage Chopper-Stabilized Amplifier for Fetal ECG Monitoring With a 1.41 Power Efficiency Factor.

    PubMed

    Song, Shuang; Rooijakkers, Michael; Harpe, Pieter; Rabotti, Chiara; Mischi, Massimo; van Roermund, Arthur H M; Cantatore, Eugenio

    2015-04-01

    This paper presents a low-voltage current-reuse chopper-stabilized frontend amplifier for fetal ECG monitoring. The proposed amplifier allows for individual tuning of the noise in each measurement channel, minimizing the total power consumption while satisfying all application requirements. The low-voltage current reuse topology exploits power optimization in both the current and the voltage domain, exploiting multiple supply voltages (0.3, 0.6 and 1.2 V). The power management circuitry providing the different supplies is optimized for high efficiency (peak charge-pump efficiency = 90%).The low-voltage amplifier together with its power management circuitry is implemented in a standard 0.18 μm CMOS process and characterized experimentally. The amplifier core achieves both good noise efficiency factor (NEF=1.74) and power efficiency factor (PEF=1.05). Experiments show that the amplifier core can provide a noise level of 0.34 μVrms in a 0.7 to 182 Hz band, consuming 1.17 μW power. The amplifier together with its power management circuitry consumes 1.56 μW, achieving a PEF of 1.41. The amplifier is also validated with adult ECG and pre-recorded fetal ECG measurements.

  18. Significance of the interleukin-1 receptor antagonist/interleukin-1 beta ratio as a prognostic factor in patients with pulmonary sarcoidosis.

    PubMed

    Mikuniya, T; Nagai, S; Takeuchi, M; Mio, T; Hoshino, Y; Miki, H; Shigematsu, M; Hamada, K; Izumi, T

    2000-01-01

    Various factors such as serum angiotensin-converting enzyme (sACE) activity, bronchoalveolar lavage (BAL) fluid lymphocyte percent, CD4/CD8 ratio, and shadows on chest radiograph have been identified as indexes of disease activity in patients with sarcoidosis. However, it remains to be confirmed whether these factors can predict clinical outcomes. To examine whether the interleukin-1 receptor antagonist (IL-1ra)/IL-1 beta ratio can predict the clinical course, we prospectively followed the clinical courses of 30 patients with pulmonary sarcoidosis 4 years after measurement of immunoreactive amounts of IL-1ra or IL-1 beta in the culture supernatants obtained from BAL fluid macrophages. Immunoreactive amounts of IL-1ra or IL-1 beta were measured using ELISA. Changes in pulmonary function, sACE activity, and shadows on chest radiographs during observation periods were evaluated as markers of changes in disease activity. We found that the patients whose shadows on chest radiographs showed improvement had a higher molar IL-1ra/IL-1 beta ratio than the patients whose shadows persistently remained 4 years after BAL examination (p < 0.05). The molar ratio was found to be positively correlated with improvement of percent vital capacity (p < 0.05) and negatively correlated with the ratio of sACE activity at the time of the last observation to sACE activity at the time of BAL (sACE(LAST)/sACE(BAL), p < 0.01). The sACE(LAST)/sACE(BAL) ratio was significantly lower in patients whose shadows on chest radiographs decreased than in those whose shadows remained unchanged (p < 0.005). The IL-1ra/IL-1 beta ratio in the BAL fluid macrophage culture supernatants in patients with pulmonary sarcoidosis could be a useful marker in predicting the persistence of granulomatous lesions (chronicity). Copyright 2000 S. Karger AG, Basel

  19. Adenovirus E1A and E1B-19K Proteins Protect Human Hepatoma Cells from Transforming Growth Factor β1-induced Apoptosis

    PubMed Central

    Tarakanova, Vera L.; Wold, William S. M.

    2009-01-01

    Primary and some transformed hepatocytes undergo apoptosis in response to transforming growth factor β1 (TGFβ). We report that infection with species C human adenovirus conferred resistance to TGFβ-induced apoptosis in human hepatocellular carcinoma cells (Huh-7). Protection against TGFβ-mediated cell death in adenovirus-infected cells correlated with the maintenance of normal nuclear morphology, lack of pro-caspases 8 and 3 processing, maintenance of the mitochondrial membrane potential, and lack of cellular DNA degradation. The TGFβ pro-apoptotic signaling pathway was blocked upstream of mitochondria in adenovirus-infected cells. Both the N-terminal sequences of the E1A proteins and the E1B-19K protein were necessary to protect infected cells against TGFβ-induced apoptosis. PMID:19854227

  20. Investigation of hypoxia-inducible factor-1α in hippocampal sclerosis: a postmortem study.

    PubMed

    Feast, Alexandra; Martinian, Lillian; Liu, Joan; Catarino, Claudia B; Thom, Maria; Sisodiya, Sanjay M

    2012-08-01

    Hypoxia-inducible factor-1α (HIF-1α) is involved in critical aspects of cell survival in response to hypoxia and regulates vascular endothelial growth factor (VEGF) expression. Previous experimental and human studies in epilepsy show up-regulation of VEGF following seizures, although expression of HIF-1α as its potential regulator has not been explored. We used a postmortem (PM) series from patients with epilepsy and hippocampal sclerosis (HS) to investigate patterns of expression of HIF-1α and VEGF and their potential contribution to neuroprotection. In 33 PMs (17 cases with unilateral HS, 3 with bilateral HS, 3 with No-HS, and 10 controls), we quantified neuronal immunolabeling for HIF-1α and VEGF in hippocampal subfields. HIF-1α- and VEGF-immunopositive hippocampal neurones were observed in HS, No-HS, and also in control cases; there was no significant difference in overall labeling between epilepsy cases and controls. In positive cases, HIF-1α and VEGF neuronal labeling localized primarily in CA1, CA4, and CA3 subfields in all groups; significantly more positive neurons were seen in the entorhinal cortex in epilepsy cases (p < 0.05). Labeling lateralized to the side of sclerosis in unilateral HS cases, with significant differences between hemispheres (p < 0.05). There was a trend for high HIF-1α labeling scores in patients with Dravet syndrome without HS and sudden unexpected death in epilepsy (SUDEP) cases, and lower scores with long seizure-free periods prior to death. Hippocampal HIF-1α and VEGF labeling showed a significant correlation. There was neuronal colocalization of HIF-1α and VEGF. Regional expression patterns are in keeping with seizure-related activation of HIF-1α and VEGF. The prominent expression in non-HS cases could support an overall neuroprotective effect. Correlation between HIF-1α and VEGF neuronal immunolabeling supports HIF-1α-mediated induction of VEGF in epilepsy. Wiley Periodicals, Inc. © 2012 International League

  1. Psychosocial family factors and glycemic control among children aged 1-15 years with type 1 diabetes: a population-based survey.

    PubMed

    Haugstvedt, Anne; Wentzel-Larsen, Tore; Rokne, Berit; Graue, Marit

    2011-12-20

    Being the parents of children with diabetes is demanding. Jay Belsky's determinants of parenting model emphasizes both the personal psychological resources, the characteristics of the child and contextual sources such as parents' work, marital relations and social network support as important determinants for parenting. To better understand the factors influencing parental functioning among parents of children with type 1 diabetes, we aimed to investigate associations between the children's glycated hemoglobin (HbA1c) and 1) variables related to the parents' psychological and contextual resources, and 2) frequency of blood glucose measurement as a marker for diabetes-related parenting behavior. Mothers (n = 103) and fathers (n = 97) of 115 children younger than 16 years old participated in a population-based survey. The questionnaire comprised the Life Orientation Test, the Oslo 3-item Social Support Scale, a single question regarding perceived social limitation because of the child's diabetes, the Relationship Satisfaction Scale and demographic and clinical variables. We investigated associations by using regression analysis. Related to the second aim hypoglycemic events, child age, diabetes duration, insulin regimen and comorbid diseases were included as covariates. The mean HbA1c was 8.1%, and 29% had HbA1c ≤ 7.5%. In multiple regression analysis, lower HbA1c was associated with higher education and stronger perceptions of social limitation among the mothers. A higher frequency of blood glucose measurement was significantly associated with lower HbA1c in bivariate analysis. Higher child age was significantly associated with higher HbA1c both in bivariate and multivariate analysis. A scatterplot indicated this association to be linear. Most families do not reach recommended treatment goals for their child with type 1 diabetes. Concerning contextual sources of stress and support, the families who successfully reached the treatment goals had mothers with higher

  2. USF-related transcription factor, HIV-TF1, stimulates transcription of human immunodeficiency virus-1.

    PubMed

    Maekawa, T; Sudo, T; Kurimoto, M; Ishii, S

    1991-09-11

    The transcription factor HIV-TF1, which binds to a region about 60 bp upstream from the enhancer of the human immunodeficiency virus-1 (HIV-1), was purified from human B cells. HIV-TF1 had a molecular weight of 39,000. Binding of HIV-TF1 to the HIV long terminal repeat (LTR) activated transcription from the HIV promoter in vitro. The HIV-TF1-binding site in HIV LTR was similar to the site recognized by upstream stimulatory factor (USF) in the adenovirus major late promoter. DNA-binding properties of HIV-TF1 suggested that HIV-TF1 might be identical or related to USF. Interestingly, treatment of purified HIV-TF1 by phosphatase greatly reduced its DNA-binding activity, suggesting that phosphorylation of HIV-TF1 was essential for DNA binding. The disruption of HIV-TF1-binding site induced a 60% decrease in the level of transcription from the HIV promoter in vivo. These results suggest that HIV-TF1 is involved in transcriptional regulation of HIV-1.

  3. A novel polymorphism in the PAI-1 gene promoter enhances gene expression. A novel pro-thrombotic risk factor?

    PubMed

    Liguori, Renato; Quaranta, Sandro; Di Fiore, Rosanna; Elce, Ausilia; Castaldo, Giuseppe; Amato, Felice

    2014-12-01

    Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of tissue-type plasminogen activator in plasma and the most important regulator of the fibrinolytic pathway. The 4G/5G polymorphism (rs1799889) in the PAI-1 promoter is associated with altered PAI-1 transcription. We have identified a new 4G/5G allele, in which a T is inserted near the 4G tract or replaces a G in the 5G tract, forming a T plus 4G (T4G) region. This new variant was first identified in two women, one had experienced juvenile myocardial infarction, the other repeated miscarriage; both had increased PAI-1 plasma activity. In view of the important influence of this promoter region on PAI-1 protein plasma level, we performed in vitro evaluation of the effects of the T4G variant on the transcription activity of the PAI-1 gene promoter. In silico prediction analysis showed that presence of the T4G allele disrupts the E-Box region upstream of the T4G variant, altering the affinity of the target sequence for E-Box binding factors like upstream stimulatory factor-1 (USF-1). Basal T4G promoter activity was 50% higher compared to 4G and 5G variants, but it was less stimulated by USF-1 overexpression. We also analyzed the effects of IL-1β and IL-6 on the PAI-1 promoter activity of our three constructs and showed that the T4G variant was less affected by IL-1β than the other variants. These findings indicate that the T4G variant may be a novel risk factor for thrombotic events. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Social factors related to the clinical severity of influenza cases in Spain during the A (H1N1) 2009 virus pandemic

    PubMed Central

    2013-01-01

    Background During the 2009 influenza pandemic, a change in the type of patients most often affected by influenza was observed. The objective of this study was to assess the role of individual and social determinants in hospitalizations due to influenza A (H1N1) 2009 infection. Methods We studied hospitalized patients (cases) and outpatients (controls) with confirmed influenza A (H1N1) 2009 infection. A standardized questionnaire was used to collect data. Variables that might be related to the hospitalization of influenza cases were compared by estimation of the odds ratio (OR) and 95% confidence intervals (CI) and the variables entered into binomial logistic regression models. Results Hospitalization due to pandemic A (H1N1) 2009 influenza virus infections was associated with non-Caucasian ethnicity (OR: 2.18, 95% CI 1.17 − 4.08), overcrowding (OR: 2.84, 95% CI 1.20 − 6.72), comorbidity and the lack of previous preventive information (OR: 2.69, 95% CI: 1.50 − 4.83). Secondary or higher education was associated with a lower risk of hospitalization (OR 0.56, 95% CI: 0.36 − 0.87) Conclusions In addition to individual factors such as comorbidity, other factors such as educational level, ethnicity or overcrowding were associated with hospitalization due to A (H1N1) 2009 influenza virus infections. PMID:23391376

  5. Dexras1 links glucocorticoids to insulin-like growth factor-1 signaling in adipogenesis

    PubMed Central

    Kim, Hyo Jung; Cha, Jiyoung Y.; Seok, Jo Woon; Choi, Yoonjeong; Yoon, Bo Kyung; Choi, Hyeonjin; Yu, Jung Hwan; Song, Su Jin; Kim, Ara; Lee, Hyemin; Kim, Daeun; Han, Ji Yoon; Kim, Jae-woo

    2016-01-01

    Glucocorticoids are associated with obesity, but the underlying mechanism by which they function remains poorly understood. Previously, we showed that small G protein Dexras1 is expressed by glucocorticoids and leads to adipocyte differentiation. In this study, we explored the mechanism by which Dexras1 mediates adipogenesis and show a link to the insulin-like growth factor-1 (IGF-1) signaling pathway. Without Dexras1, the activation of MAPK and subsequent phosphorylation of CCAAT/enhancer binding protein β (C/EBPβ) is abolished, thereby inhibiting mitotic clonal expansion and further adipocyte differentiation. Dexras1 translocates to the plasma membrane upon insulin or IGF-1 treatment, for which the unique C-terminal domain (amino acids 223–276) is essential. Dexras1-dependent MAPK activation is selectively involved in the IGF-1 signaling, because another Ras protein, H-ras localized to the plasma membrane independently of insulin treatment. Moreover, neither epidermal growth factor nor other cell types shows Dexras1-dependent MAPK activation, indicating the importance of Dexras1 in IGF-1 signaling in adipogenesis. Dexras1 interacts with Shc and Raf, indicating that Dexras1-induced activation of MAPK is largely dependent on the Shc-Grb2-Raf complex. These results suggest that Dexras1 is a critical mediator of the IGF-1 signal to activate MAPK, linking glucocorticoid signaling to IGF-1 signaling in adipogenesis. PMID:27345868

  6. Mit1 Transcription Factor Mediates Methanol Signaling and Regulates the Alcohol Oxidase 1 (AOX1) Promoter in Pichia pastoris*

    PubMed Central

    Wang, Xiaolong; Wang, Qi; Wang, Jinjia; Bai, Peng; Shi, Lei; Shen, Wei; Zhou, Mian; Zhou, Xiangshan; Zhang, Yuanxing; Cai, Menghao

    2016-01-01

    The alcohol oxidase 1 (AOX1) promoter (PAOX1) of Pichia pastoris is the most powerful and commonly used promoter for driving protein expression. However, mechanisms regulating its transcriptional activity are unclear. Here, we identified a Zn(II)2Cys6-type methanol-induced transcription factor 1 (Mit1) and elucidated its roles in regulating PAOX1 activity in response to glycerol and methanol. Mit1 regulated the expression of many genes involved in methanol utilization pathway, including AOX1, but did not participate in peroxisome proliferation and transportation of peroxisomal proteins during methanol metabolism. Structural analysis of Mit1 by performing domain deletions confirmed its specific and critical role in the strict repression of PAOX1 in glycerol medium. Importantly, Mit1, Mxr1, and Prm1, which positively regulated PAOX1 in response to methanol, were bound to PAOX1 at different sites and did not interact with each other. However, these factors cooperatively activated PAOX1 through a cascade. Mxr1 mainly functioned during carbon derepression, whereas Mit1 and Prm1 functioned during methanol induction, with Prm1 transmitting methanol signal to Mit1 by binding to the MIT1 promoter (PMIT1), thus increasingly expressing Mit1 and subsequently activating PAOX1. PMID:26828066

  7. Interaction of the Transcription Start Site Core Region and Transcription Factor YY1 Determine Ascorbate Transporter SVCT2 Exon 1a Promoter Activity

    PubMed Central

    Qiao, Huan; May, James M.

    2012-01-01

    Transcription of the ascorbate transporter, SVCT2, is driven by two distinct promoters in exon 1 of the transporter sequence. The exon 1a promoter lacks a classical transcription start site and little is known about regulation of promoter activity in the transcription start site core (TSSC) region. Here we present evidence that the TSSC binds the multifunctional initiator-binding protein YY1. Electrophoresis shift assays using YY1 antibody showed that YY1 is present as one of two major complexes that specifically bind to the TSSC. The other complex contains the transcription factor NF-Y. Mutations in the TSSC that decreased YY1 binding also impaired the exon 1a promoter activity despite the presence of an upstream activating NF-Y/USF complex, suggesting that YY1 is involved in the regulation of the exon 1a transcription. Furthermore, YY1 interaction with NF-Y and/or USF synergistically enhanced the exon 1a promoter activity in transient transfections and co-activator p300 enhanced their synergistic activation. We propose that the TSSC plays a vital role in the exon 1a transcription and that this function is partially carried out by the transcription factor YY1. Moreover, co-activator p300 might be able to synergistically enhance the TSSC function via a “bridge” mechanism with upstream sequences. PMID:22532872

  8. Heterogeneity of the Stearoyl-CoA desaturase-1 (SCD1) Gene and Metabolic Risk Factors in the EPIC-Potsdam Study

    PubMed Central

    Arregui, Maria; Buijsse, Brian; Stefan, Norbert; Corella, Dolores; Fisher, Eva; di Giuseppe, Romina; Coltell, Oscar; Knüppel, Sven; Aleksandrova, Krasimira; Joost, Hans-Georg; Boeing, Heiner; Weikert, Cornelia

    2012-01-01

    Background Stearoyl-CoA desaturase-1 (SCD1) is an enzyme involved in lipid metabolism. In mice and humans its activity has been associated with traits of the metabolic syndrome, but also with the prevention of saturated fatty acids accumulation and subsequent inflammation, whereas for liver fat content inconsistent results have been reported. Thus, variants of the gene encoding SCD1 (SCD1) could potentially modify metabolic risk factors, but few human studies have addressed this question. Methods In a sample of 2157 middle-aged men and women randomly drawn from the Potsdam cohort of the European Prospective Investigation into Cancer and Nutrition, we investigated the impact of 7 SCD1 tagging-single nucleotide polymorphisms (rs1502593, rs522951, rs11190480, rs3071, rs3793767, rs10883463 and rs508384) and 5 inferred haplotypes with frequency >5% describing 90.9% of the genotype combinations in our population, on triglycerides, body mass index (BMI), waist circumference (WC), glycated haemoglobin (HbA1c), high-sensitivity C-reactive protein (hs-CRP), gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT) and fetuin-A. Results No significant associations between any of the SNPs or haplotypes and BMI, WC, fetuin-A and hs-CRP were observed. Associations of rs10883463 with triglycerides, GGT and HbA1c as well as of rs11190480 with ALT activity, were weak and became non-significant after multiple-testing correction. Also associations of the haplotype harbouring the minor allele of rs1502593 with HbA1c levels, the haplotype harbouring the minor alleles of rs11190480 and rs508384 with activity of ALT, and the haplotype harbouring the minor alleles of rs522951, rs10883463 and rs508384 with triglyceride and HbA1C levels and GGT activities did not withstand multiple-testing correction. Conclusion These findings suggest that there are no associations between common variants of SCD1 or its inferred haplotypes and the investigated metabolic risk factors. However, given

  9. Hypoxia-Inducible Factor-1α Polymorphisms and Risk of Cancer Metastasis: A Meta-Analysis

    PubMed Central

    Shi, Bin; Weng, Wenjun; Chen, Zhipeng; Guo, Nannan; Hua, Yibing; Zhu, Lingjun

    2013-01-01

    Background HIF-1α is a major regulator in tumor progression and metastasis which responds to hypoxia. Many studies have demonstrated that hypoxia-inducible factor1-α (HIF-1α) polymorphisms are significantly associated with cancer metastasis, but the results are inconsistent. We conducted a comprehensive meta-analysis to estimate the associations between HIF-1α C1772 T polymorphism and cancer metastasis. Methods Comprehensive searches were conducted on PubMed and EMBASE database. Fifteen studies were included in the meta-analysis. We used the OR and 95%CI to assess the associations between HIF-1α C1772T polymorphism and cancer metastasis. Heterogeneity and publication bias were also assessed by Q test, I 2, and funnel plot. Results Totally, fifteen studies including 1239 cases with metastasis-positive (M+) and 2711 cases with metastasis-negative (M−) were performed in this meta-analysis. The results showed that HIF-1a C1772T polymorphism was associated with the increased risk of cancer metastasis (T allele vs. C allele, OR  = 1.36, 95% CI  = 1.12–1.64; TT+ TC vs. CC, OR  = 1.39, 95% CI  = 1.13–1.71; TT vs. TC+ CC, OR  = 1.93, 95% CI  = 0.86–4.36). In the subgroup analyses, the significant associations remained significant among Asians, Caucasians and other cancers in the dominant model. Publication bias was not observed in the analysis. Conclusions Our results indicate that the HIF-1αC1772T polymorphism T allele may increase the risk of cancer metastasis, which might be a potential risk factor of cancer progress. PMID:24015181

  10. Daintain/AIF-1 (Allograft Inflammatory Factor-1) accelerates type 1 diabetes in NOD mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhao, Yan-Ying, E-mail: biozyy@163.com; Huang, Xin-Yuan; Chen, Zheng-Wang

    Highlights: Black-Right-Pointing-Pointer Daintain/AIF-1 is over-expressed in the blood of NOD mice suffering from insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 stimulates white blood cell proliferation in NOD mice. Black-Right-Pointing-Pointer Daintain/AIF-1 increases blood glucose levels and triggers type 1 diabetes. Black-Right-Pointing-Pointer Daintain/AIF-1 accelerates insulitis, while its antibody prevents insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 enhances the levels of nitric oxide in the pancreases of NOD mice. -- Abstract: A large body of experimental evidence suggests that cytokines trigger pancreatic {beta}-cell death in type 1 diabetes mellitus. Daintain/AIF-1 (Allograft Inflammatory Factor-1), a specific marker for activated macrophages, is accumulated in the pancreatic islets of pre-diabetic BB rats. In themore » present study, we demonstrate that daintain/AIF-1 is released into blood and the levels of daintain/AIF-1 in the blood of type 1 diabetes-prone non-obese diabetic (NOD) mice suffering from insulitis are significantly higher than that in healthy NOD mice. When injected intravenously into NOD mice, daintain/AIF-1 stimulates white blood cell proliferation, increases the concentrations of blood glucose, impairs insulin expression, up-regulates nitric oxide (NO) production in pancreases and accelerates diabetes in NOD mice, while the antibody against daintain/AIF-1 delays or prevents insulitis in NOD mice. These results imply daintain/AIF-1 triggers type 1 diabetes probably via arousing immune cells activation and induction of NO production in pancreas of NOD mice.« less

  11. Opposite Effects of Dihydrosphingosine 1-Phosphate and Sphingosine 1-Phosphate on Transforming Growth Factor-β/Smad Signaling Are Mediated through the PTEN/PPM1A-dependent Pathway*S⃞

    PubMed Central

    Bu, Shizhong; Kapanadze, Bagrat; Hsu, Tien; Trojanowska, Maria

    2008-01-01

    Transforming growth factor-β (TGF-β) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-β through cross-activation of Smad signaling. Here we report that another product of sphingosine kinase, dihydrosphingosine 1-phosphate (dhS1P), has an opposite role in the regulation of TGF-β signaling. In contrast to S1P, dhS1P inhibits TGF-β-induced Smad2/3 phosphorylation and up-regulation of collagen synthesis. The effects of dhS1P require a lipid phosphatase, PTEN, a key modulator of cell growth and survival. dhS1P stimulates phosphorylation of the C-terminal domain of PTEN and its subsequent translocation into the nucleus. We demonstrate a novel function of nuclear PTEN as a co-factor of the Smad2/3 phosphatase, PPM1A. Complex formation of PTEN with PPM1A does not require the lipid phosphatase activity but depends on phosphorylation of the serine/threonine residues located in the C-terminal domain of PTEN. Upon complex formation with PTEN, PPM1A is protected from degradation induced by the TGF-β signaling. Consequently, overexpression of PTEN abrogates TGF-β-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. PTEN-mediated cross-talk between the sphingolipid and TGF-β signaling pathways may play an important role in physiological and pathological TGF-β signaling. PMID:18482992

  12. The Ethylene Responsive Factor Required for Nodulation 1 (ERN1) Transcription Factor Is Required for Infection-Thread Formation in Lotus japonicus.

    PubMed

    Kawaharada, Yasuyuki; James, Euan K; Kelly, Simon; Sandal, Niels; Stougaard, Jens

    2017-03-01

    Several hundred genes are transcriptionally regulated during infection-thread formation and development of nitrogen-fixing root nodules. We have characterized a set of Lotus japonicus mutants impaired in root-nodule formation and found that the causative gene, Ern1, encodes a protein with a characteristic APETALA2/Ethylene Responsive Factor (AP2/ERF) transcription-factor domain. Phenotypic characterization of four ern1 alleles shows that infection pockets are formed but root-hair infection threads are absent. Formation of root-nodule primordia is delayed and no normal transcellular infection threads are found in the infected nodules. Corroborating the role of ERN1 (ERF Required for Nodulation1) in nodule organogenesis, spontaneous nodulation induced by an autoactive CCaMK and cytokinin-induced nodule primordia were not observed in ern1 mutants. Expression of Ern1 is induced in the susceptible zone by Nod factor treatment or rhizobial inoculation. At the cellular level, the pErn1:GUS reporter is highly expressed in root epidermal cells of the susceptible zone and in the cortical cells that form nodule primordia. The genetic regulation of this cellular expression pattern was further investigated in symbiotic mutants. Nod factor induction of Ern1 in epidermal cells was found to depend on Nfr1, Cyclops, and Nsp2 but was independent of Nin and Nf-ya1. These results suggest that ERN1 functions as a transcriptional regulator involved in the formation of infection threads and development of nodule primordia and may coordinate these two processes.

  13. Capsicum annuum homeobox 1 (CaHB1) is a nuclear factor that has roles in plant development, salt tolerance, and pathogen defense

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Oh, Sang-Keun; Yoon, Joonseon; Choi, Gyung Ja

    Highlights: •The CaHB1 is a nuclear factor, belonging to HD-Zip proteins. •SA and ET, as signal molecules, modulate CaHB1-mediated responses. •Overexpression of CaHB1 in tomato resulted in a thicker cell wall. •CaHB1-transgenic tomato confers resistance to Phytophthora infestans. •CaHB1 enhanced tolerance to saline stress in tomato. -- Abstract: Homeodomain-leucine zipper (HD-Zip) family proteins are unique to plants, but little is known about their role in defense responses. CaHB1 is a nuclear factor in peppers, belonging to subfamily II of HD-Zip proteins. Here, we determined the role of CaHB1 in the defense response. CaHB1 expression was induced when pepper plants weremore » challenged with Phytophthora capsici, a plant pathogen to which peppers are susceptible, or environmental stresses such as drought and salt stimuli. CaHB1 was also highly expressed in pepper leaves following application of SA, whereas ethephon and MeJA had a moderate effect. To further investigate the function of CaHB1 in plants, we performed gain-of-function study by overexpression of CaHB1 in tomato. CaHB1-transgenic tomatoes showed significant growth enhancement including increased leaf thickness and enlarged cell size (1.8-fold larger than control plants). Microscopic analysis revealed that leaves from CaHB1-transgenic plants had thicker cell walls and cuticle layers than those from controls. Moreover, CaHB1-transgenic plants displayed enhanced resistance against Phytophthora infestans and increased tolerance to salt stress. Additionally, RT-PCR analysis of CaHB1-transgenic tomatoes revealed constitutive up-regulation of multiple genes involved in plant defense and osmotic stress. Therefore, our findings suggest roles for CaHB1 in development, salt stress, and pathogen defense.« less

  14. Alcohol induces synaptotagmin 1 expression in neurons via activation of heat shock factor 1.

    PubMed

    Varodayan, F P; Pignataro, L; Harrison, N L

    2011-10-13

    Many synapses within the central nervous system are sensitive to ethanol. Although alcohol is known to affect the probability of neurotransmitter release in specific brain regions, the effects of alcohol on the underlying synaptic vesicle fusion machinery have been little studied. To identify a potential pathway by which ethanol can regulate neurotransmitter release, we investigated the effects of acute alcohol exposure (1-24 h) on the expression of the gene encoding synaptotagmin 1 (Syt1), a synaptic protein that binds calcium to directly trigger vesicle fusion. Syt1 was identified in a microarray screen as a gene that may be sensitive to alcohol and heat shock. We found that Syt1 mRNA and protein expression are rapidly and robustly up-regulated by ethanol in mouse cortical neurons, and that the distribution of Syt1 protein along neuronal processes is also altered. Syt1 mRNA up-regulation is dependent on the activation of the transcription factor heat shock factor 1 (HSF1). The transfection of a constitutively active Hsf1 construct into neurons stimulates Syt1 transcription, while transfection of Hsf1 small interfering RNA (siRNA) or a constitutively inactive Hsf1 construct into neurons attenuates the induction of Syt1 by ethanol. This suggests that the activation of HSF1 can induce Syt1 expression and that this may be a mechanism by which alcohol regulates neurotransmitter release during brief exposures. Further analysis revealed that a subset of the genes encoding the core synaptic vesicle fusion (soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor; SNARE) proteins share this property of induction by ethanol, suggesting that alcohol may trigger a specific coordinated adaptation in synaptic function. This molecular mechanism could explain some of the changes in synaptic function that occur following alcohol administration and may be an important step in the process of neuronal adaptation to alcohol. Copyright © 2011 IBRO. Published by

  15. Environmental Risk Factors for Type 1 Diabetes Mellitus Development.

    PubMed

    Antonela, Boljat; Ivana, Gunjača; Ivan, Konstantinović; Nikolina, Vidan; Vesna, Boraska Perica; Marina, Pehlić; Veselin, Škrabić; Tatijana, Zemunik

    2017-09-01

    Background Although environmental factors induce development of type 1 diabetes mellitus (T1DM) in genetically susceptible individuals, many of those factors have been uncovered. Therefore, the aim of the present study was to analyze associations of T1DM with a wide range of environmental factors. Material and Methods A case-control study was conducted on 249 diabetic and 255 healthy individuals from the Dalmatian region of South Croatia. Data regarding risk factors during pregnancy and early life period of the child were evaluated. Results History of antihypertensive intake ( p =0.04) and frequency of stressful life events during pregnancy ( p =0.01) were associated with higher risk of T1DM, while hypertension was associated with lower risk of T1DM ( p =0.01). Maternal age<25 years at delivery was associated with a higher risk of T1DM ( p =0.01).Diabetic patients had a positive family history of T1DM or T2DM ( p =0.002) more frequently than controls, while history of infectious diseases was inversely associated with the risk of T1DM ( p =0.03). A higher risk of T1DM was significantly associated with earlier introduction of cow's milk ( p =0.001), higher number of meals consumed per day ( p =0.02), higher frequency of carbohydrate ( p =0.001) and meat ( p =0.01) consumption and stressful life events during childhood ( p =0.02) while earlier introduction of fruit was associated with a lower risk of T1DM ( p =0.03) Conclusion This case-control study confirmed associations of a large number of environmental factors with development of T1DM with emphasis on the association of mother's antihypertensive intake during pregnancy, which extends our knowledge about environmental factors related with development of T1DM. © Georg Thieme Verlag KG Stuttgart · New York.

  16. Transcription Factor Interplay between LEAFY and APETALA1/CAULIFLOWER during Floral Initiation1

    PubMed Central

    Zheng, Beibei; Kwaśniewska, Kamila; Thomson, Bennett

    2017-01-01

    The transcription factors LEAFY (LFY) and APETALA1 (AP1), together with the AP1 paralog CAULIFLOWER (CAL), control the onset of flower development in a partially redundant manner. This redundancy is thought to be mediated, at least in part, through the regulation of a shared set of target genes. However, whether these genes are independently or cooperatively regulated by LFY and AP1/CAL is currently unknown. To better understand the regulatory relationship between LFY and AP1/CAL and to obtain deeper insights into the control of floral initiation, we monitored the activity of LFY in the absence of AP1/CAL function. We found that the regulation of several known LFY target genes is unaffected by AP1/CAL perturbation, while others appear to require AP1/CAL activity. Furthermore, we obtained evidence that LFY and AP1/CAL control the expression of some genes in an antagonistic manner. Notably, these include key regulators of floral initiation such as TERMINAL FLOWER1 (TFL1), which had been previously reported to be directly repressed by both LFY and AP1. We show here that TFL1 expression is suppressed by AP1 but promoted by LFY. We further demonstrate that LFY has an inhibitory effect on flower formation in the absence of AP1/CAL activity. We propose that LFY and AP1/CAL act as part of an incoherent feed-forward loop, a network motif where two interconnected pathways or transcription factors act in opposite directions on a target gene, to control the establishment of a stable developmental program for the formation of flowers. PMID:28385730

  17. Novel host restriction factors implicated in HIV-1 replication.

    PubMed

    Ghimire, Dibya; Rai, Madhu; Gaur, Ritu

    2018-04-01

    Human immunodeficiency virus-1 (HIV-1) is known to interact with multiple host cellular proteins during its replication in the target cell. While many of these host cellular proteins facilitate viral replication, a number of them are reported to inhibit HIV-1 replication at various stages of its life cycle. These host cellular proteins, which are known as restriction factors, constitute an integral part of the host's first line of defence against the viral pathogen. Since the discovery of apolipoprotein B mRNA-editing enzyme 3G (APOBEC3G) as an HIV-1 restriction factor, several human proteins have been identified that exhibit anti-HIV-1 restriction. While each restriction factor employs a distinct mechanism of inhibition, the HIV-1 virus has equally evolved complex counter strategies to neutralize their inhibitory effect. APOBEC3G, tetherin, sterile alpha motif and histidine-aspartate domain 1 (SAMHD1), and trim-5α are some of the best known HIV-1 restriction factors that have been studied in great detail. Recently, six novel restriction factors were discovered that exhibit significant antiviral activity: endoplasmic reticulum α1,2-mannosidase I (ERManI), translocator protein (TSPO), guanylate-binding protein 5 (GBP5), serine incorporator (SERINC3/5) and zinc-finger antiviral protein (ZAP). The focus of this review is to discuss the antiviral mechanism of action of these six restriction factors and provide insights into the probable counter-evasion strategies employed by the HIV-1 virus. The recent discovery of new restriction factors substantiates the complex host-pathogen interactions occurring during HIV-1 pathogenesis and makes it imperative that further investigations are conducted to elucidate the molecular basis of HIV-1 replication.

  18. Mit1 Transcription Factor Mediates Methanol Signaling and Regulates the Alcohol Oxidase 1 (AOX1) Promoter in Pichia pastoris.

    PubMed

    Wang, Xiaolong; Wang, Qi; Wang, Jinjia; Bai, Peng; Shi, Lei; Shen, Wei; Zhou, Mian; Zhou, Xiangshan; Zhang, Yuanxing; Cai, Menghao

    2016-03-18

    The alcohol oxidase 1 (AOX1) promoter (P AOX1) of Pichia pastoris is the most powerful and commonly used promoter for driving protein expression. However, mechanisms regulating its transcriptional activity are unclear. Here, we identified a Zn(II)2Cys6-type methanol-induced transcription factor 1 (Mit1) and elucidated its roles in regulating PAOX1 activity in response to glycerol and methanol. Mit1 regulated the expression of many genes involved in methanol utilization pathway, including AOX1, but did not participate in peroxisome proliferation and transportation of peroxisomal proteins during methanol metabolism. Structural analysis of Mit1 by performing domain deletions confirmed its specific and critical role in the strict repression of P AOX1 in glycerol medium. Importantly, Mit1, Mxr1, and Prm1, which positively regulated P AOX1 in response to methanol, were bound to P AOX1 at different sites and did not interact with each other. However, these factors cooperatively activated P AOX1 through a cascade. Mxr1 mainly functioned during carbon derepression, whereas Mit1 and Prm1 functioned during methanol induction, with Prm1 transmitting methanol signal to Mit1 by binding to the MIT1 promoter (P MIT1), thus increasingly expressing Mit1 and subsequently activating P AOX1. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Natural product-derived small molecule activators of hypoxia-inducible factor-1 (HIF-1).

    PubMed

    Nagle, Dale G; Zhou, Yu-Dong

    2006-01-01

    Hypoxia-inducible factor-1 (HIF-1) is a key mediator of oxygen homeostasis that was first identified as a transcription factor that is induced and activated by decreased oxygen tension. Upon activation, HIF-1 upregulates the transcription of genes that promote adaptation and survival under hypoxic conditions. HIF-1 is a heterodimer composed of an oxygen-regulated subunit known as HIF-1alpha and a constitutively expressed HIF-1beta subunit. In general, the availability and activity of the HIF-1alpha subunit determines the activity of HIF-1. Subsequent studies have revealed that HIF-1 is also activated by environmental and physiological stimuli that range from iron chelators to hormones. Preclinical studies suggest that HIF-1 activation may be a valuable therapeutic approach to treat tissue ischemia and other ischemia/hypoxia-related disorders. The focus of this review is natural product-derived small molecule HIF-1 activators. Natural products, relatively low molecular weight organic compounds produced by plants, animals, and microbes, have been and continue to be a major source of new drugs and molecular probes. The majority of known natural product-derived HIF-1 activators were discovered through the pharmacological evaluation of specifically selected individual compounds. On the other hand, the combination of natural products chemistry with appropriate high-throughput screening bioassays may yield novel natural product-derived HIF-1 activators. Potent natural product-derived HIF-1 activators that exhibit a low level of toxicity and side effects hold promise as new treatment options for diseases such as myocardial and peripheral ischemia, and as chemopreventative agents that could be used to reduce the level of ischemia/reperfusion injury following heart attack and stroke.

  20. The influence of social-cognitive factors on personal hygiene practices to protect against influenzas: using modelling to compare avian A/H5N1 and 2009 pandemic A/H1N1 influenzas in Hong Kong.

    PubMed

    Liao, Qiuyan; Cowling, Benjamin J; Lam, Wendy Wing Tak; Fielding, Richard

    2011-06-01

    Understanding population responses to influenza helps optimize public health interventions. Relevant theoretical frameworks remain nascent. To model associations between trust in information, perceived hygiene effectiveness, knowledge about the causes of influenza, perceived susceptibility and worry, and personal hygiene practices (PHPs) associated with influenza. Cross-sectional household telephone surveys on avian influenza A/H5N1 (2006) and pandemic influenza A/H1N1 (2009) gathered comparable data on trust in formal and informal sources of influenza information, influenza-related knowledge, perceived hygiene effectiveness, worry, perceived susceptibility, and PHPs. Exploratory factor analysis confirmed domain content while confirmatory factor analysis was used to evaluate the extracted factors. The hypothesized model, compiled from different theoretical frameworks, was optimized with structural equation modelling using the A/H5N1 data. The optimized model was then tested against the A/H1N1 dataset. The model was robust across datasets though corresponding path weights differed. Trust in formal information was positively associated with perceived hygiene effectiveness which was positively associated with PHPs in both datasets. Trust in formal information was positively associated with influenza worry in A/H5N1 data, and with knowledge of influenza cause in A/H1N1 data, both variables being positively associated with PHPs. Trust in informal information was positively associated with influenza worry in both datasets. Independent of information trust, perceived influenza susceptibility associated with influenza worry. Worry associated with PHPs in A/H5N1 data only. Knowledge of influenza cause and perceived PHP effectiveness were associated with PHPs. Improving trust in formal information should increase PHPs. Worry was significantly associated with PHPs in A/H5N1.

  1. Is Neurofibromatosis Type 1-Noonan Syndrome a Phenotypic Result of Combined Genetic and Epigenetic Factors?

    PubMed

    Yapijakis, Christos; Pachis, Nikos; Natsis, Stavros; Voumvourakis, Costas

    2016-01-01

    Neurofibromatosis 1-Noonan syndrome (NFNS) presents combined characteristics of both autosomal dominant disorders: NF1 and Noonan syndrome (NS). The genes causing NF1 and NS are located on different chromosomes, making it uncertain whether NFNS is a separate entity as previously suggested, or rather a clinical variation. We present a four-membered Greek family. The father was diagnosed with familial NF1 and the mother with generalized epilepsy, being under hydantoin treatment since the age of 18 years. Their two male children exhibited NFNS characteristics. The father and his sons shared R1947X mutation in the NF1 gene. The two children with NFNS phenotype presented with NF1 signs inherited from their father and fetal hydantoin syndrome-like phenotype due to exposure to that anticonvulsant during fetal development. The NFNS phenotype may be the result of both a genetic factor (mutation in the NF1 gene) and an epigenetic/environmental factor (e.g. hydantoin). Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. A review of the alpha-1 foundation: its formation, impact, and critical success factors.

    PubMed

    Walsh, John W; Snider, Gordon L; Stoller, James K

    2006-05-01

    Patient-advocacy organizations have proliferated because they can be an effective method to advance research and clinical care for those with the index condition, and can produce substantial benefits for the affected community, especially when the condition is uncommon. To clarify critical success factors in organizing a patient-advocacy organization and to provide a blueprint for others, including the respiratory-care advocacy community, this report examines features of one highly successful organization, the Alpha-1 Foundation, which is committed to helping those with the genetic condition alpha-1 antitrypsin deficiency. Features of the Alpha-1 Foundation that underlie its success include: consistently creating partnerships with key stakeholders, including the scientific and clinical communities, government, and pharmaceutical manufacturers; bringing passion to the cause (eg, by assuring that organizational leadership is provided by individuals affected by alpha-1 antitrypsin deficiency); and developing strategic business partnerships, as with a company that administers alpha-1 antitrypsin treatment (so-called intravenous augmentation therapy) and employs individuals with alpha-1 antitrypsin deficiency. Funds allocated by the company help to underwrite the foundation's research-funding commitment. The foundation also recruits and retains talent, including alpha-1 patients, to leadership roles (eg, on the board of directors) and has a voluntary group of committed scientists and clinicians. We believe that attention to these factors can help assure the success of patient-advocacy groups.

  3. Quantitative phosphoproteomics analysis reveals a key role of insulin growth factor 1 receptor (IGF1R) tyrosine kinase in human sperm capacitation.

    PubMed

    Wang, Jing; Qi, Lin; Huang, Shaoping; Zhou, Tao; Guo, Yueshuai; Wang, Gaigai; Guo, Xuejiang; Zhou, Zuomin; Sha, Jiahao

    2015-04-01

    One of the most important changes during sperm capacitation is the enhancement of tyrosine phosphorylation. However, the mechanisms of protein tyrosine phosphorylation during sperm capacitation are not well studied. We used label-free quantitative phosphoproteomics to investigate the overall phosphorylation events during sperm capacitation in humans and identified 231 sites with increased phosphorylation levels. Motif analysis using the NetworKIN algorithm revealed that the activity of tyrosine phosphorylation kinases insulin growth factor 1 receptor (IGF1R)/insulin receptor is significantly enriched among the up-regulated phosphorylation substrates during capacitation. Western blotting further confirmed inhibition of IGF1R with inhibitors GSK1904529A and NVP-AEW541, which inhibited the increase in tyrosine phosphorylation levels during sperm capacitation. Additionally, sperm hyperactivated motility was also inhibited by GSK1904529A and NVP-AEW541 but could be up-regulated by insulin growth factor 1, the ligand of IGF1R. Thus, the IGF1R-mediated tyrosine phosphorylation pathway may play important roles in the regulation of sperm capacitation in humans and could be a target for improvement in sperm functions in infertile men. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Soybean SAT1 (Symbiotic Ammonium Transporter 1) encodes a bHLH transcription factor involved in nodule growth and NH4+ transport

    PubMed Central

    Chiasson, David M.; Loughlin, Patrick C.; Mazurkiewicz, Danielle; Mohammadidehcheshmeh, Manijeh; Fedorova, Elena E.; Okamoto, Mamoru; McLean, Elizabeth; Glass, Anthony D. M.; Smith, Sally E.; Bisseling, Ton; Tyerman, Stephen D.; Day, David A.; Kaiser, Brent N.

    2014-01-01

    Glycine max symbiotic ammonium transporter 1 was first documented as a putative ammonium (NH4+) channel localized to the symbiosome membrane of soybean root nodules. We show that Glycine max symbiotic ammonium transporter 1 is actually a membrane-localized basic helix–loop–helix (bHLH) DNA-binding transcription factor now renamed Glycine max bHLH membrane 1 (GmbHLHm1). In yeast, GmbHLHm1 enters the nucleus and transcriptionally activates a unique plasma membrane NH4+ channel Saccharomyces cerevisiae ammonium facilitator 1. Ammonium facilitator 1 homologs are present in soybean and other plant species, where they often share chromosomal microsynteny with bHLHm1 loci. GmbHLHm1 is important to the soybean rhizobium symbiosis because loss of activity results in a reduction of nodule fitness and growth. Transcriptional changes in nodules highlight downstream signaling pathways involving circadian clock regulation, nutrient transport, hormone signaling, and cell wall modification. Collectively, these results show that GmbHLHm1 influences nodule development and activity and is linked to a novel mechanism for NH4+ transport common to both yeast and plants. PMID:24707045

  5. Soybean SAT1 (Symbiotic Ammonium Transporter 1) encodes a bHLH transcription factor involved in nodule growth and NH4+ transport.

    PubMed

    Chiasson, David M; Loughlin, Patrick C; Mazurkiewicz, Danielle; Mohammadidehcheshmeh, Manijeh; Fedorova, Elena E; Okamoto, Mamoru; McLean, Elizabeth; Glass, Anthony D M; Smith, Sally E; Bisseling, Ton; Tyerman, Stephen D; Day, David A; Kaiser, Brent N

    2014-04-01

    Glycine max symbiotic ammonium transporter 1 was first documented as a putative ammonium (NH4(+)) channel localized to the symbiosome membrane of soybean root nodules. We show that Glycine max symbiotic ammonium transporter 1 is actually a membrane-localized basic helix-loop-helix (bHLH) DNA-binding transcription factor now renamed Glycine max bHLH membrane 1 (GmbHLHm1). In yeast, GmbHLHm1 enters the nucleus and transcriptionally activates a unique plasma membrane NH4(+) channel Saccharomyces cerevisiae ammonium facilitator 1. Ammonium facilitator 1 homologs are present in soybean and other plant species, where they often share chromosomal microsynteny with bHLHm1 loci. GmbHLHm1 is important to the soybean rhizobium symbiosis because loss of activity results in a reduction of nodule fitness and growth. Transcriptional changes in nodules highlight downstream signaling pathways involving circadian clock regulation, nutrient transport, hormone signaling, and cell wall modification. Collectively, these results show that GmbHLHm1 influences nodule development and activity and is linked to a novel mechanism for NH4(+) transport common to both yeast and plants.

  6. Steroidogenic Factor 1, Pit-1, and Adrenocorticotropic Hormone: A Rational Starting Place for the Immunohistochemical Characterization of Pituitary Adenoma.

    PubMed

    McDonald, William C; Banerji, Nilanjana; McDonald, Kelsey N; Ho, Bridget; Macias, Virgilia; Kajdacsy-Balla, Andre

    2017-01-01

    -Pituitary adenoma classification is complex, and diagnostic strategies vary greatly from laboratory to laboratory. No optimal diagnostic algorithm has been defined. -To develop a panel of immunohistochemical (IHC) stains that provides the optimal combination of cost, accuracy, and ease of use. -We examined 136 pituitary adenomas with stains of steroidogenic factor 1 (SF-1), Pit-1, anterior pituitary hormones, cytokeratin CAM5.2, and α subunit of human chorionic gonadotropin. Immunohistochemical staining was scored using the Allred system. Adenomas were assigned to a gold standard class based on IHC results and available clinical and serologic information. Correlation and cluster analyses were used to develop an algorithm for parsimoniously classifying adenomas. -The algorithm entailed a 1- or 2-step process: (1) a screening step consisting of IHC stains for SF-1, Pit-1, and adrenocorticotropic hormone; and (2) when screening IHC pattern and clinical history were not clearly gonadotrophic (SF-1 positive only), corticotrophic (adrenocorticotropic hormone positive only), or IHC null cell (negative-screening IHC), we subsequently used IHC for prolactin, growth hormone, thyroid-stimulating hormone, and cytokeratin CAM5.2. -Comparison between diagnoses generated by our algorithm and the gold standard diagnoses showed excellent agreement. When compared with a commonly used panel using 6 IHC for anterior pituitary hormones plus IHC for a low-molecular-weight cytokeratin in certain tumors, our algorithm uses approximately one-third fewer IHC stains and detects gonadotroph adenomas with greater sensitivity.

  7. Growth factor deprivation induces cytosolic translocation of SIRT1

    NASA Astrophysics Data System (ADS)

    Meng, Chengbo; Xing, Da; Wu, Shengnan; Huang, Lei

    2010-02-01

    Sirtuin type 1 (SIRT1), a NAD+-dependent histone deacetylases, plays a critical role in cellular senescence, aging and longevity. In general, SIRT1 is localized in nucleus and is believed as a nuclear protein. Though overexpression of SIRT1 delays senescence, SIRT1-protein levels decline naturally in thymus and heart during aging. In the present studies, we investigated the subcellular localization of SIRT1 in response to growth factor deprivation in African green monkey SV40-transformed kidney fibroblast cells (COS-7). Using SIRT1-EGFP fluorescence reporter, we found that SIRT1 localized to nucleus in physiological conditions. We devised a model enabling cell senescence via growth factor deprivation, and we found that SIRT1 partially translocated to cytosol under the treatment, suggesting a reduced level of SIRT1's activity. We found PI3K/Akt pathway was involved in the inhibition of SIRT1's cytosolic translocation, because inhibition of these kinases significantly decreased the amount of SIRT1 maintained in nucleus. Taken together, we demonstrated that growth factor deprivation induces cytosolic translocation of SIRT1, which suggesting a possible connection between cytoplasm-localized SIRT1 and the aging process.

  8. A Novel WRKY transcription factor is required for induction of PR-1a gene expression by salicylic acid and bacterial elicitors.

    PubMed

    van Verk, Marcel C; Pappaioannou, Dimitri; Neeleman, Lyda; Bol, John F; Linthorst, Huub J M

    2008-04-01

    PR-1a is a salicylic acid-inducible defense gene of tobacco (Nicotiana tabacum). One-hybrid screens identified a novel tobacco WRKY transcription factor (NtWRKY12) with specific binding sites in the PR-1a promoter at positions -564 (box WK(1)) and -859 (box WK(2)). NtWRKY12 belongs to the class of transcription factors in which the WRKY sequence is followed by a GKK rather than a GQK sequence. The binding sequence of NtWRKY12 (WK box TTTTCCAC) deviated significantly from the consensus sequence (W box TTGAC[C/T]) shown to be recognized by WRKY factors with the GQK sequence. Mutation of the GKK sequence in NtWRKY12 into GQK or GEK abolished binding to the WK box. The WK(1) box is in close proximity to binding sites in the PR-1a promoter for transcription factors TGA1a (as-1 box) and Myb1 (MBSII box). Expression studies with PR-1a promoterbeta-glucuronidase (GUS) genes in stably and transiently transformed tobacco indicated that NtWRKY12 and TGA1a act synergistically in PR-1a expression induced by salicylic acid and bacterial elicitors. Cotransfection of Arabidopsis thaliana protoplasts with 35SNtWRKY12 and PR-1aGUS promoter fusions showed that overexpression of NtWRKY12 resulted in a strong increase in GUS expression, which required functional WK boxes in the PR-1a promoter.

  9. Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1

    PubMed Central

    Hong, Zebin; De Meulemeester, Laura; Jacobi, Annemarie; Pedersen, Jan Skov; Morth, J. Preben; Andreasen, Peter A.; Jensen, Jan K.

    2016-01-01

    Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a type I transmembrane protein and inhibitor of several serine proteases, including hepatocyte growth factor activator and matriptase. The protein is essential for development as knock-out mice die in utero due to placental defects caused by misregulated extracellular proteolysis. HAI-1 contains two Kunitz-type inhibitor domains (Kunitz), which are generally thought of as a functionally self-contained protease inhibitor unit. This is not the case for HAI-1, where our results reveal how interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. Here we present an x-ray crystal structure of an HAI-1 fragment covering the internal domain and Kunitz-1. The structure reveals not only that the previously uncharacterized internal domain is a member of the polycystic kidney disease domain family but also how the two domains engage in interdomain interactions. Supported by solution small angle x-ray scattering and a combination of site-directed mutagenesis and functional assays, we show that interdomain interactions not only stabilize the fold of the internal domain but also stimulate the inhibitory activity of Kunitz-1. By completing our structural characterization of the previously unknown N-terminal region of HAI-1, we provide new insight into the interplay between tertiary structure and the inhibitory activity of a multidomain protease inhibitor. We propose a previously unseen mechanism by which the association of an auxiliary domain stimulates the inhibitory activity of a Kunitz-type inhibitor (i.e. the first structure of an intramolecular interaction between a Kunitz and another domain). PMID:27189939

  10. Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wu, Zehua; Cui, Feifei; Yu, Fudong

    2014-06-27

    Highlights: • We identified that CHAF1A was up-regulated in colon tumor mucosa in TMA. • The expression pattern of CHAF1A was validated with qPCR and western-blot. • CHAF1A overexpression is an independent indicator for poor colon cancer survival. • CHAF1A facilitates cell proliferation of colon cancer both in vitro and in vivo. - Abstract: Deregulation of chromatin assembly factor 1, p150 subunit A (CHAF1A) has recently been reported to be involved in the development of some cancer types. In this study, we identified that the frequency of positive CHAF1A staining in primary tumor mucosa (45.8%, 93 of 203 samples) wasmore » significantly elevated compared to that in paired normal mucosa (18.7%, 38 of 203 samples). The increased expression was strongly associated with cancer stage, tumor invasion, and histological grade. The five-year survival rate of patients with CHAF1A-positive tumors was remarkably lower than that of patients with CHAF1A-negative tumors. Colon cancer cells with CHAF1A knockdown exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate as well as impaired colon tumorigenicity in nude mice. Hence, CHAF1A upregulation functions as a poor prognostic indicator of colon cancer, potentially contributing to its progression by mediating cancer cell proliferation.« less

  11. Purification and characterization of FBI-1, a cellular factor that binds to the human immunodeficiency virus type 1 inducer of short transcripts.

    PubMed Central

    Pessler, F; Pendergrast, P S; Hernandez, N

    1997-01-01

    The human immunodeficiency virus (HIV-1) promoter directs the synthesis of two classes of RNA molecules, short transcripts and full-length transcripts. The synthesis of short transcripts depends on a bipartite DNA element, the inducer of short transcripts (IST), located in large part downstream of the HIV-1 start site of transcription. IST does not require any viral product for function and is thought to direct the assembly of transcription complexes that are incapable of efficient elongation. Nothing is known, however, about the biochemical mechanisms that mediate IST function. Here, we report the identification and purification of a factor that binds specifically to the IST. This factor, FBI-1, recognizes a large bipartite binding site that coincides with the bipartite IST element. It is constituted at least in part by an 86-kDa polypeptide that can be specifically cross-linked to IST. FBI-1 also binds to promoter and attenuation regions of a number of cellular and viral transcription units that are regulated by a transcription elongation block. This observation, together with the observation that the binding of FBI-1 to IST mutants correlates with the ability of these mutants to direct IST function, suggests that FBI-1 may be involved in the establishment of abortive transcription complexes. PMID:9199312

  12. Purification and characterization of FBI-1, a cellular factor that binds to the human immunodeficiency virus type 1 inducer of short transcripts.

    PubMed

    Pessler, F; Pendergrast, P S; Hernandez, N

    1997-07-01

    The human immunodeficiency virus (HIV-1) promoter directs the synthesis of two classes of RNA molecules, short transcripts and full-length transcripts. The synthesis of short transcripts depends on a bipartite DNA element, the inducer of short transcripts (IST), located in large part downstream of the HIV-1 start site of transcription. IST does not require any viral product for function and is thought to direct the assembly of transcription complexes that are incapable of efficient elongation. Nothing is known, however, about the biochemical mechanisms that mediate IST function. Here, we report the identification and purification of a factor that binds specifically to the IST. This factor, FBI-1, recognizes a large bipartite binding site that coincides with the bipartite IST element. It is constituted at least in part by an 86-kDa polypeptide that can be specifically cross-linked to IST. FBI-1 also binds to promoter and attenuation regions of a number of cellular and viral transcription units that are regulated by a transcription elongation block. This observation, together with the observation that the binding of FBI-1 to IST mutants correlates with the ability of these mutants to direct IST function, suggests that FBI-1 may be involved in the establishment of abortive transcription complexes.

  13. Transcription factor Sp1 regulates T-type Ca(2+) channel CaV 3.1 gene expression.

    PubMed

    González-Ramírez, Ricardo; Martínez-Hernández, Elizabeth; Sandoval, Alejandro; Felix, Ricardo

    2014-05-01

    Voltage-gated T-type Ca(2+) (CaV 3) channels mediate a number of physiological events in developing and mature cells, and are implicated in neurological and cardiovascular diseases. In mammals, there are three distinct T-channel genes (CACNA1G, CACNA1H, and CACNA1I) encoding proteins (CaV 3.1-CaV 3.3) that differ in their localization as well as in molecular, biophysical, and pharmacological properties. The CACNA1G is a large gene that contains 38 exons and is localized in chromosome 17q22. Only basic characteristics of the CACNA1G gene promoter region have been investigated classifying it as a TATA-less sequence containing several potential transcription factor-binding motifs. Here, we cloned and characterized a proximal promoter region and initiated the analysis of transcription factors that control CaV 3.1 channel expression using the murine Cacna1g gene as a model. We isolated a1.5 kb 5'-upstream region of Cacna1g and verified its transcriptional activity in the mouse neuroblastoma N1E-115 cell line. In silico analysis revealed that this region possesses a TATA-less minimal promoter that includes two potential transcription start sites and four binding sites for the transcription factor Sp1. The ability of one of these sites to interact with the transcription factor was confirmed by electrophoretic mobility shift assays. Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression. © 2013 Wiley Periodicals, Inc.

  14. YY1 as a controlling factor for the Peg3 and Gnas imprinted domains

    PubMed Central

    Kim, Jeong Do; Hinz, Angela K.; Choo, Jung Ha; Stubbs, Lisa; Kim, Joomyeong

    2007-01-01

    Imprinting Control Regions (ICRs) often harbor tandem arrays of transcription factor binding sites, as demonstrated by the identification of multiple YY1 binding sites within the ICRs of Peg3, Nespas, and Xist/Tsix domains. In the current study, we have sought to characterize possible roles of YY1 in transcriptional control and epigenetic modification of these imprinted domains. RNA interference-based knockdown experiments in Neuro2A cells resulted in overall transcriptional up-regulation of most of the imprinted genes within the Peg3 domain and also, concomitantly, caused significant loss in the DNA methylation of Peg3-DMR (Differentially Methylated Regions). A similar overall and coordinated expression change was also observed for the imprinted genes of the Gnas domain: up-regulation of Nespas and down-regulation of Nesp and Gnasxl. YY1 knockdown also resulted in changes in the expression levels of Xist and Snrpn. These results support the idea that YY1 plays a major role, as a trans factor, for the control of these imprinted domains. PMID:17067777

  15. Incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities - a nationwide population-based study.

    PubMed

    Lehtonen, Arttu O; Langén, Ville L; Puukka, Pauli J; Kähönen, Mika; Nieminen, Markku S; Jula, Antti M; Niiranen, Teemu J

    Scant data exist on incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities in the general population. We recorded ECG and measured conventional cardiovascular risk factors in 5667 Finns who were followed up for incident atrial fibrillation (AF). We obtained repeat ECGs from 3089 individuals 11years later. The incidence rates of prolonged P-wave duration, abnormal P terminal force (PTF), left P-wave axis deviation, and right P-wave axis deviation were 16.0%, 7.4%, 3.4%, and 2.2%, respectively. Older age and higher BMI were associated with incident prolonged P-wave duration and abnormal PTF (P≤0.01). Higher blood pressure was associated with incident prolonged P-wave duration and right P-wave axis deviation (P≤0.01). During follow-up, only prolonged P-wave duration predicted AF (multivariable-adjusted hazard ratio, 1.38; P=0.001). Modifiable risk factors associate with P-wave abnormalities that are common and may represent intermediate steps of atrial cardiomyopathy on a pathway leading to AF. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Hypoxia-Inducible Factor-1α (HIF-1α) Expression on Endothelial Cells in Juvenile Nasopharyngeal Angiofibroma: A Review of 70 cases and Tissue Microarray Analysis.

    PubMed

    Song, Xiaole; Yang, Chenhe; Zhang, Huankang; Wang, Jingjing; Sun, Xicai; Hu, Li; Liu, Zhuofu; Wang, Dehui

    2018-06-01

    To examine the expression of hypoxia-inducible factor-1α (HIF-1α) and its related molecules (cellular repressor of E1A-stimulated genes [CREG], osteopontin [OPN], proto-oncogene tyrosine-protein kinase Src [c-Src], and vascular endothelial growth factor [VEGF]) in juvenile nasopharyngeal angiofibroma (JNA) and explore the correlation between clinical prognosis and HIF-1α expression. The study performed a retrospective review of the clinical records of patients with JNA treated between 2003 and 2007. Specimens were analyzed by immunohistochemistry for HIF-1α, CREG, OPN, c-Src, and VEGF expression, and microvessel density (MVD) was assessed by tissue microarray. The correlation between expression levels and clinicopathological features including age, tumor stage, intraoperative blood loss, and recurrence was analyzed. HIF-1α, CREG, OPN, c-Src, and VEGF were upregulated in endothelial cells (ECs) of patients with JNA, and strong correlations in the expression of these molecules were observed. HIF-1α expression was higher in young patients ( P = .032) and in recurrent cases ( P = .01). Survival analysis showed that low HIF-1α levels in ECs predicted longer time to recurrence (log rank test P = .006). Receiver operating characteristic curve analysis showed that HIF-1α was a prognostic factor for recurrence (area under the curve = 0.690, P = .019). No correlation was found between the expression of molecules and Radkowski stage or intraoperative blood loss. In cases of JNA treated surgically, HIF-1α expression in ECs is a useful prognostic factor for tumor recurrence.

  17. The Arabidopsis SR45 Splicing Factor, a Negative Regulator of Sugar Signaling, Modulates SNF1-Related Protein Kinase 1 Stability

    PubMed Central

    Barbosa, Inês C.R.

    2016-01-01

    The ability to sense and respond to sugar signals allows plants to cope with environmental and metabolic changes by adjusting growth and development accordingly. We previously reported that the SR45 splicing factor negatively regulates glucose signaling during early seedling development in Arabidopsis thaliana. Here, we show that under glucose-fed conditions, the Arabidopsis sr45-1 loss-of-function mutant contains higher amounts of the energy-sensing SNF1-Related Protein Kinase 1 (SnRK1) despite unaffected SnRK1 transcript levels. In agreement, marker genes for SnRK1 activity are upregulated in sr45-1 plants, and the glucose hypersensitivity of sr45-1 is attenuated by disruption of the SnRK1 gene. Using a high-resolution RT-PCR panel, we found that the sr45-1 mutation broadly targets alternative splicing in vivo, including that of the SR45 pre-mRNA itself. Importantly, the enhanced SnRK1 levels in sr45-1 are suppressed by a proteasome inhibitor, indicating that SR45 promotes targeting of the SnRK1 protein for proteasomal destruction. Finally, we demonstrate that SR45 regulates alternative splicing of the Arabidopsis 5PTase13 gene, which encodes an inositol polyphosphate 5-phosphatase previously shown to interact with and regulate the stability of SnRK1 in vitro, thus providing a mechanistic link between SR45 function and the modulation of degradation of the SnRK1 energy sensor in response to sugars. PMID:27436712

  18. Repression of Virus-Induced Interferon A Promoters by Homeodomain Transcription Factor Ptx1

    PubMed Central

    Lopez, Sébastien; Island, Marie-Laure; Drouin, Jacques; Bandu, Marie-Thérese; Christeff, Nicolas; Darracq, Nicole; Barbey, Régine; Doly, Janine; Thomas, Dominique; Navarro, Sébastien

    2000-01-01

    Interferon A (IFN-A) genes are differentially expressed after virus induction. The differential expression of individual IFN-A genes is modulated by substitutions in the proximal positive virus responsive element A (VRE-A) of their promoters and by the presence or absence of a distal negative regulatory element (DNRE). The functional feature of the DNRE is to specifically act by repression of VRE-A activity. With the use of the yeast one-hybrid system, we describe here the identification of a specific DNRE-binding protein, the pituitary homeobox 1 (Ptx1 or Pitx1). Ptx1 is detectable in different cell types that differentially express IFN-A genes, and the endogenous Ptx1 protein binds specifically to the DNRE. Upon virus induction, Ptx1 negatively regulates the transcription of DNRE-containing IFN-A promoters, and the C-terminal region, as well as the homeodomain of the Ptx1 protein, is required for this repression. After virus induction, the expression of the Ptx1 antisense RNA leads to a significant increase of endogenous IFN-A gene transcription and is able to modify the pattern of differential expression of individual IFN-A genes. These studies suggest that Ptx1 contributes to the differential transcriptional strength of the promoters of different IFN-A genes and that these genes may provide new targets for transcriptional regulation by a homeodomain transcription factor. PMID:11003649

  19. Tyrosine Phosphorylation of the Pioneer Transcription Factor FoxA1 Promotes Activation of Estrogen Signaling.

    PubMed

    Yamaguchi, Noritaka; Shibazaki, Misato; Yamada, Chiaki; Anzai, Erina; Morii, Mariko; Nakayama, Yuji; Kuga, Takahisa; Hashimoto, Yuuki; Tomonaga, Takeshi; Yamaguchi, Naoto

    2017-06-01

    The pioneer transcription factor FoxA1 plays an important role in estrogen signaling by opening closed chromatin and promoting recruitment of the estrogen receptor to its target regions in DNA. In this study, we analyzed tyrosine phosphorylation of FoxA1 by the non-receptor-type tyrosine kinase c-Abl. c-Abl was shown to phosphorylate FoxA1 at multiple sites, especially in the N- and C-terminal regions. Tyr429 and Tyr464 were identified as the major phosphorylation sites in the FoxA1 C-terminal region. The phosphomimetic and nonphosphorylatable FoxA1 mutants were generated by glutamic acid and phenylalanine substitutions at these tyrosine residues, respectively. The phosphomimetic FoxA1 promoted the activation of estrogen signaling, whereas the nonphosphorylatable FoxA1 suppressed its activation. Stimulation with the epidermal growth factor, which activates c-Abl, enhanced the activation of estrogen signaling. In contrast, the c-Abl inhibitor imatinib reduced its activation. The phosphomimetic FoxA1 mutant showed a higher affinity toward histone H3 than the wild-type. These results suggest that c-Abl-mediated phosphorylation of FoxA1 promotes the activation of estrogen signaling by inducing its binding to histones. J. Cell. Biochem. 118: 1453-1461, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  20. Akirin1 (Mighty), a novel promyogenic factor regulates muscle regeneration and cell chemotaxis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Salerno, Monica Senna; Dyer, Kelly; Bracegirdle, Jeremy

    2009-07-15

    Akirin1 (Mighty) is a downstream target gene of myostatin and has been shown to be a promyogenic factor. Although expressed in many tissues, akirin1 is negatively regulated by myostatin specifically in skeletal muscle tissue. In this manuscript we have characterized the possible function of akirin1 in postnatal muscle growth. Molecular and immunohistological analyses indicated that while low levels of akirin1 are associated with quiescent satellite cells (SC), higher levels of akirin1 are detected in activated proliferating SC indicating that akirin1 could be associated with satellite cell activation. In addition to SC, macrophages also express akirin1, and increased expression of akirin1more » resulted in more efficient chemotaxis of both macrophages and myoblasts. Akirin1 appears to regulate chemotaxis of both macrophages and myoblasts by reorganising actin cytoskeleton, leading to more efficient lamellipodia formation via a PI3 kinase dependent pathway. Expression analysis during muscle regeneration also indicated that akirin1 expression is detected very early (day 2) in regenerating muscle, and expression gradually peaks to coincide the nascent myotube formation stage of muscle regeneration. Based on these results we propose that akirin1 could be acting as a transducer of early signals of muscle regeneration. Thus, we speculate that myostatin regulates key steps of muscle regeneration including chemotaxis of inflammatory cells, SC activation and migration through akirin1.« less

  1. Eop1 from a Rubus strain of Erwinia amylovora functions as a host-range limiting factor.

    PubMed

    Asselin, J E; Bonasera, J M; Kim, J F; Oh, C-S; Beer, S V

    2011-08-01

    Strains of Erwinia amylovora, the bacterium causing the disease fire blight of rosaceous plants, are separated into two groups based on host range: Spiraeoideae and Rubus strains. Spiraeoideae strains have wide host ranges, infecting plants in many rosaceous genera, including apple and pear. In the field, Rubus strains infect the genus Rubus exclusively, which includes raspberry and blackberry. Based on comparisons of limited sequence data from a Rubus and a Spiraeoideae strain, the gene eop1 was identified as unusually divergent, and it was selected as a possible host specificity factor. To test this, eop1 genes from a Rubus strain and a Spiraeoideae strain were cloned and mutated. Expression of the Rubus-strain eop1 reduced the virulence of E. amylovora in immature pear fruit and in apple shoots. Sequencing the orfA-eop1 regions of several strains of E. amylovora confirmed that forms of eop1 are conserved among strains with similar host ranges. This work provides evidence that eop1 from a Rubus-specific strain can function as a determinant of host specificity in E. amylovora.

  2. Age-related macular degeneration-associated silent polymorphisms in HtrA1 impair its ability to antagonize insulin-like growth factor 1.

    PubMed

    Jacobo, Sarah Melissa P; Deangelis, Margaret M; Kim, Ivana K; Kazlauskas, Andrius

    2013-05-01

    Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular age-related macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD.

  3. Inhibition of hypoxia inducible factor-1alpha by dihydroxyphenylethanol, a product from olive oil, blocks microsomal prostaglandin-E synthase-1/vascular endothelial growth factor expression and reduces tumor angiogenesis.

    PubMed

    Terzuoli, Erika; Donnini, Sandra; Giachetti, Antonio; Iñiguez, Miguel A; Fresno, Manuel; Melillo, Giovanni; Ziche, Marina

    2010-08-15

    2-(3,4-dihydroxyphenil)-ethanol (DPE), a polyphenol present in olive oil, has been found to attenuate the growth of colon cancer cells, an effect presumably related to its anti-inflammatory activity. To further explore the effects of DPE on angiogenesis and tumor growth we investigated the in vivo efficacy of DPE in a HT-29 xenograft model and in vitro activities in colon cancer cells exposed to interleukin-1beta (IL-1beta) and prostaglandin E-2 (PGE-2). DPE (10 mg/kg/day for 14 days) inhibited tumor growth, reducing vessel lumina and blood perfusion to tumor, and diminished expression of hypoxia inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), and microsomal prostaglandin-E synthase-1 (mPGEs-1). In vitro, DPE (100 mumol/L) neither affected cell proliferation nor induced apoptosis in HT-29 and WiDr cells. DPE prevented the IL-1beta-mediated increase of mPGEs-1 expression and PGE-2 generation, as it did the silencing of HIF-1alpha. Moreover, DPE blocked mPGEs-1-dependent expression of VEGF and inhibited endothelial sprouting induced by tumor cells in a coculture system. PGE-2 triggers a feed-forward loop involving HIF-1alpha, which impinges on mPGEs-1 and VEGF expression, events prevented by DPE via extracellular signal-related kinase 1/2. The reduction of PGE-2 and VEGF levels, caused by DPE, was invariably associated with a marked decrease in HIF-1alpha expression and activity, independent of proteasome activity, indicating that the DPE effects on tumor growth and angiogenesis are dependent on the inhibition of HIF-1alpha translation. We show that the in vivo DPE antitumor effect is associated with anti-inflammatory and antiangiogenic activities resulting from the downregulation of the HIF-1alpha/mPGEs-1/VEGF axis.

  4. Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors.

    PubMed

    Bernhard, Felix P; Heinzel, Sebastian; Binder, Gerhard; Weber, Karin; Apel, Anja; Roeben, Benjamin; Deuschle, Christian; Maechtel, Mirjam; Heger, Tanja; Nussbaum, Susanne; Gasser, Thomas; Maetzler, Walter; Berg, Daniela

    2016-01-01

    Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinson's disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: ≤3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders.

  5. Sda1, a Cys2-His2 Zinc Finger Transcription Factor, Is Involved in Polyol Metabolism and Fumonisin B1 Production in Fusarium verticillioides

    PubMed Central

    Malapi-Wight, Martha; Smith, Jonathon; Campbell, Jacquelyn; Bluhm, Burton H.; Shim, Won-Bo

    2013-01-01

    The ubiquitous ascomycete Fusarium verticillioides causes ear rot and stalk rot of maize, both of which reduce grain quality and yield. Additionally, F. verticillioides produces the mycotoxin fumonisin B1 (FB1) during infection of maize kernels, and thus potentially compromises human and animal health. The current knowledge is fragmentary regarding the regulation of FB1 biosynthesis, particularly when considering interplay with environmental factors such as nutrient availability. In this study, SDA1 of F. verticillioides, predicted to encode a Cys-2 His-2 zinc finger transcription factor, was shown to play a key role in catabolizing select carbon sources. Growth of the SDA1 knock-out mutant (Δsda1) was completely inhibited when sorbitol was the sole carbon source and was severely impaired when exclusively provided mannitol or glycerol. Deletion of SDA1 unexpectedly increased FB1 biosynthesis, but reduced arabitol and mannitol biosynthesis, as compared to the wild-type progenitor. Trichoderma reesei ACE1, a regulator of cellulase and xylanase expression, complemented the F. verticillioides Δsda1 mutant, which indicates that Ace1 and Sda1 are functional orthologs. Taken together, the data indicate that Sda1 is a transcriptional regulator of carbon metabolism and toxin production in F. verticillioides. PMID:23844049

  6. Hospitalized children with 2009 pandemic influenza A (H1N1): comparison to seasonal influenza and risk factors for admission to the ICU.

    PubMed

    Bagdure, Dayanand; Curtis, Donna J; Dobyns, Emily; Glodé, Mary P; Dominguez, Samuel R

    2010-12-15

    Limited data are available describing the clinical presentation and risk factors for admission to the intensive care unit for children with 2009 H1N1 infection. We conducted a retrospective chart review of all hospitalized children with 2009 influenza A (H1N1) and 2008-09 seasonal influenza at The Children's Hospital, Denver, Colorado. Of the 307 children identified with 2009 H1N1 infections, the median age was 6 years, 61% were male, and 66% had underlying medical conditions. Eighty children (26%) were admitted to the ICU. Thirty-two (40%) of the ICU patients required intubation and 17 (53%) of the intubated patients developed acute respiratory distress syndrome (ARDS). Four patients required extracorporeal membrane oxygenation. Eight (3%) of the hospitalized children died. Admission to the ICU was significantly associated with older age and underlying neurological condition. Compared to the 90 children admitted during the 2008-09 season, children admitted with 2009 H1N1 influenza were significantly older, had a shorter length of hospitalization, more use of antivirals, and a higher incidence of ARDS. Compared to the 2008-09 season, hospitalized children with 2009 H1N1 influenza were much older and had more severe respiratory disease. Among children hospitalized with 2009 H1N1 influenza, risk factors for admission to the ICU included older age and having an underlying neurological condition. Children under the age of 2 hospitalized with 2009 H1N1 influenza were significantly less likely to require ICU care compared to older hospitalized children.

  7. Modulation of p53 and met expression by Krüppel-like factor 8 regulates zebrafish cerebellar development.

    PubMed

    Tsai, Ming-Yuan; Lu, Yu-Fen; Liu, Yu-Hsiu; Lien, Huang-Wei; Huang, Chang-Jen; Wu, Jen-Leih; Hwang, Sheng-Ping L

    2015-09-01

    Krüppel-like factor 8 (Klf8) is a zinc-finger transcription factor implicated in cell proliferation, and cancer cell survival and invasion; however, little is known about its role in normal embryonic development. Here, we show that Klf8 is required for normal cerebellar development in zebrafish embryos. Morpholino knockdown of klf8 resulted in abnormal cerebellar primordium morphology and the induction of p53 in the brain region at 24 hours post-fertilization (hpf). Both p53-dependent reduction of cell proliferation and augmentation of apoptosis were observed in the cerebellar anlage of 24 hpf-klf8 morphants. In klf8 morphants, expression of ptf1a in the ventricular zone was decreased from 48 to 72 hpf; on the other hand, expression of atohla in the upper rhombic lip was unaffected. Consistent with this finding, Purkinje cell development was perturbed and granule cell number was reduced in 72 hpf-klf8 morphants; co-injection of p53 MO(sp) or klf8 mRNA substantially rescued development of cerebellar Purkinje cells in klf8 morphants. Hepatocyte growth factor/Met signaling is known to regulate cerebellar development in zebrafish and mouse. We observed decreased met expression in the tectum and rhombomere 1 of 24 hpf-klf8 morphants, which was largely rescued by co-injection with klf8 mRNA. Moreover, co-injection of met mRNA substantially rescued formation of Purkinje cells in klf8 morphants at 72 hpf. Together, these results demonstrate that Klf8 modulates expression of p53 and met to maintain ptf1a-expressing neuronal progenitors, which are required for the appropriate development of cerebellar Purkinje and granule cells in zebrafish embryos. © 2014 Wiley Periodicals, Inc.

  8. Insulin-Like Growth Factor-1 Bioactivity Plays a Prosurvival Role in Older Participants

    PubMed Central

    2013-01-01

    The aim of this study was to address the intriguing issue of the role of the insulin-like growth factor (IGF)-1 system in longevity looking at the role of different components of IGF system. Vital status was ascertained in 1,197 men and women aged greater than or equal to 65 years from the InCHIANTI study. Hormonal levels were categorized into quartiles, and ratio of IGF-1 to IGF-binding protein (IGFBP)-1 was calculated. The relationship between hormones and mortality was tested by Cox proportional hazard models adjusted for age, sex, and confounders. During the 8-year follow-up period, 240 died and 957 survived. Lowest quartiles of IGF-1 and IGFBP-1 were considered as reference. Compared with the lowest quartiles, IGF-1 in upper quartiles was a negative predictor of mortality independent of age and sex (p = .01) but not independent of IGFBP-1 and other confounders. IGFBP-1 in second–third quartiles was negatively associated and that in the fourth quartiles was positively associated with risk of death. IGF-1/IGFBP-1 ratio in the lowest quartiles was a strong positive predictor of mortality, in age- and sex-adjusted model (p = .005), and independent of additional confounders (p = .037). High IGFBP-1 and low IGF-1/IGFBP-1 ratio are associated with all-cause mortality in older population. PMID:23671288

  9. Insulin-like growth factor-1 bioactivity plays a prosurvival role in older participants.

    PubMed

    Maggio, Marcello; Cattabiani, Chiara; Lauretani, Fulvio; Bandinelli, Stefania; De Vita, Francesca; Dall'Aglio, Elisabetta; Corsonello, Andrea; Lattanzio, Fabrizia; Paolisso, Giuseppe; Ferrucci, Luigi; Ceda, Gian Paolo

    2013-11-01

    The aim of this study was to address the intriguing issue of the role of the insulin-like growth factor (IGF)-1 system in longevity looking at the role of different components of IGF system. Vital status was ascertained in 1,197 men and women aged greater than or equal to 65 years from the InCHIANTI study. Hormonal levels were categorized into quartiles, and ratio of IGF-1 to IGF-binding protein (IGFBP)-1 was calculated. The relationship between hormones and mortality was tested by Cox proportional hazard models adjusted for age, sex, and confounders. During the 8-year follow-up period, 240 died and 957 survived. Lowest quartiles of IGF-1 and IGFBP-1 were considered as reference. Compared with the lowest quartiles, IGF-1 in upper quartiles was a negative predictor of mortality independent of age and sex (p = .01) but not independent of IGFBP-1 and other confounders. IGFBP-1 in second-third quartiles was negatively associated and that in the fourth quartiles was positively associated with risk of death. IGF-1/IGFBP-1 ratio in the lowest quartiles was a strong positive predictor of mortality, in age- and sex-adjusted model (p = .005), and independent of additional confounders (p = .037). High IGFBP-1 and low IGF-1/IGFBP-1 ratio are associated with all-cause mortality in older population.

  10. A role for APETALA1/fruitfull transcription factors in tomato leaf development.

    PubMed

    Burko, Yogev; Shleizer-Burko, Sharona; Yanai, Osnat; Shwartz, Ido; Zelnik, Iris Daphne; Jacob-Hirsch, Jasmine; Kela, Itai; Eshed-Williams, Leor; Ori, Naomi

    2013-06-01

    Flexible maturation rates underlie part of the diversity of leaf shape, and tomato (Solanum lycopersicum) leaves are compound due to prolonged organogenic activity of the leaf margin. The CINCINNATA-teosinte branched1, cycloidea, PCF (CIN-TCP) transcription factor lanceolate (LA) restricts this organogenic activity and promotes maturation. Here, we show that tomato APETALA1/fruitfull (AP1/FUL) MADS box genes are involved in tomato leaf development and are repressed by LA. AP1/FUL expression is correlated negatively with LA activity and positively with the organogenic activity of the leaf margin. LA binds to the promoters of the AP1/FUL genes MBP20 and TM4. Overexpression of MBP20 suppressed the simple-leaf phenotype resulting from upregulation of LA activity or from downregulation of class I knotted like homeobox (KNOXI) activity. Overexpression of a dominant-negative form of MBP20 led to leaf simplification and partly suppressed the increased leaf complexity of plants with reduced LA activity or increased KNOXI activity. Tomato plants overexpressing miR319, a negative regulator of several CIN-TCP genes including LA, flower with fewer leaves via an SFT-dependent pathway, suggesting that miR319-sensitive CIN-TCPs delay flowering in tomato. These results identify a role for AP1/FUL genes in vegetative development and show that leaf and plant maturation are regulated via partially independent mechanisms.

  11. The forkhead-like transcription factor (Fhl1p) maintains yeast replicative lifespan by regulating ribonucleotide reductase 1 (RNR1) gene transcription

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tai, Akiko; Kamei, Yuka; Mukai, Yukio

    In eukaryotes, numerous genetic factors contribute to the lifespan including metabolic enzymes, signal transducers, and transcription factors. As previously reported, the forkhead-like transcription factor (FHL1) gene was required for yeast replicative lifespan and cell proliferation. To determine how Fhl1p regulates the lifespan, we performed a DNA microarray analysis of a heterozygous diploid strain deleted for FHL1. We discovered numerous Fhl1p-target genes, which were then screened for lifespan-regulating activity. We identified the ribonucleotide reductase (RNR) 1 gene (RNR1) as a regulator of replicative lifespan. RNR1 encodes a large subunit of the RNR complex, which consists of two large (Rnr1p/Rnr3p) and twomore » small (Rnr2p/Rnr4p) subunits. Heterozygous deletion of FHL1 reduced transcription of RNR1 and RNR3, but not RNR2 and RNR4. Chromatin immunoprecipitation showed that Fhl1p binds to the promoter regions of RNR1 and RNR3. Cells harboring an RNR1 deletion or an rnr1-C428A mutation, which abolishes RNR catalytic activity, exhibited a short lifespan. In contrast, cells with a deletion of the other RNR genes had a normal lifespan. Overexpression of RNR1, but not RNR3, restored the lifespan of the heterozygous FHL1 mutant to the wild-type (WT) level. The Δfhl1/FHL1 mutant conferred a decrease in dNTP levels and an increase in hydroxyurea (HU) sensitivity. These findings reveal that Fhl1p regulates RNR1 gene transcription to maintain dNTP levels, thus modulating longevity by protection against replication stress. - Highlights: • Fhl1p regulates replicative lifespan and transcription of RNR large subunit genes. • Rnr1p uniquely acts as a lifespan regulator independent of the RNR complex. • dNTP levels modulate longevity by protection against replication stress.« less

  12. Risk Factors for Childhood Obesity in the First 1,000 Days: A Systematic Review.

    PubMed

    Woo Baidal, Jennifer A; Locks, Lindsey M; Cheng, Erika R; Blake-Lamb, Tiffany L; Perkins, Meghan E; Taveras, Elsie M

    2016-06-01

    Mounting evidence suggests that the origins of childhood obesity and related disparities can be found as early as the "first 1,000 days"-the period from conception to age 2 years. The main goal of this study is to systematically review existing evidence for modifiable childhood obesity risk factors present from conception to age 2 years. PubMed, Embase, and Web of Science were searched for studies published between January 1, 1980, and December 12, 2014, of childhood obesity risk factors present during the first 1,000 days. Prospective, original human subject, English-language research with exposure occurrence during the first 1,000 days and with the outcome of childhood overweight or obesity (BMI ≥85th percentile for age and sex) collected between age 6 months and 18 years were analyzed between December 13, 2014, and March 15, 2015. Of 5,952 identified citations, 282 studies met inclusion criteria. Several risk factors during the first 1,000 days were consistently associated with later childhood obesity. These included higher maternal pre-pregnancy BMI, prenatal tobacco exposure, maternal excess gestational weight gain, high infant birth weight, and accelerated infant weight gain. Fewer studies also supported gestational diabetes, child care attendance, low strength of maternal-infant relationship, low SES, curtailed infant sleep, inappropriate bottle use, introduction of solid food intake before age 4 months, and infant antibiotic exposure as risk factors for childhood obesity. Modifiable risk factors in the first 1,000 days can inform future research and policy priorities and intervention efforts to prevent childhood obesity. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

  13. The Arabidopsis SR45 Splicing Factor, a Negative Regulator of Sugar Signaling, Modulates SNF1-Related Protein Kinase 1 Stability.

    PubMed

    Carvalho, Raquel F; Szakonyi, Dóra; Simpson, Craig G; Barbosa, Inês C R; Brown, John W S; Baena-González, Elena; Duque, Paula

    2016-08-01

    The ability to sense and respond to sugar signals allows plants to cope with environmental and metabolic changes by adjusting growth and development accordingly. We previously reported that the SR45 splicing factor negatively regulates glucose signaling during early seedling development in Arabidopsis thaliana Here, we show that under glucose-fed conditions, the Arabidopsis sr45-1 loss-of-function mutant contains higher amounts of the energy-sensing SNF1-Related Protein Kinase 1 (SnRK1) despite unaffected SnRK1 transcript levels. In agreement, marker genes for SnRK1 activity are upregulated in sr45-1 plants, and the glucose hypersensitivity of sr45-1 is attenuated by disruption of the SnRK1 gene. Using a high-resolution RT-PCR panel, we found that the sr45-1 mutation broadly targets alternative splicing in vivo, including that of the SR45 pre-mRNA itself. Importantly, the enhanced SnRK1 levels in sr45-1 are suppressed by a proteasome inhibitor, indicating that SR45 promotes targeting of the SnRK1 protein for proteasomal destruction. Finally, we demonstrate that SR45 regulates alternative splicing of the Arabidopsis 5PTase13 gene, which encodes an inositol polyphosphate 5-phosphatase previously shown to interact with and regulate the stability of SnRK1 in vitro, thus providing a mechanistic link between SR45 function and the modulation of degradation of the SnRK1 energy sensor in response to sugars. © 2016 American Society of Plant Biologists. All rights reserved.

  14. Immunohistochemical study of the growth factors, aFGF, bFGF, PDGF-AB, VEGF-A and its receptor (Flk-1) during arteriogenesis.

    PubMed

    Wu, Song; Wu, Xiaoqiong; Zhu, Wu; Cai, Wei-Jun; Schaper, Jutta; Schaper, Wolfgang

    2010-10-01

    Growth factors are viewed as main arteriogenic stimulators for collateral vessel growth. However, the information about their native expression and distribution in collateral vessels is still limited. This study was designed to profile expression of acidic and basic FGF, platelet-derived growth factor (PDGF-AB) and vascular endothelial growth factor (VEGF-A) and its receptor, fetal liver kinase-1 (Flk-1) during arteriogenesis by confocal immunofluorescence in both dog ameroid constrictor model and rabbit arteriovenous shunt model of arteriogenesis. We found that: (1) in normal arteries (NA) in dog heart, aFGF, bFGF, and PDGF-AB all were mainly expressed in endothelial cells (EC) and media smooth muscle cells (SMC), but the expression of aFGF was very weak, with those of the other two being moderate; (2) in collateral arteries (CAs), aFGF, bFGF, and PDGF-AB all were significantly upregulated (P < 0.05); they were present in all the layers of the vascular wall and were 2.1, 1.7, and 1.9 times higher than that in NA, respectively; and (3) in NA in rabbit hind limb, VEGF-A was absent, Flk-1 was only weakly present in endothelial cells, but in one week CAs VEGF-A and Flk-1 were significantly increased in both shunt and ligation sides; this was more evident in the shunt-side CAs, 2.3, and 2 times higher than that in the ligation side, respectively. In conclusion, our data demonstrate for the first time that growth factors, aFGF, bFGF, and PDGF-AB are significantly upregulated in collateral vessels in dog heart, and enhanced VEGF-A and its receptor, Flk-1, are associated with rapid and lasting increased shear stress. These findings suggest that endogenous production of growth factors could be an important factor promoting collateral vessel growth.

  15. 1,4-Bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene, a small molecule, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular Lens epithelium-derived growth factor.

    PubMed

    Gu, Wan-gang; Ip, Denis Tsz-Ming; Liu, Si-jie; Chan, Joseph H; Wang, Yan; Zhang, Xuan; Zheng, Yong-tang; Wan, David Chi-Cheong

    2014-04-25

    Translocation of viral integrase (IN) into the nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). As the first discovered cellular factor to interact with IN, Lens epithelium-derived growth factor (LEDGF/p75) plays an important role in the process of integration. Disruption of the LEDGF/p75-IN interaction has provided a great interest for anti-HIV agent discovery. In this work, we reported that one small molecular compound, 1,4-bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene(Compound 15), potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution at 1 μM. The putative binding mode of Compound 15 was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Compound 15 suppressed viral replication by measuring p24 antigen production in HIV-1IIIB acute infected C8166 cells with EC50 value of 11.19 μM. Compound 15 might supply useful structural information for further anti-HIV agent discovery. Copyright © 2014. Published by Elsevier Ireland Ltd.

  16. Transforming growth factor1 promotes breast cancer metastasis by downregulating miR-196a-3p expression.

    PubMed

    Chen, Yan; Huang, Shai; Wu, Bo; Fang, Jiankai; Zhu, Minsheng; Sun, Li; Zhang, Lifeng; Zhang, Yongsheng; Sun, Maomin; Guo, Lingling; Wang, Shouli

    2017-07-25

    Transforming growth factor1 is considered a key contributor to the progression of breast cancer. MicroRNAs are important factors in the development and progression of many malignancies. In the present study, upon studies of breast cancer cell lines and tissues, we showed that microRNA -196a-3p is decreased by transforming growth factor1 in breast cancer cells and associated with breast cancer progression. We identified neuropilin-2 as a target gene of microRNA -196a-3p and showed that it is regulated by transforming growth factor1. Moreover, transforming growth factor1-mediated inhibition of microRNA -196a-3p and activation of neuropilin-2were required for transforming growth factor1-induced migration and invasion of breast cancer cells. In addition, neuropilin-2 expression was suppressed in breast tumors, particularly in triple-negative breast cancers. Collectively, our findings strongly indicate that microRNA -196a-3p is a predictive biomarker of breast cancer metastasis and patient survival and a potential therapeutic target in metastatic breast cancer.

  17. Structure and dynamics of translation initiation factor aIF-1A from the archaeon Methanococcus jannaschii determined by NMR spectroscopy

    PubMed Central

    Li, Wei; Hoffman, David W.

    2001-01-01

    Translation initiation factor 1A (aIF-1A) from the archaeon Methanococcus jannaschii was expressed in Escherichia coli, purified, and characterized in terms of its structure and dynamics using multidimensional NMR methods. The protein was found to be a member of the OB-fold family of RNA-associated proteins, containing a barrel of five beta-strands, a feature that is shared with the homologous eukaryotic translation initiation factor 1A (eIF-1A), as well as the prokaryotic translation initiation factor IF1. External to the β barrel, aIF-1A contains an α-helix at its C-terminal and a flexible loop at its N-terminal, features that are qualitatively similar to those found in eIF-1A, but not present in prokaryotic IF1. The structural model of aIF-1A, when used in combination with primary sequence information for aIF-1A in divergent species, permitted the most-conserved residues on the protein surface to be identified, including the most likely candidates for direct interaction with the 16S ribosomal RNA and other components of the translational apparatus. Several of the conserved surface residues appear to be unique to the archaea. Nitrogen-15 relaxation and amide exchange rate data were used to characterize the internal motions within aIF-1A, providing evidence that the protein surfaces that are most likely to participate in intermolecular interactions are relatively flexible. A model is proposed, suggesting some specific interactions that may occur between aIF-1A and the small subunit of the archaeal ribosome. PMID:11714910

  18. Peptidyl Prolyl Isomerase PIN1 Directly Binds to and Stabilizes Hypoxia-Inducible Factor-1α

    PubMed Central

    Han, Hyeong-jun; Kwon, Nayoung; Choi, Min-A; Jung, Kyung Oh; Piao, Juan-Yu; Ngo, Hoang Kieu Chi; Kim, Su-Jung; Kim, Do-Hee; Chung, June-Key; Cha, Young-Nam; Youn, Hyewon; Choi, Bu Young; Min, Sang-Hyun; Surh, Young-Joon

    2016-01-01

    Peptidyl prolyl isomerase (PIN1) regulates the functional activity of a subset of phosphoproteins through binding to phosphorylated Ser/Thr-Pro motifs and subsequently isomerization of the phosphorylated bonds. Interestingly, PIN1 is overexpressed in many types of malignancies including breast, prostate, lung and colon cancers. However, its oncogenic functions have not been fully elucidated. Here, we report that PIN1 directly interacts with hypoxia-inducible factor (HIF)-1α in human colon cancer (HCT116) cells. PIN1 binding to HIF-1α occurred in a phosphorylation-dependent manner. We also found that PIN1 interacted with HIF-1α at both exogenous and endogenous levels. Notably, PIN1 binding stabilized the HIF-1α protein, given that their levels were significantly increased under hypoxic conditions. The stabilization of HIF-1α resulted in increased transcriptional activity, consequently upregulating expression of vascular endothelial growth factor, a major contributor to angiogenesis. Silencing of PIN1 or pharmacologic inhibition of its activity abrogated the angiogenesis. By utilizing a bioluminescence imaging technique, we were able to demonstrate that PIN1 inhibition dramatically reduced the tumor volume in a subcutaneous mouse xenograft model and angiogenesis as well as hypoxia-induced transcriptional activity of HIF-1α. These results suggest that PIN1 interacting with HIF-1α is a potential cancer chemopreventive and therapeutic target. PMID:26784107

  19. Kinetics of Interaction between ADP-ribosylation Factor-1 (Arf1) and the Sec7 Domain of Arno Guanine Nucleotide Exchange Factor, Modulation by Allosteric Factors, and the Uncompetitive Inhibitor Brefeldin A

    PubMed Central

    Rouhana, Jad; Padilla, André; Estaran, Sébastien; Bakari, Sana; Delbecq, Stephan; Boublik, Yvan; Chopineau, Joel; Pugnière, Martine; Chavanieu, Alain

    2013-01-01

    The GDP/GTP nucleotide exchange of Arf1 is catalyzed by nucleotide exchange factors (GEF), such as Arno, which act through their catalytic Sec7 domain. This exchange is a complex mechanism that undergoes conformational changes and intermediate complex species involving several allosteric partners such as nucleotides, Mg2+, and Sec7 domains. Using a surface plasmon resonance approach, we characterized the kinetic binding parameters for various intermediate complexes. We first confirmed that both GDP and GTP counteract equivalently to the free-nucleotide binary Arf1-Arno complex stability and revealed that Mg2+ potentiates by a factor of 2 the allosteric effect of GDP. Then we explored the uncompetitive inhibitory mechanism of brefeldin A (BFA) that conducts to an abortive pentameric Arf1-Mg2+-GDP-BFA-Sec7 complex. With BFA, the association rate of the abortive complex is drastically reduced by a factor of 42, and by contrast, the 15-fold decrease of the dissociation rate concurs to stabilize the pentameric complex. These specific kinetic signatures have allowed distinguishing the level and nature as well as the fate in real time of formed complexes according to experimental conditions. Thus, we showed that in the presence of GDP, the BFA-resistant Sec7 domain of Arno can also associate to form a pentameric complex, which suggests that the uncompetitive inhibition by BFA and the nucleotide allosteric effect combine to stabilize such abortive complex. PMID:23255605

  20. COUP-TF (chicken ovalbumin upstream promoter transcription factor)-interacting protein 1 (CTIP1) is a sequence-specific DNA binding protein.

    PubMed Central

    Avram, Dorina; Fields, Andrew; Senawong, Thanaset; Topark-Ngarm, Acharawan; Leid, Mark

    2002-01-01

    Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting proteins 1 and 2 [CTIP1/Evi9/B cell leukaemia (Bcl) l1a and CTIP2/Bcl11b respectively] are highly related C(2)H(2) zinc finger proteins that are abundantly expressed in brain and the immune system, and are associated with immune system malignancies. A selection procedure was employed to isolate high-affinity DNA binding sites for CTIP1. The core binding site on DNA identified in these studies, 5'-GGCCGG-3' (upper strand), is highly related to the canonical GC box and was bound by a CTIP1 oligomeric complex(es) in vitro. Furthermore, both CTIP1 and CTIP2 repressed transcription of a reporter gene harbouring a multimerized CTIP binding site, and this repression was neither reversed by trichostatin A (an inhibitor of known class I and II histone deacetylases) nor stimulated by co-transfection of a COUP-TF family member. These results demonstrate that CTIP1 is a sequence-specific DNA binding protein and a bona fide transcriptional repressor that is capable of functioning independently of COUP-TF family members. These findings may be relevant to the physiological and/or pathological action(s) of CTIPs in cells that do not express COUP-TF family members, such as cells of the haematopoietic and immune systems. PMID:12196208

  1. The Myb-domain protein ULTRAPETALA1 INTERACTING FACTOR 1 controls floral meristem activities in Arabidopsis.

    PubMed

    Moreau, Fanny; Thévenon, Emmanuel; Blanvillain, Robert; Lopez-Vidriero, Irene; Franco-Zorrilla, Jose Manuel; Dumas, Renaud; Parcy, François; Morel, Patrice; Trehin, Christophe; Carles, Cristel C

    2016-04-01

    Higher plants continuously and iteratively produce new above-ground organs in the form of leaves, stems and flowers. These organs arise from shoot apical meristems whose homeostasis depends on coordination between self-renewal of stem cells and their differentiation into organ founder cells. This coordination is stringently controlled by the central transcription factor WUSCHEL (WUS), which is both necessary and sufficient for stem cell specification in Arabidopsis thaliana ULTRAPETALA1 (ULT1) was previously identified as a plant-specific, negative regulator of WUS expression. However, molecular mechanisms underlying this regulation remain unknown. ULT1 protein contains a SAND putative DNA-binding domain and a B-box, previously proposed as a protein interaction domain in eukaryotes. Here, we characterise a novel partner of ULT1, named ULT1 INTERACTING FACTOR 1 (UIF1), which contains a Myb domain and an EAR motif. UIF1 and ULT1 function in the same pathway for regulation of organ number in the flower. Moreover, UIF1 displays DNA-binding activity and specifically binds to WUS regulatory elements. We thus provide genetic and molecular evidence that UIF1 and ULT1 work together in floral meristem homeostasis, probably by direct repression of WUS expression. © 2016. Published by The Company of Biologists Ltd.

  2. MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity

    PubMed Central

    Sun, Hui Bin; Zhu, Yuan Xiao; Yin, Tinggui; Sledge, George; Yang, Yu-Chung

    1998-01-01

    Identification of cytokine-inducible genes is imperative for determining the mechanisms of cytokine action. A cytokine-inducible gene, mrg1 [melanocyte-specific gene (msg1) related gene], was identified through mRNA differential display of interleukin (IL) 9-stimulated and unstimulated mouse helper T cells. In addition to IL-9, mrg1 can be induced by other cytokines and biological stimuli, including IL-1α, -2, -4, -6, and -11, granulocyte/macrophage colony-stimulating factor, interferon γ, platelet-derived growth factor, insulin, serum, and lipopolysaccharide in diverse cell types. The induction of mrg1 by these stimuli appears to be transient, with induction kinetics similar to other primary response genes, implicating its role in diverse biological processes. Deletion or point mutations of either the Box1 motif (binds Janus kinase 1) or the signal transducer and activator of transcription 3 binding site-containing region within the intracellular domain of the IL-9 receptor ligand binding subunit abolished or greatly reduced mrg1 induction by IL-9, suggesting that the Janus kinase/signal transducer and activator of transcription signaling pathway is required for mrg1 induction, at least in response to IL-9. Transfection of mrg1 cDNA into TS1, an IL-9-dependent mouse T cell line, converted these cells to IL-9-independent growth through a nonautocrine mechanism. Overexpression of mrg1 in Rat1 cells resulted in loss of cell contact inhibition, anchorage-independent growth in soft agar, and tumor formation in nude mice, demonstrating that mrg1 is a transforming gene. MRG1 is a transcriptional activator and may represent a founding member of an additional family of transcription factors. PMID:9811838

  3. Microtubule actin crosslinking factor 1 promotes osteoblast differentiation by promoting β-catenin/TCF1/Runx2 signaling axis.

    PubMed

    Hu, Lifang; Su, Peihong; Yin, Chong; Zhang, Yan; Li, Runzhi; Yan, Kun; Chen, Zhihao; Li, Dijie; Zhang, Ge; Wang, Liping; Miao, Zhiping; Qian, Airong; Xian, Cory J

    2018-02-01

    Osteoblast differentiation is a multistep process delicately regulated by many factors, including cytoskeletal dynamics and signaling pathways. Microtubule actin crosslinking factor 1 (MACF1), a key cytoskeletal linker, has been shown to play key roles in signal transduction and in diverse cellular processes; however, its role in regulating osteoblast differentiation is still needed to be elucidated. To further uncover the functions and mechanisms of action of MACF1 in osteoblast differentiation, we examined effects of MACF1 knockdown (MACF1-KD) in MC3T3-E1 osteoblastic cells on their osteoblast differentiation and associated molecular mechanisms. The results showed that knockdown of MACF1 significantly suppressed mineralization of MC3T3-E1 cells, down-regulated the expression of key osteogenic genes alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and type I collagen α1 (Col Iα1). Knockdown of MACF1 dramatically reduced the nuclear translocation of β-catenin, decreased the transcriptional activation of T cell factor 1 (TCF1), and down-regulated the expression of TCF1, lymphoid enhancer-binding factor 1 (LEF1), and Runx2, a target gene of β-catenin/TCF1. In addition, MACF1-KD increased the active level of glycogen synthase kinase-3β (GSK-3β), which is a key regulator for β-catenin signal transduction. Moreover, the reduction of nuclear β-catenin amount and decreased expression of TCF1 and Runx2 were significantly reversed in MACF1-KD cells when treated with lithium chloride, an agonist for β-catenin by inhibiting GSK-3β activity. Taken together, these findings suggest that knockdown of MACF1 in osteoblastic cells inhibits osteoblast differentiation through suppressing the β-catenin/TCF1-Runx2 axis. Thus, a novel role of MACF1 in and a new mechanistic insight of osteoblast differentiation are uncovered. © 2017 Wiley Periodicals, Inc.

  4. The POU Transcription Factor Oct-1 Represses Virus-Induced Interferon A Gene Expression

    PubMed Central

    Mesplède, Thibault; Island, Marie-Laure; Christeff, Nicolas; Petek, Fahrettin; Doly, Janine; Navarro, Sébastien

    2005-01-01

    Alpha interferon (IFN-α) and IFN-β are able to interfere with viral infection. They exert a vast array of biologic functions, including growth arrest, cell differentiation, and immune system regulation. This regulation extends from innate immunity to cellular and humoral adaptive immune responses. A strict control of expression is needed to prevent detrimental effects of unregulated IFN. Multiple IFN-A subtypes are coordinately induced in human and mouse cells infected by virus and exhibit differences in expression of their individual mRNAs. We demonstrated that the weakly expressed IFN-A11 gene is negatively regulated after viral infection, due to a distal negative regulatory element, binding homeoprotein pituitary homeobox 1 (Pitx1). Here we show that the POU protein Oct-1 binds in vitro and in vivo to the IFN-A11 promoter and represses IFN-A expression upon interferon regulatory factor overexpression. Furthermore, we show that Oct-1-deficient MEFs exhibit increased in vivo IFN-A gene expression and increased antiviral activity. Finally, the IFN-A expression pattern is modified in Oct-1-deficient MEFs. The broad representation of effective and potent octamer-like sequences within IFN-A promoters suggests an important role for Oct-1 in IFN-A regulation. PMID:16166650

  5. Is there a relationship between genetic factors and the incidence and severity of H1N1 in Kosova?: A preliminary investigation and pointers for further research.

    PubMed

    Dreshaj, Shemsedin; Alija, Avdulla J; Schlagenhauf, Patricia; Doda, Teuta; Geca, Njomeza; Bajraktari, Ismet; Bresgen, Nikolaus; Eckl, Peter M

    Host genetic factors may impact susceptibility to infection. A small number of studies have investigated the association between factors such as ABO blood groups and selected phenotypes on the incidence and severity of H1N1 infections with inconclusive results. Using data from the Clinic of Infectious Diseases - University Clinical Centre Prishtina and based on the examination of 125 patients hospitalized with H1N1 in the period 2009-2014, the frequency of blood groups from ABO and Rhesus (Rh) systems as phenotypical markers were evaluated. In addition, other phenotypes such as ear lobe free/ear lobe attached, normal chin/cleft chin, tongue roller/non roller, hand clasping right thumb over/hand clasping left thumb over, right-handed/left-handed, dark eyes/light eyes were also analyzed. The data obtained from the 125 hospitalized patients were compared with the data from the Kosovar population (n = 2000) as a reference group. A total of 303 patients with H1N1 were hospitalized in the period 2009-2015. Blood group and phenotype data available from 125 hospitalized H1N1 patients showed significant differences in the frequencies of the blood groups from Rh system as well as in two (out of six) phenotypes of the selected morphological traits compared to reference groups. The findings from this preliminary study indicate that these Rh system and phenotype differences may be linked to H1N1 susceptibility and may guide identification of risk groups and populations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. HIF-1 α as a Key Factor in Bile Duct Ligation-Induced Liver Fibrosis in Rats.

    PubMed

    Moczydlowska, Joanna; Miltyk, Wojciech; Hermanowicz, Adam; Lebensztejn, Dariusz M; Palka, Jerzy A; Debek, Wojciech

    2017-02-01

    Although several studies suggested hypoxia as an important microenvironmental factor contributing to inflammation and fibrosis in chronic liver diseases, the mechanism of this process is not fully understood. We considered hypoxia inducible factor (HIF-1α) as a key transcription factor in liver fibrosis. The aim of the study was to evaluate the mechanisms of signaling pathway during bile duct ligation (BDL)-induced liver fibrosis in rats. BDL animal model of liver fibrosis was used in the study. Male Wistar rats were divided randomly into two experimental groups: sham group (n = 15), BDL group (n = 30). Hydroxyproline (Hyp) content as a marker of collagen accumulation in liver of rats subjected to BDL was evaluated according to the method described by Gerling B et al. Expression of signaling proteins [integrin β 1 receptor, HIF-1α, nuclear factor kappa B (NF-κB), and transforming growth factor (TGF-β)] was evaluated applying Western-immunoblot analysis. In all experiments, the mean values for six assays ± standard deviations (SD) were calculated. The results were submitted to the statistical analysis using the Student's "t" test, accepting p < 0.05 as significant. Ligation of bile ducts was found to increase Hyp content in rat liver, accompanied by increase of HIF-1α expression during 10 weeks after BDL. The Hyp level was time dependent. There was not such a difference in control group (p < 0.001). Simultaneously expression of NF-κB, TGF-β, β 1 -integrin receptor was significantly elevated starting from sixth week after ligation. Activity of metalloproteinases 2 and 9 in the livers were increased 1 week after surgery and remained increased until the end of the experiment. The mechanism of development of liver fibrosis involves activation of Matrix metalloproteinase-2 (MMP-2) and Matrix metalloproteinase-9 (MMP-9), upregulation of HIF-1α transcriptional activity and its related factors, NF-κB and TGF-β. It suggests that they may represent targets for

  7. Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors

    PubMed Central

    Binder, Gerhard; Weber, Karin; Apel, Anja; Roeben, Benjamin; Deuschle, Christian; Maechtel, Mirjam; Heger, Tanja; Nussbaum, Susanne; Gasser, Thomas; Maetzler, Walter; Berg, Daniela

    2016-01-01

    Introduction Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinson's disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). Materials and Methods IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: ≤3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. Results PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. Discussion Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders. PMID:26967642

  8. Sociodemographic Factors and Clinical Conditions Associated to Hospitalization in Influenza A (H1N1) 2009 Virus Infected Patients in Spain, 2009–2010

    PubMed Central

    González-Candelas, Fernando; Astray, Jenaro; Alonso, Jordi; Castro, Ady; Cantón, Rafael; Galán, Juan Carlos; Garin, Olatz; Sáez, Marc; Soldevila, Nuria; Baricot, Maretva; Castilla, Jesús; Godoy, Pere; Delgado-Rodríguez, Miguel; Martín, Vicente; Mayoral, José María; Pumarola, Tomás; Quintana, José María; Tamames, Sonia; Domínguez, Angela

    2012-01-01

    The emergence and pandemic spread of a new strain of influenza A (H1N1) virus in 2009 resulted in a serious alarm in clinical and public health services all over the world. One distinguishing feature of this new influenza pandemic was the different profile of hospitalized patients compared to those from traditional seasonal influenza infections. Our goal was to analyze sociodemographic and clinical factors associated to hospitalization following infection by influenza A(H1N1) virus. We report the results of a Spanish nationwide study with laboratory confirmed infection by the new pandemic virus in a case-control design based on hospitalized patients. The main risk factors for hospitalization of influenza A (H1N1) 2009 were determined to be obesity (BMI≥40, with an odds-ratio [OR] 14.27), hematological neoplasia (OR 10.71), chronic heart disease, COPD (OR 5.16) and neurological disease, among the clinical conditions, whereas low education level and some ethnic backgrounds (Gypsies and Amerinds) were the sociodemographic variables found associated to hospitalization. The presence of any clinical condition of moderate risk almost triples the risk of hospitalization (OR 2.88) and high risk conditions raise this value markedly (OR 6.43). The risk of hospitalization increased proportionally when for two (OR 2.08) or for three or more (OR 4.86) risk factors were simultaneously present in the same patient. These findings should be considered when a new influenza virus appears in the human population. PMID:22412995

  9. TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I assembly factor through association with the MCIA complex.

    PubMed

    Guarani, Virginia; Paulo, Joao; Zhai, Bo; Huttlin, Edward L; Gygi, Steven P; Harper, J Wade

    2014-03-01

    Complex I (CI) of the electron transport chain, a large membrane-embedded NADH dehydrogenase, couples electron transfer to the release of protons into the mitochondrial inner membrane space to promote ATP production through ATP synthase. In addition to being a central conduit for ATP production, CI activity has been linked to neurodegenerative disorders, including Parkinson's disease. CI is built in a stepwise fashion through the actions of several assembly factors. We employed interaction proteomics to interrogate the molecular associations of 15 core subunits and assembly factors previously linked to human CI deficiency, resulting in a network of 101 proteins and 335 interactions (edges). TIMMDC1, a predicted 4-pass membrane protein, reciprocally associated with multiple members of the MCIA CI assembly factor complex and core CI subunits and was localized in the mitochondrial inner membrane, and its depletion resulted in reduced CI activity and cellular respiration. Quantitative proteomics demonstrated a role for TIMMDC1 in assembly of membrane-embedded and soluble arms of the complex. This study defines a new membrane-embedded CI assembly factor and provides a resource for further analysis of CI biology.

  10. Tissue factor transcription driven by Egr-1 is a critical mechanism of murine pulmonary fibrin deposition in hypoxia

    PubMed Central

    Yan, Shi-Fang; Zou, Yu Shan; Gao, Yun; Zhai, Chao; Mackman, Nigel; Lee, Stephen L.; Milbrandt, Jeffrey; Pinsky, David; Kisiel, Walter; Stern, David

    1998-01-01

    Local hypoxemia and stasis trigger thrombosis. We have demonstrated previously that in a murine model of normobaric hypoxia pulmonary fibrin deposition is a result of expression of tissue factor, especially in oxygen-deprived mononuclear phagocytes (MPs). We now show that transcription factor early-growth-response gene product (Egr-1) is rapidly activated in hypoxia, both in vitro and in vivo, and is responsible for transcription and expression of tissue factor in hypoxic lung. MPs and HeLa cells subjected to hypoxia (pO2 ≈13 torr) had increased levels of tissue factor transcripts (≈18-fold) and an increased rate of transcription (≈15-fold), based on nuclear run-on analysis. Gel-shift analysis of nuclear extracts from hypoxic MPs and HeLa cells demonstrated increased DNA-binding activity at the serum response region (SRR; −111/+14 bp) of the tissue factor promoter at Egr-1 motifs. Using 32P-labeled Egr consensus oligonucleotide, we observed induction of DNA-binding activity in nuclear extracts from hypoxic lung and HeLa cells because of activation of Egr-1, by means of supershift analysis. Transient transfection of HeLa cells with chimeric plasmids containing wild-type or mutant SRR from the tissue factor promoter showed that intact Sp1 sites are necessary for basal promoter activity, whereas the integrity of Egr-1 sites was required for hypoxia-enhanced expression. A central role for Egr-1 in hypoxia-mediated tissue factor expression was confirmed by experiments with homozygous Egr-1 null mice; wild-type mice subjected to oxygen deprivation expressed tissue factor and showed fibrin deposition, but hypoxic homozygous Egr-1 null mice displayed neither tissue factor nor fibrin. These data delineate a novel biology for hypoxia-induced fibrin deposition, in which oxygen deprivation-induced activation of Egr-1, resulting in expression of tissue factor, has an unexpected and central role. PMID:9653181

  11. HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA.

    PubMed

    Ren, Xiao-Xin; Wang, Hai-Bo; Li, Chuan; Jiang, Jin-Feng; Xiong, Si-Dong; Jin, Xia; Wu, Li; Wang, Jian-Hua

    2016-02-26

    HIV-1 depends on host-cell-encoded factors to complete its life cycle. A comprehensive understanding of how HIV-1 manipulates host machineries during viral infection can facilitate the identification of host targets for antiviral drugs or gene therapy. The cellular protein Naf1 (HIV-1 Nef-associated factor 1) is a CRM1-dependent nucleo-cytoplasmic shuttling protein, and has been identified to regulate multiple receptor-mediated signal pathways in inflammation. The cytoplasm-located Naf1 can inhibit NF-κB activation through binding to A20, and the loss of Naf1 controlled NF-κB activation is associated with multiple autoimmune diseases. However, the effect of Naf1 on HIV-1 mRNA expression has not been characterized. In this study we found that the nucleus-located Naf1 could promote nuclear export of unspliced HIV-1 gag mRNA. We demonstrated that the association between Naf1 and CRM1 was required for this function as the inhibition or knockdown of CRM1 expression significantly impaired Naf1-promoted HIV-1 production. The mutation of Naf1 nuclear export signals (NESs) that account for CRM1 recruitment for nuclear export decreased Naf1 function. Additionally, the mutation of the nuclear localization signal (NLS) of Naf1 diminished its ability to promote HIV-1 production, demonstrating that the shuttling property of Naf1 is required for this function. Our results reveal a novel role of Naf1 in enhancing HIV-1 production, and provide a potential therapeutic target for controlling HIV-1 infection. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. A Cyclin T1 point mutation that abolishes positive transcription elongation factor (P-TEFb) binding to Hexim1 and HIV tat

    PubMed Central

    2014-01-01

    Background The positive transcription elongation factor b (P-TEFb) plays an essential role in activating HIV genome transcription. It is recruited to the HIV LTR promoter through an interaction between the Tat viral protein and its Cyclin T1 subunit. P-TEFb activity is inhibited by direct binding of its subunit Cyclin T (1 or 2) with Hexim (1 or 2), a cellular protein, bound to the 7SK small nuclear RNA. Hexim1 competes with Tat for P-TEFb binding. Results Mutations that impair human Cyclin T1/Hexim1 interaction were searched using systematic mutagenesis of these proteins coupled with a yeast two-hybrid screen for loss of protein interaction. Evolutionary conserved Hexim1 residues belonging to an unstructured peptide located N-terminal of the dimerization domain, were found to be critical for P-TEFb binding. Random mutagenesis of the N-terminal region of Cyclin T1 provided identification of single amino-acid mutations that impair Hexim1 binding in human cells. Furthermore, conservation of critical residues supported the existence of a functional Hexim1 homologue in nematodes. Conclusions Single Cyclin T1 amino-acid mutations that impair Hexim1 binding are located on a groove between the two cyclin folds and define a surface overlapping the HIV-1 Tat protein binding surface. One residue, Y175, in the centre of this groove was identified as essential for both Hexim1 and Tat binding to P-TEFb as well as for HIV transcription. PMID:24985203

  13. The role of socio-economic and clinical factors on HbA1c in children and adolescents with type 1 diabetes: an Italian multicentre survey.

    PubMed

    Gesuita, Rosaria; Skrami, Edlira; Bonfanti, Riccardo; Cipriano, Paola; Ferrito, Lucia; Frongia, Paola; Iafusco, Dario; Iannilli, Antonio; Lombardo, Fortunato; Mozzillo, Enza; Paleari, Renata; Rabbone, Ivana; Sabbion, Alberto; Salvatoni, Alessandro; Scaramuzza, Andrea; Schiaffini, Riccardo; Sulli, Nicoletta; Toni, Sonia; Carle, Flavia; Cherubini, Valentino

    2017-05-01

    To identify the role of the family's socio-economic and clinical characteristics on metabolic control in children and adolescents with type 1 diabetes. In this cross-sectional, multicentre study, 768 subjects with type 1 diabetes under 18 years of age were consecutively recruited from January 2008 to February 2009. Target condition was considered for HbA 1c values <7.5% (<58 mmol/mol). A multiple correspondence analysis (MCA) was performed to analyze the association between the socio-economic and clinical characteristics of the participants. A logistic regression analysis was performed to identify factors associated with the subjects metabolic control. In both analyses, the family's socio-economic status was represented, measured by the Hollingshead Four-Factor Index of Social Status (SES) or by parental years of education. A total of 28.1% of subjects reached target HbA1c values. The MCA identified a strong association between at-target condition and several factors: high levels of SES or high levels of parental education, the use of the carbohydrate counting system, the use of insulin pumps, the use of the insulin delivery system over a short period of time, a normal body mass index. The logistic regression analysis showed that SES and the mother's years of education were significantly associated with the target condition [odds ratio (OR): 1.01, 95% confidence interval (CI): 1.01-1.03, p = 0.029; OR: 1.05, 95% CI: 1.01-1.10, p = 0.027, respectively). Personal, clinical, and family characteristics were found to be associated with HbA 1c target. Their identification can be crucial in addressing strategies to optimize metabolic control and improve diabetes management. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Transcription factor EGR-1 suppresses the growth and transformation of human HT-1080 fibrosarcoma cells by induction of transforming growth factor beta 1.

    PubMed Central

    Liu, C; Adamson, E; Mercola, D

    1996-01-01

    The early growth response 1 (EGR-1) gene product is a transcription factor with role in differentiation and growth. We have previously shown that expression of exogenous EGR-1 in various human tumor cells unexpectedly and markedly reduces growth and tumorigenicity and, conversely, that suppression of endogenous Egr-1 expression by antisense RNA eliminates protein expression, enhances growth, and promotes phenotypic transformation. However, the mechanism of these effects remained unknown. The promoter of human transforming growth factor beta 1 (TGF-beta 1) contains two GC-rich EGR-1 binding sites. We show that expression of EGR-1 in human HT-1080 fibrosarcoma cells uses increased secretion of biologically active TGF-beta 1 in direct proportion (rPearson = 0.96) to the amount of EGR-1 expressed and addition of recombinant human TGF-beta 1 is strongly growth-suppressive for these cells. Addition of monoclonal anti-TGF-beta 1 antibodies to EGR-1-expressing HT-1080 cells completely reverses the growth inhibitory effects of EGR-1. Reporter constructs bearing the EGR-1 binding segment of the TGF-beta 1 promoter was activated 4- to 6-fold relative to a control reporter in either HT-1080 cells that stably expressed or parental cells cotransfected with an EGR-1 expression vector. Expression of delta EGR-1, a mutant that cannot interact with the corepressors, nerve growth factor-activated factor binding proteins NAB1 and NAB2, due to deletion of the repressor domain, exhibited enhanced transactivation of 2- to 3.5-fold over that of wild-type EGR-1 showing that the reporter construct reflected the appropriate in vivo regulatory context. The EGR-1-stimulated transactivation was inhibited by expression of the Wilms tumor suppressor, a known specific DNA-binding competitor. These results indicate that EGR-1 suppresses growth of human HT-1080 fibrosarcoma cells by induction of TGF-beta 1. Images Fig. 1 Fig. 5 PMID:8876223

  15. Hox repertoires for motor neuron diversity and connectivity gated by a single accessory factor, FoxP1.

    PubMed

    Dasen, Jeremy S; De Camilli, Alessandro; Wang, Bin; Tucker, Philip W; Jessell, Thomas M

    2008-07-25

    The precision with which motor neurons innervate target muscles depends on a regulatory network of Hox transcription factors that translates neuronal identity into patterns of connectivity. We show that a single transcription factor, FoxP1, coordinates motor neuron subtype identity and connectivity through its activity as a Hox accessory factor. FoxP1 is expressed in Hox-sensitive motor columns and acts as a dose-dependent determinant of columnar fate. Inactivation of Foxp1 abolishes the output of the motor neuron Hox network, reverting the spinal motor system to an ancestral state. The loss of FoxP1 also changes the pattern of motor neuron connectivity, and in the limb motor axons appear to select their trajectories and muscle targets at random. Our findings show that FoxP1 is a crucial determinant of motor neuron diversification and connectivity, and clarify how this Hox regulatory network controls the formation of a topographic neural map.

  16. BRCA1: A Novel Prognostic Factor in Resected Non-Small-Cell Lung Cancer

    PubMed Central

    Rosell, Rafael; Skrzypski, Marcin; Jassem, Ewa; Taron, Miquel; Bartolucci, Roberta; Sanchez, Jose Javier; Mendez, Pedro; Chaib, Imane; Perez-Roca, Laia; Szymanowska, Amelia; Rzyman, Witold; Puma, Francesco; Kobierska-Gulida, Grazyna; Farabi, Raffaele; Jassem, Jacek

    2007-01-01

    Background Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). Methodology and Principal Findings We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). Conclusions Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional

  17. Type 1 diabetes in children is not a predisposing factor for oral yeast colonization.

    PubMed

    Costa, Ana L; Silva, Branca M A; Soares, Rui; Mota, Diana; Alves, Vera; Mirante, Alice; Ramos, João C; Maló de Abreu, João; Santos-Rosa, Manuel; Caramelo, Francisco; Gonçalves, Teresa

    2017-06-01

    Type 1 diabetes mellitus (T1D) is considered a risk factor associated with oral yeast infections. The aim of this study was to evaluate the yeast oral carriage (in saliva and mucosal surface) of children with T1D and potential relation with host factors, particularly the subset of CD4+ T cells. Yeasts were quantified and identified in stimulated saliva and in cheek mucosal swabs of 133 diabetic T1D and 72 healthy control subjects. Salivary lymphocytes were quantified using flow cytometry. The presence of yeasts in the oral cavity (60% of total patients) was not affected by diabetes, metabolic control, duration of the disease, salivary flow rate or saliva buffer capacity, by age, sex, place of residence, number of daily meals, consumption of sweets or frequency of tooth brushing. Candida albicans was the most prevalent yeast species, but a higher number of yeast species was isolated in nondiabetics. T1D children with HbA1c ≤ 7.5 (metabolically controlled) presented higher number of CD4+ T salivary subsets when compared with the other groups of children (non-diabetic and nonmetabolically controlled) and also presented the highest number of individuals without oral yeast colonization. In conclusion, T1D does not predisposes for increased oral yeast colonization and a higher number of salivary CD4+T cells seems to result in the absence of oral colonization by yeasts. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Human brain factor 1, a new member of the fork head gene family

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Murphy, D.B.; Wiese, S.; Burfeind, P.

    1994-06-01

    Analysis of cDNA clones that cross-hybridized with the fork head domain of the rat HNF-3 gene family revealed 10 cDNAs from human fetal brain and human testis cDNA libraries containing this highly conserved DNA-binding domain. Three of these cDNAs (HFK1, HFK2, and HFK3) were further analyzed. The cDNA HFK1 has a length of 2557 nucleotides and shows strong homology at the nucleotide level (91.2%) to brain factor 1 (BF-1) from rat. The HFK1 cDNA codes for a putative 476 amino acid protein. The homology to BF-1 from rat in the coding region at the amino acid level is 87.5%. Themore » fork head homologous region includes 111 amino acids starting at amino acid 160 and has a 97.5% homology to BF-1. Southern hybridization revealed that HFK1 is highly conserved among mammalian species and possibly birds. Northern analysis with total RNA from human tissues and poly(A)-rich RNA from mouse revealed a 3.2-kb transcript that is present in human and mouse fetal brain and in adult mouse brain. In situ hybridization with sections of mouse embryo and human fetal brain reveals that HFK1 expression is restricted to the neuronal cells in the telencepthalon, with strong expression being observed in the developing dentate gyrus and hippocampus. HFK1 was chromosomally localized by in situ hybridization to 14q12. The cDNA clones HFK2 and HFK3 were analyzed by restriction analysis and sequencing. HFK2 and HFK3 were found to be closely related but different from HFK1. Therefore, it would appear that HFK1, HFK2, HFK3, and BF-1 form a new fork head related subfamily. 33 refs., 6 figs.« less

  19. RNAi of COL1A1 in mesenchymal progenitor cells.

    PubMed

    Millington-Ward, Sophia; McMahon, Helena P; Allen, Danny; Tuohy, Gearóid; Kiang, Anna-Sophia; Palfi, Arpad; Kenna, Paul F; Humphries, Peter; Farrar, G Jane

    2004-10-01

    Given that mutant COL1A1 is known to cause Osteogenesis Imperfecta (OI), tools to modulate COL1A1 expression are likely to be of significant therapeutic value. In this context, we have evaluated RNA interference (RNAi) as a means to downregulate COL1A1 expression in Cos-7 cells and in human mesenchymal progenitor stem cells (MPCs), the latter cells giving rise to bone and therefore representing a target cell type for collagen-related disorders. In addition, allele-specificity, a key factor to the success of RNAi-based suppression, was explored with a view to developing a mutation-independent RNAi-based therapeutic for OI by targeting an intragenic SNP within transcripts derived from the COL1A1 gene. Preferential suppression of individual polymorphic alleles that differed by a single nucleotide was observed.

  20. TRPV1 recapitulates native capsaicin receptor in sensory neurons in association with Fas-associated factor 1.

    PubMed

    Kim, Sangsung; Kang, Changjoong; Shin, Chan Young; Hwang, Sun Wook; Yang, Young Duk; Shim, Won Sik; Park, Min-Young; Kim, Eunhee; Kim, Misook; Kim, Byung-Moon; Cho, Hawon; Shin, Youngki; Oh, Uhtaek

    2006-03-01

    TRPV1, a cloned capsaicin receptor, is a molecular sensor for detecting adverse stimuli and a key element for inflammatory nociception and represents biophysical properties of native channel. However, there seems to be a marked difference between TRPV1 and native capsaicin receptors in the pharmacological response profiles to vanilloids or acid. One plausible explanation for this overt discrepancy is the presence of regulatory proteins associated with TRPV1. Here, we identify Fas-associated factor 1 (FAF1) as a regulatory factor, which is coexpressed with and binds to TRPV1 in sensory neurons. When expressed heterologously, FAF1 reduces the responses of TRPV1 to capsaicin, acid, and heat, to the pharmacological level of native capsaicin receptor in sensory neurons. Furthermore, silencing FAF1 by RNA interference augments capsaicin-sensitive current in native sensory neurons. We therefore conclude that FAF1 forms an integral component of the vanilloid receptor complex and that it constitutively modulates the sensitivity of TRPV1 to various noxious stimuli in sensory neurons.

  1. Transforming growth factor-beta1 accelerates resorption of a calcium carbonate biomaterial in periodontal defects.

    PubMed

    Koo, Ki-Tae; Susin, Cristiano; Wikesjö, Ulf M E; Choi, Seong-Ho; Kim, Chong-Kwan

    2007-04-01

    In a previous study, recombinant human transforming growth factor-beta1 (rhTGF-beta(1)) in a calcium carbonate carrier was implanted into critical-size, supraalveolar periodontal defects under conditions for guided tissue regeneration (GTR) to study whether rhTGF-beta(1) would enhance or accelerate periodontal regeneration. The results showed minimal benefits of rhTGF-beta(1), and a clear account for this could not be offered. One potential cause may be that the rhTGF-beta(1) formulation was biologically inactive. Several growth or differentiation factors have been suggested to accelerate degradation of biomaterials used as carriers. The objective of this study was to evaluate possible activity of rhTGF-beta(1) on biodegradation of the calcium carbonate carrier. rhTGF-beta(1) in a putty-formulated particulate calcium carbonate carrier was implanted into critical-size, supraalveolar periodontal defects under conditions for GTR in five beagle dogs. Contralateral defects received the calcium carbonate carrier combined with GTR without rhTGF-beta(1) (control). The animals were euthanized at week 4 post-surgery and block biopsies of the defect sites were collected for histologic and histometric analysis. Radiographs were obtained at defect creation and weeks 2 and 4 after defect creation. No statistically significant differences were observed in new bone formation (bone height and area) among the treatments. However, total residual carrier was significantly reduced in sites receiving rhTGF-beta(1) compared to control (P = 0.04). Similarly, carrier density was considerably reduced in sites receiving rhTGF-beta(1) compared to control; the difference was borderline statistically significant (P = 0.06). Within the limitations of the study, it may be concluded that rhTGF-beta(1) accelerates biodegradation of a particulate calcium carbonate biomaterial, indicating a biologic activity of the rhTGF-beta(1) formulation apparently not encompassing enhanced or accelerated

  2. Splicing Factor 1 Modulates Dietary Restriction and TORC1 Pathway Longevity in C. elegans

    PubMed Central

    Heintz, Caroline; Escoubas, Caroline; Zhang, Yue; Weir, Heather J.; Dutta, Sneha; Silva-García, Carlos Giovanni; Bruun, Gitte Hoffmann; Morantte, Ianessa; Hoxhaj, Gerta; Manning, Brendan D.; Andresen, Brage S.; Mair, William B.

    2016-01-01

    Ageing is driven by a loss of transcriptional and protein homeostasis1–3 and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction seen with age therefore have potential to reduce overall disease risk in the elderly. Pre-mRNA splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to multiple age-related chronic diseases4,5. However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or on dietary restriction (DR), we find defects in global pre-mRNA splicing with age that are reduced by DR via the branch point binding protein (BBP)/splicing factor 1 (SFA-1). We show that SFA-1 is specifically required for lifespan extension both by DR, and modulation of TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 Kinase. Lastly, we demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in DR longevity and suggest modulation of specific spliceosome components can prolong healthy ageing. PMID:27919065

  3. Egr-1: A Candidate Transcription Factor Involved in Molecular Processes Underlying Time-Memory.

    PubMed

    Shah, Aridni; Jain, Rikesh; Brockmann, Axel

    2018-01-01

    In honey bees, continuous foraging is accompanied by a sustained up-regulation of the immediate early gene Egr-1 (early growth response protein-1) and candidate downstream genes involved in learning and memory. Here, we present a series of feeder training experiments indicating that Egr-1 expression is highly correlated with the time and duration of training even in the absence of the food reward. Foragers that were trained to visit a feeder over the whole day and then collected on a day without food presentation showed Egr-1 up-regulation over the whole day with a peak expression around 14:00. When exposed to a time-restricted feeder presentation, either 2 h in the morning or 2 h in the evening, Egr-1 expression in the brain was up-regulated only during the hours of training. Foragers that visited a feeder in the morning as well as in the evening showed two peaks of Egr-1 expression. Finally, when we prevented time-trained foragers from leaving the colony using artificial rain, Egr-1 expression in the brains was still slightly but significantly up-regulated around the time of feeder training. In situ hybridization studies showed that active foraging and time-training induced Egr-1 up-regulation occurred in the same brain areas, preferentially the small Kenyon cells of the mushroom bodies and the antennal and optic lobes. Based on these findings we propose that foraging induced Egr-1 expression can get regulated by the circadian clock after time-training over several days and Egr-1 is a candidate transcription factor involved in molecular processes underlying time-memory.

  4. Inhibition of Gluconeogenesis in Primary Hepatocytes by Stromal Cell-derived Factor-1 (SDF-1) through a c-Src/Akt-dependent Signaling Pathway*

    PubMed Central

    Liu, Hui-Yu; Wen, Ge-Bo; Han, Jianmin; Hong, Tao; Zhuo, Degen; Liu, Zhenqi; Cao, Wenhong

    2008-01-01

    Hepatic gluconeogenesis is elevated in diabetes and a major contributor to hyperglycemia. Stromal cell-derived factor-1 (SDF-1) is a chemokine and an activator of Akt. In this study, we tested the hypothesis that SDF-1 suppresses hepatic gluconeogenesis through Akt. Our results from isolated primary hepatocytes show that SDF-1α and SDF-1β inhibited glucose production via gluconeogenesis and reduced transcript levels of key gluconeogenic genes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Additionally, SDF-1α and SDF-1β both inhibited activation of the PEPCK promoter. In examining the mechanism by which SDF-1 inhibits gluconeogenesis, we found that SDF-1 promoted phosphorylation of Akt, FoxO1, and c-Src, but did not activate insulin receptor substrate-1-like insulin. Blockade of Akt activation by LY294002, FoxO1 translocation by constitutively nuclear FoxO1 mutant, or c-Src activation by the chemical inhibitor PP2, respectively, blunted SDF-1 suppression of gluconeogenesis. Finally, our results show that knocking down the level of SDF-1 receptor CXCR4 mRNA blocked SDF-1 suppression of gluconeogenesis. Together, our results demonstrate that SDF-1 is capable of inhibiting gluconeogenesis in primary hepatocytes through a signaling pathway distinct from the insulin signaling. PMID:18786922

  5. Structural analysis of the Sil1-Bip complex reveals the mechanism for Sil1 to function as a nucleotide-exchange factor

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yan, Ming; Li, Jingzhi; Sha, Bingdong

    2013-01-16

    Sil1 functions as a NEF (nucleotide-exchange factor) for the ER (endoplasmic reticulum) Hsp70 (heat-shock protein of 70 kDa) Bip in eukaryotic cells. Sil1 may catalyse the ADP release from Bip by interacting directly with the ATPase domain of Bip. In the present study we show the complex crystal structure of the yeast Bip and the NEF Sil1 at the resolution of 2.3 {angstrom} (1 {angstrom} = 0.1 nm). In the Sil1-Bip complex structure, the Sil1 molecule acts as a 'clamp' which binds lobe IIb of the Bip ATPase domain. The binding of Sil1 causes the rotation of lobe IIb {approx}more » 13.5{sup o} away from the ADP-binding pocket. The complex formation also induces lobe Ib to swing in the opposite direction by {approx} 3.7{sup o}. These conformational changes open up the nucleotide-binding pocket in the Bip ATPase domain and disrupt the hydrogen bonds between Bip and bound ADP, which may catalyse ADP release. Mutation of the Sil1 residues involved in binding the Bip ATPase domain compromise the binding affinity of Sil1 to Bip, and these Sil1 mutants also abolish the ability to stimulate the ATPase activity of Bip.« less

  6. Regulation of tissue factor and inflammatory mediators by Egr-1 in a mouse endotoxemia model.

    PubMed

    Pawlinski, Rafal; Pedersen, Brian; Kehrle, Bettina; Aird, William C; Frank, Rolf D; Guha, Mausumee; Mackman, Nigel

    2003-05-15

    In septic shock, tissue factor (TF) activates blood coagulation, and cytokines and chemokines orchestrate an inflammatory response. In this study, the role of Egr-1 in lipopolysaccharide (LPS) induction of TF and inflammatory mediators in vivo was evaluated using Egr-1(+/+) and Egr-1(-/-) mice. Administration of LPS transiently increased the steady-state levels of Egr-1 mRNA in the kidneys and lungs of Egr-1(+/+) mice with maximal induction at one hour. Egr-1 was expressed in epithelial cells in the kidneys and lungs in untreated and LPS-treated mice. LPS induction of monocyte chemoattractant protein mRNA in the kidneys and lungs of Egr-1(-/-) mice was not affected at 3 hours, but its expression was significantly reduced at 8 hours compared with the expression observed in Egr-1(+/+) mice. Similarly, LPS induction of TF mRNA expression in the kidneys and lungs at 8 hours was reduced in Egr-1(-/-) mice. However, Egr-1 deficiency did not affect plasma levels of tumor necrosis factor alpha in endotoxemic mice. Moreover, Egr-1(+/+) and Egr-1(-/-) mice exhibited similar survival times in a model of acute endotoxemia. These data indicate that Egr-1 does not contribute to the early inflammatory response in the kidneys and lungs or the early systemic inflammatory response in endotoxemic mice. However, Egr-1 does contribute to the sustained expression of inflammatory mediators and to the maximal expression of TF at 8 hours in the kidneys and lungs.

  7. Malat1 regulates serum response factor through miR-133 as a competing endogenous RNA in myogenesis.

    PubMed

    Han, Xiaorui; Yang, Feng; Cao, Huiqing; Liang, Zicai

    2015-07-01

    Metastasis-associated lung adenocarcinoma transcript 1 (Malat1) is an example of a functional long noncoding RNA involved in many biologic processes. However, the mechanisms for Malat1 in myogenesis are unclear. Serum response factor (SRF) is a pivotal transcription factor for muscle proliferation and differentiation and is reported to be a target gene for muscle-specific microRNA-133 (miR-133). In this study, we initially found that silencing Malat1 in the mouse myoblast C2C12 cell line inhibited myocyte differentiation and decreased Srf at both the RNA and protein levels. Srf silencing decreased Malat1 expression as well. Further study revealed that Malat1 contained an miR-133 functional target site, and the interplay between Malat1 and Srf was miR-133 dependent. We demonstrated that Malat1 modulates Srf through miR-133 as a competing endogenous RNA and established a novel connection among Malat1, miR-133, and Srf in myoblast differentiation. © FASEB.

  8. PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia

    PubMed Central

    Mudie, Sharon; Bandarra, Daniel; Batie, Michael; Biddlestone, John; Moniz, Sonia; Ortmann, Brian; Shmakova, Alena; Rocha, Sonia

    2014-01-01

    Hypoxia is an important developmental cue for multicellular organisms but it is also a contributing factor for several human pathologies, such as stroke, cardiovascular diseases and cancer. In cells, hypoxia activates a major transcriptional program coordinated by the Hypoxia Inducible Factor (HIF) family. HIF can activate more than one hundred targets but not all of them are activated at the same time, and there is considerable cell type variability. In this report we identified the paired-like homeodomain pituitary transcription factor (PITX1), as a transcription factor that helps promote specificity in HIF-1α dependent target gene activation. Mechanistically, PITX1 associates with HIF-1β and it is important for the induction of certain HIF-1 dependent genes but not all. In particular, PITX1 controls the HIF-1α-dependent expression of the histone demethylases; JMJD2B, JMJD2A, JMJD2C and JMJD1B. Functionally, PITX1 is required for the survival and proliferation responses in hypoxia, as PITX1 depleted cells have higher levels of apoptotic markers and reduced proliferation. Overall, our study identified PITX1 as a key specificity factor in HIF-1α dependent responses, suggesting PITX1 as a protein to target in hypoxic cancers. PMID:25558831

  9. The Role of Factor Inhibiting HIF (FIH-1) in Inhibiting HIF-1 Transcriptional Activity in Glioblastoma Multiforme

    PubMed Central

    Liu, Fengming; Wu, Gang; Schroeder, Mark A.; Lau, Julie S.; Mukhopadhyay, Debabrata; Jiang, Shi-Wen; O'Neill, Brian Patrick; Datta, Kaustubh; Li, Jinping

    2014-01-01

    Glioblastoma multiforme (GBM) accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1), which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis. PMID:24465898

  10. Regulation of RE1 Protein Silencing Transcription Factor (REST) Expression by HIP1 Protein Interactor (HIPPI)*

    PubMed Central

    Datta, Moumita; Bhattacharyya, Nitai P.

    2011-01-01

    Earlier we have shown that the proapoptotic protein HIPPI (huntingtin interacting protein 1 (HIP1) protein interactor) along with its molecular partner HIP1 could regulate transcription of the caspase-1 gene. Here we report that RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a new transcriptional target of HIPPI. HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). The ability of HIPPI to activate REST gene transcription was dependent on HIP1, the nuclear transporter of HIPPI. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease. PMID:21832040

  11. Regulation of RE1 protein silencing transcription factor (REST) expression by HIP1 protein interactor (HIPPI).

    PubMed

    Datta, Moumita; Bhattacharyya, Nitai P

    2011-09-30

    Earlier we have shown that the proapoptotic protein HIPPI (huntingtin interacting protein 1 (HIP1) protein interactor) along with its molecular partner HIP1 could regulate transcription of the caspase-1 gene. Here we report that RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a new transcriptional target of HIPPI. HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). The ability of HIPPI to activate REST gene transcription was dependent on HIP1, the nuclear transporter of HIPPI. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease.

  12. Combined caveolin-1 and epidermal growth factor receptor expression as a prognostic marker for breast cancer.

    PubMed

    Liang, Ya-Nan; Liu, Yu; Wang, Letian; Yao, Guodong; Li, Xiaobo; Meng, Xiangning; Wang, Fan; Li, Ming; Tong, Dandan; Geng, Jingshu

    2018-06-01

    Previous studies have indicated that caveolin-1 (Cav-1) is able to bind the signal transduction factor epidermal growth factor receptor (EGFR) to regulate its tyrosine kinase activity. The aim of the present study was to evaluate the clinical significance of Cav-1 gene expression in association with the expression of EGFR in patients with breast cancer. Primary breast cancer samples from 306 patients were analyzed for Cav-1 and EGFR expression using immunohistochemistry, and clinical significance was assessed using multivariate Cox regression analysis, Kaplan-Meier estimator curves and the log-rank test. Stromal Cav-1 was downregulated in 38.56% (118/306) of tumor tissues, whereas cytoplasmic EGFR and Cav-1 were overexpressed in 53.92% (165/306) and 44.12% (135/306) of breast cancer tissues, respectively. EGFR expression was positively associated with cytoplasmic Cav-1 and not associated with stromal Cav-1 expression in breast cancer samples; however, low expression of stromal Cav-1 was negatively associated with cytoplasmic Cav-1 expression in total tumor tissues, and analogous results were identified in the chemotherapy group. Multivariate Cox's proportional hazards model analysis revealed that, for patients in the estrogen receptor (ER)(+) group, the expression of stromal Cav-1 alone was a significant prognostic marker of breast cancer. However, in the chemotherapy, human epidermal growth factor receptor 2 (HER-2)(-), HER-2(+) and ER(-) groups, the use of combined markers was more effective prognostic marker. Stromal Cav-1 has a tumor suppressor function, and the combined marker stromal Cav-1/EGFR expression was identified as an improved prognostic marker in the diagnosis of breast cancer. Parenchymal expression of Cav-1 is able to promote EGFR signaling in breast cancer, potentially being required for EGFR-mediated initiation of mitosis.

  13. A Fully Reconfigurable Low-Noise Biopotential Sensing Amplifier With 1.96 Noise Efficiency Factor.

    PubMed

    Tzu-Yun Wang; Min-Rui Lai; Twigg, Christopher M; Sheng-Yu Peng

    2014-06-01

    A fully reconfigurable biopotential sensing amplifier utilizing floating-gate transistors is presented in this paper. By using the complementary differential pairs along with the current reuse technique, the theoretical limit for the noise efficiency factor of the proposed amplifier is below 1.5. Without consuming any extra power, floating-gate transistors are employed to program the low-frequency cutoff corner of the amplifier and to implement the common-mode feedback. A concept proving prototype chip was designed and fabricated in a 0.35 μm CMOS process occupying 0.17 mm (2) silicon area. With a supply voltage of 2.5 V, the measured midband gain is 40.7 dB and the measured input-referred noise is 2.8 μVrms. The chip was tested under several configurations with the amplifier bandwidth being programmed to 100 Hz, 1 kHz , and 10 kHz. The measured noise efficiency factors in these bandwidth settings are 1.96, 2.01, and 2.25, respectively, which are among the best numbers reported to date. The measured common-mode rejection and the supply rejection are above 70 dB . When the bandwidth is configured to be 10 kHz, the dynamic range measured at 1 kHz is 60 dB with total harmonic distortion less than 0.1%. The proposed amplifier is also demonstrated by recording electromyography (EMG), electrocardiography (ECG), electrooculography (EOG), and electroencephalography (EEG) signals from human bodies.

  14. Selenitetriglicerydes affect CYP1A1 and QR activity by involvement of reactive oxygen species and Nrf2 transcription factor.

    PubMed

    Suchocki, Piotr; Misiewicz-Krzemińska, Irena; Skupińska, Katarzyna; Niedźwiecka, Katarzyna; Lubelska, Katarzyna; Fijałek, Zbigniew; Kasprzycka-Guttman, Teresa

    2010-01-01

    Selenitetriglycerides are a group of compounds that contain selenium (Se) (IV). In this paper, we present the results of examinations of three structurally-related selenitetriglicerydes that contain various Se concentrations: 2%, 5% and 7% Selol. The present study concentrates on the effect of Selol on phase 1 and 2 enzyme activity and the implications of free radicals and the nuclear erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway in the activity of this compound. The cytotoxic and cytostatic activities of the three kinds of Selol were evaluated; however, the cytotoxic effect was observed only for 7% Selol. Our results show that 2% Selol acts as a monofunctional inducer of phase 2 enzyme activity, and the induction is mediated by the Nrf2 transcription factor. Selol 7% acts in an opposite manner and induces phase 1 with simultaneous inhibition of phase 2 enzyme activity. The differential effect can be associated with the increase in Se content, leading to a change in the structure of the compound.

  15. Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1α transcription factor and its target genes in mice.

    PubMed

    Adluri, Ram Sudheer; Thirunavukkarasu, Mahesh; Dunna, Nageswara Rao; Zhan, Lijun; Oriowo, Babatunde; Takeda, Kotaro; Sanchez, Juan A; Otani, Hajime; Maulik, Gautam; Fong, Guo-Hua; Maulik, Nilanjana

    2011-10-01

    Hypoxia-inducible transcription factor (HIF)-prolyl hydroxylases domain (PHD-1-3) are oxygen sensors that regulate the stability of the HIFs in an oxygen-dependent manner. Suppression of PHD enzymes leads to stabilization of HIFs and offers a potential treatment option for many ischemic disorders, such as peripheral artery occlusive disease, myocardial infarction, and stroke. Here, we show that homozygous disruption of PHD-1 (PHD-1(-/-)) could facilitate HIF-1α-mediated cardioprotection in ischemia/reperfused (I/R) myocardium. Wild-type (WT) and PHD-1(-/-) mice were randomized into WT time-matched control (TMC), PHD-1(-/-) TMC (PHD1TMC), WT I/R, and PHD-1(-/-) I/R (PHD1IR). Isolated hearts from each group were subjected to 30 min of global ischemia followed by 2 h of reperfusion. TMC hearts were perfused for 2 h 30 min without ischemia. Decreased infarct size (35%±0.6% vs. 49%±0.4%) and apoptotic cardiomyocytes (106±13 vs. 233±21 counts/100 high-power field) were observed in PHD1IR compared to wild-type ischemia/reperfusion (WTIR). Protein expression of HIF-1α was significantly increased in PHD1IR compared to WTIR. mRNA expression of β-catenin (1.9-fold), endothelial nitric oxide synthase (1.9-fold), p65 (1.9-fold), and Bcl-2 (2.7-fold) were upregulated in the PHD1IR compared with WTIR, which was studied by real-time quantitative polymerase chain reaction. Further, gel-shift analysis showed increased DNA binding activity of HIF-1α and nuclear factor-kappaB in PHD1IR compared to WTIR. In addition, nuclear translocation of β-catenin was increased in PHD1IR compared with WTIR. These findings indicated that silencing of PHD-1 attenuates myocardial I/R injury probably by enhancing HIF-1α/β-catenin/endothelial nitric oxide synthase/nuclear factor-kappaB and Bcl-2 signaling pathway.

  16. Low hypoxia inducible factor-1α (HIF-1α) expression in testicular germ cell tumors - a major reason for enhanced chemosensitivity?

    PubMed

    Shenoy, Niraj; Dronca, Roxana; Quevedo, Fernando; Boorjian, Stephen A; Cheville, John; Costello, Brian; Kohli, Manish; Witzig, Thomas; Pagliaro, Lance

    2017-08-01

    The molecular basis for enhanced chemosensitivity of testicular germ cell tumors (GCT) has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of GCT has been variously attributed to multiple factors - an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-1α (HIF-1α) expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.

  17. Factors determining insulin requirements in women with type 1 diabetes mellitus during pregnancy: a review

    PubMed Central

    McIntyre, Harold David; Callaway, Leonie

    2014-01-01

    Most women with type 1 diabetes mellitus (T1DM) have increased insulin requirements during pregnancy. However, a minority of women have a fall in insulin requirements. When this occurs in late gestation, it often provokes concern regarding possible compromise of the feto-placental unit. In some centres, this is considered as an indication for delivery, including premature delivery. There are, however, many other factors that affect insulin requirements in pregnancy in women with type 1 diabetes mellitus and the decline in insulin requirements may represent a variant of normal pregnancy. If there is no underlying pathological process, expedited delivery in these women is not warranted and confers increased risks to the newborn. We will explore the factors affecting insulin requirements in gestation in this review. We will also discuss some novel concepts regarding beta-cell function in pregnancy. PMID:27512424

  18. Overexpression of early growth response-1 as a metastasis-regulatory factor in gastric cancer.

    PubMed

    Kobayashi, Daisuke; Yamada, Mikako; Kamagata, Chinatsu; Kaneko, Reiko; Tsuji, Naoki; Nakamura, Masashi; Yagihashi, Atsuhito; Watanabe, Naoki

    2002-01-01

    To investigate the potential role of a nuclear transcription factor, early growth response-1 (Egr-1), in formation and progression of gastric cancer, we compared its expression in gastric cancers with that in non-cancerous tissues. Egr-1 mRNA expression was measured using TaqMan RT-PCR. The corresponding protein expression was examined immunohistochemically. Egr-1 mRNA expression was significantly higher in gastric cancer tissues than in normal mucosa (p < 0.0005). These differences were also reflected by protein product expression. Moreover, Egr-1 mRNA expression was higher in cases with metastasis to lymph nodes or remote organs. In cultured gastric cancer cells known to have a high metastatic potential, expression of this mRNA was higher than that of parental cells. It was suggested that Egr-1 has a significant role in carcinogenesis and in cancer progression, especially metastasis. Measurement of this mRNA should be useful for evaluation of the metastatic potential of gastric cancer.

  19. A WRKY transcription factor recruits the SYG1-like protein SHB1 to activate gene expression and seed cavity enlargement.

    PubMed

    Kang, Xiaojun; Li, Wei; Zhou, Yun; Ni, Min

    2013-01-01

    Seed development in Arabidopsis and in many dicots involves an early proliferation of the endosperm to form a large embryo sac or seed cavity close to the size of the mature seed, followed by a second phase during which the embryo grows and replaces the endosperm. Short hypocotyl under BLUE1 (SHB1) is a member of the SYG1 protein family in fungi, Caenorhabditis elegans, flies, and mammals. SHB1 gain-of-function enhances endosperm proliferation, increases seed size, and up-regulates the expression of the WRKY transcription factor gene MINISEED3 (MINI3) and the LRR receptor kinase gene HAIKU2 (IKU2). Mutations in either IKU2 or MINI3 retard endosperm proliferation and reduce seed size. However, the molecular mechanisms underlying the establishment of the seed cavity and hence the seed size remain largely unknown. Here, we show that the expression of MINI3 and IKU2 is repressed before fertilization and after 4 days after pollination (DAP), but is activated by SHB1 from 2 to 4 DAP prior to the formation of the seed cavity. SHB1 associates with their promoters but without a recognizable DNA binding motif, and this association is abolished in mini3 mutant. MINI3 binds to W-boxes in, and recruits SHB1 to, its own and IKU2 promoters. Interestingly, SHB1, but not MINI3, activates transcription of pMINI3::GUS or pIKU2::GUS. We reveal a critical developmental switch through the activation of MINI3 expression by SHB1. The recruitment of SHB1 by MINI3 to its own and IKU2 promoters represents a novel two-step amplification to counter the low expression level of IKU2, which is a trigger for endosperm proliferation and seed cavity enlargement.

  20. Xanthomonas filamentous hemagglutinin-like protein Fha1 interacts with pepper hypersensitive-induced reaction protein CaHIR1 and functions as a virulence factor in host plants.

    PubMed

    Choi, Hyong Woo; Kim, Dae Sung; Kim, Nak Hyun; Jung, Ho Won; Ham, Jong Hyun; Hwang, Byung Kook

    2013-12-01

    Pathogens have evolved a variety of virulence factors to infect host plants successfully. We previously identified the pepper plasma-membrane-resident hypersensitive-induced reaction protein (CaHIR1) as a regulator of plant disease- and immunity-associated cell death. Here, we identified the small filamentous hemagglutinin-like protein (Fha1) of Xanthomonas campestris pv. vesicatoria as an interacting partner of CaHIR1 using yeast two-hybrid screening. Coimmunoprecipitation and bimolecular fluorescence complementation experiments revealed that Fha1 specifically interacts with CaHIR1 in planta. The endocytic tracker FM4-64 staining showed that the CaHIR1-Fha1 complex localizes in the endocytic vesicle-like structure. The X. campestris pv. vesicatoria Δfha1 mutant strain exhibited significantly increased surface adherence but reduced swarming motility. Mutation of fha1 inhibited the growth of X. campestris pv. vesicatoria and X. campestris pv. vesicatoria ΔavrBsT in tomato and pepper leaves, respectively, suggesting that Fha1 acts as a virulence factor in host plants. Transient expression of fha1 and also infiltration with purified Fha1 proteins induced disease-associated cell death response through the interaction with CaHIR1 and suppressed the expression of pathogenesis-related (PR) genes. Silencing of CaHIR1 in pepper significantly reduced ΔavrBsT growth and Fha1-triggered susceptibility cell death. Overexpression of fha1 in Arabidopsis retarded plant growth and triggered disease-associated cell death, resulting in altered disease susceptibility. Taken together, these results suggest that the X. campestris pv. vesicatoria virulence factor Fha1 interacts with CaHIR1, induces susceptibility cell death, and suppresses PR gene expression in host plants.

  1. Human Factors in Automated and Robotic Space Systems: Proceedings of a symposium. Part 1

    NASA Technical Reports Server (NTRS)

    Sheridan, Thomas B. (Editor); Kruser, Dana S. (Editor); Deutsch, Stanley (Editor)

    1987-01-01

    Human factors research likely to produce results applicable to the development of a NASA space station is discussed. The particular sessions covered in Part 1 include: (1) system productivity -- people and machines; (2) expert systems and their use; (3) language and displays for human-computer communication; and (4) computer aided monitoring and decision making. Papers from each subject area are reproduced and the discussions from each area are summarized.

  2. Eukaryotic initiation factor 5A-1 (eIF5A-1) as a diagnostic marker for aberrant proliferation in intraepithelial neoplasia of the vulva.

    PubMed

    Cracchiolo, Bernadette M; Heller, Debra S; Clement, Paul M J; Wolff, Edith C; Park, Myung-Hee; Hanauske-Abel, Hartmut M

    2004-07-01

    The mature eukaryotic translation initiation factor 5A contains the unusual amino acid hypusine, formed post-translationally from a specific lysine residue and essential for proliferation of eukaryotic cells. We hypothesized that the major eIF5A isoform, eIF5A-1, is an in situ biomarker for proliferation. NIH-353, a polyclonal immunoreagent specific for hypusine-containing eIF5A-1, was used to test this proposal in biopsies of vulvar high-grade intraepithelial neoplasia (VIN), characterized by the presence of proliferating cells throughout the thickness of the epithelium. Methods. Formalin-fixed and paraffin-embedded archival samples with an independently established diagnosis of VIN 3 were stained immunohistochemically after antigen retrieval, employing NIH-353 and, for comparison, the standard Ki-67 antibody. NIH-353 labeled neoplastic keratinocytes throughout the thickness of the epithelium in all VIN 3 samples. Malignant cells in a case of focally invasive squamous cell carcinoma also stained strongly for mature, hypusine-containing eIF5A-1. Epithelium adjacent to these lesions, though still of apparently normal morphology, was immunoreactive throughout its full thickness. At inflammatory foci of lesional sites, solitary reactive lymphocytes were positive, as were individual proliferating cells within dermal appendages. The submucosal stroma lacked reactive cells. NIH-353 identifies mature eIF5A-1 as an in situ biomarker for proliferation. Like Ki-67, this immunoreagent promises broad applicability in histopathological diagnosis and may be helpful in outcome prediction. In contrast to Ki-67, NIH-353 visualizes a molecular target for antineoplastic therapy, and thus may guide the development and clinical testing of drugs that, like the fungicide ciclopirox, inhibit hypusine formation and cell proliferation.

  3. Probing gas and dust in the tidal tail of NGC 5221 with the type Ia supernova iPTF16abc

    NASA Astrophysics Data System (ADS)

    Ferretti, R.; Amanullah, R.; Goobar, A.; Petrushevska, T.; Borthakur, S.; Bulla, M.; Fox, O.; Freeland, E.; Fremling, C.; Hangard, L.; Hayes, M.

    2017-10-01

    Context. Type Ia supernovae (SNe Ia) can be used to address numerous questions in astrophysics and cosmology. Due to their well known spectral and photometric properties, SNe Ia are well suited to study gas and dust along the lines-of-sight to the explosions. For example, narrow Na I D and Ca II H&K absorption lines can be studied easily, because of the well-defined spectral continuum of SNe Ia around these features. Aims: We aim to study the gas and dust along the line-of-sight to iPTF16abc, which occurred in an unusual location, in a tidal arm, 80 kpc from centre of the galaxy NGC 5221. Methods: Using a time-series of high-resolution spectra, we have examined narrow Na I D and Ca II H&K absorption features for variations in time, which would be indicative for circumstellar (CS) matter. Furthermore, we have taken advantage of the well known photometric properties of SNe Ia to determine reddening due to dust along the line-of-sight. Results: From the lack of variations in Na I D and Ca II H&K, we determine that none of the detected absorption features originate from the CS medium of iPTF16abc. While the Na I D and Ca II H&K absorption is found to be optically thick, a negligible amount of reddening points to a small column of interstellar dust. Conclusions: We find that the gas along the line-of-sight to iPTF16abc is typical of what might be found in the interstellar medium (ISM) within a galaxy. It suggests that we are observing gas that has been tidally stripped during an interaction of NGC 5221 with one of its neighbouring galaxies in the past 109 yr. In the future, the gas clouds could become the locations of star formation. On a longer time scale, the clouds might diffuse, enriching the circum-galactic medium (CGM) with metals. The gas profile along the line-of-sight should be useful for future studies of the dynamics of the galaxy group containing NGC 5221. Based on observations collected at the European Organisation for Astronomical Research in the Southern

  4. 2009 Pandemic Influenza A Virus Subtype H1N1 in Morocco, 2009–2010: Epidemiology, Transmissibility, and Factors Associated With Fatal Cases

    PubMed Central

    Barakat, Amal; Ihazmad, Hassan; El Falaki, Fatima; Tempia, Stefano; Cherkaoui, Imad; El Aouad, Rajae

    2012-01-01

    Background. Following the emergence of 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) in the United States and Mexico in April 2009, A(H1N1)pdm09 spread rapidly all over the world. There is a dearth of information about the epidemiology of A(H1N1)pdm09 in Africa, including Morocco. We describe the epidemiologic characteristics of the A(H1N1)pdm09 epidemic in Morocco during 2009–2010, including transmissibility and risk factors associated with fatal disease. Methods. We implemented influenza surveillance for patients presenting with influenza-like illness (ILI) at 136 private and public clinics for patients with severe acute respiratory illness (SARI) at 16 regional public hospitals from June 2009 through February 2010. Respiratory samples and structured questionnaires were collected from all enrolled patients, and samples were tested by real-time reverse-transcription polymerase chain reaction for influenza viruses. We estimated the risk factors associated with fatal disease as well as the basic reproduction number (R0) and the serial interval of the pandemic virus. Results. From June 2009 through February 2010, we obtained 3937 specimens, of which 1452 tested positive for influenza virus. Of these, 1398 (96%) were A(H1N1)pdm09. Forty percent of specimens from ILI cases (1056 of 2646) and 27% from SARI cases (342 of 1291) were positive for A(H1N1)pdm09. Sixty-four deaths occurred among laboratory-confirmed A(H1N1)pdm09 SARI cases. Among these cases, those who had hypertension (age-adjusted odd ratio [aOR], 28.2; 95% confidence interval [CI], 2.0–398.7), had neurological disorders (aOR, 7.5; 95% CI, 1.5–36.4), or were obese (aOR, 7.1; 95% CI, 1.6–31.1), as well as women of gestational age who were pregnant (aOR, 2.5; 95% CI, 1.1–5.6), were at increased risk of death. Across the country, elevated numbers of locally acquired infections were detected 4 months after the detection of the first laboratory-confirmed case and coincided with the

  5. Purification and characterization of human mitochondrial transcription factor 1.

    PubMed Central

    Fisher, R P; Clayton, D A

    1988-01-01

    We purified to near homogeneity a transcription factor from human KB cell mitochondria. This factor, designated mitochondrial transcription factor 1 (mtTF1), is required for the in vitro recognition of both major promoters of human mitochondrial DNA by the homologous mitochondrial RNA polymerase. Furthermore, it has been shown to bind upstream regulatory elements of the two major promoters. After separation from RNA polymerase by phosphocellulose chromatography, mtTF1 was chromatographed on a MonoQ anion-exchange fast-performance liquid chromatography column. Analysis of mtTF1-containing fractions by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a single major polypeptide with an Mr of approximately 25,000. Centrifugation in analytical glycerol gradients indicated a sedimentation coefficient of approximately 2.5 S, consistent with a monomeric 25-kilodalton protein. Finally, when the 25-kilodalton polypeptide was excised from a stained sodium dodecyl sulfate-polyacrylamide gel and allowed to renature, it regained DNA-binding and transcriptional stimulatory activities at both promoters. Although mtTF1 is the only mitochondrial DNA-binding transcription factor to be purified and characterized, its properties, such as a high affinity for random DNA and a weak specificity for one of its target sequences, may typify this class of regulatory proteins. Images PMID:3211148

  6. Abscisic acid affects transcription of chloroplast genes via protein phosphatase 2C-dependent activation of nuclear genes: repression by guanosine-3'-5'-bisdiphosphate and activation by sigma factor 5.

    PubMed

    Yamburenko, Maria V; Zubo, Yan O; Börner, Thomas

    2015-06-01

    Abscisic acid (ABA) represses the transcriptional activity of chloroplast genes (determined by run-on assays), with the exception of psbD and a few other genes in wild-type Arabidopsis seedlings and mature rosette leaves. Abscisic acid does not influence chloroplast transcription in the mutant lines abi1-1 and abi2-1 with constitutive protein phosphatase 2C (PP2C) activity, suggesting that ABA affects chloroplast gene activity by binding to the pyrabactin resistance (PYR)/PYR1-like or regulatory component of ABA receptor protein family (PYR/PYL/RCAR) and signaling via PP2Cs and sucrose non-fermenting protein-related kinases 2 (SnRK2s). Further we show by quantitative PCR that ABA enhances the transcript levels of RSH2, RSH3, PTF1 and SIG5. RelA/SpoT homolog 2 (RSH2) and RSH3 are known to synthesize guanosine-3'-5'-bisdiphosphate (ppGpp), an inhibitor of the plastid-gene-encoded chloroplast RNA polymerase. We propose, therefore, that ABA leads to an inhibition of chloroplast gene expression via stimulation of ppGpp synthesis. On the other hand, sigma factor 5 (SIG5) and plastid transcription factor 1 (PTF1) are known to be necessary for the transcription of psbD from a specific light- and stress-induced promoter (the blue light responsive promoter, BLRP). We demonstrate that ABA activates the psbD gene by stimulation of transcription initiation at BLRP. Taken together, our data suggest that ABA affects the transcription of chloroplast genes by a PP2C-dependent activation of nuclear genes encoding proteins involved in chloroplast transcription. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

  7. The transcription factor CCAAT-binding factor CBF/NF-Y regulates the proximal promoter activity in the human alpha 1(XI) collagen gene (COL11A1).

    PubMed

    Matsuo, Noritaka; Yu-Hua, Wang; Sumiyoshi, Hideaki; Sakata-Takatani, Keiko; Nagato, Hitoshi; Sakai, Kumiko; Sakurai, Mami; Yoshioka, Hidekatsu

    2003-08-29

    We have characterized the proximal promoter region of the human COL11A1 gene. Transient transfection assays indicate that the segment from -199 to +1 is necessary for the activation of basal transcription. Electrophoretic mobility shift assays (EMSAs) demonstrated that the ATTGG sequence, within the -147 to -121 fragment, is critical to bind nuclear proteins in the proximal COL11A1 promoter. We demonstrated that the CCAAT binding factor (CBF/NF-Y) bound to this region using an interference assay with consensus oligonucleotides and a supershift assay with specific antibodies in an EMSA. In a chromatin immunoprecipitation assay and EMSA using DNA-affinity-purified proteins, CBF/NF-Y proteins directly bound this region in vitro and in vivo. We also showed that four tandem copies of the CBF/NF-Y-binding fragment produced higher transcriptional activity than one or two copies, whereas the absence of a CBF/NF-Y-binding fragment suppressed the COL11A1 promoter activity. Furthermore, overexpression of a dominant-negative CBF-B/NF-YA subunit significantly inhibited promoter activity in both transient and stable cells. These results indicate that the CBF/NF-Y proteins regulate the transcription of COL11A1 by directly binding to the ATTGG sequence in the proximal promoter region.

  8. Adenovirus E1a prevents the retinoblastoma gene product from repressing the activity of a cellular transcription factor.

    PubMed Central

    Zamanian, M; La Thangue, N B

    1992-01-01

    The retinoblastoma (Rb) gene product forms a complex with the cellular transcription factor DRTF1, a property assumed to be important for mediating negative growth control because certain viral oncogenes, such as adenovirus E1a, prevent this interaction and mutant Rb alleles, which have lost the capacity to regulate growth, encode proteins that fail to associate with DRTF1. In this study, we show that the wild-type Rb protein can specifically repress transcription from promoters driven by DRTF1 whereas a naturally occurring mutant Rb protein cannot. Furthermore, Rb-mediated transcriptional repression can be overridden by adenovirus E1a; this requires regions in E1a necessary for cellular transformation. The Rb protein therefore acts in trans to repress the transcriptional activity of DRTF1 whereas adenovirus E1a prevents this interaction and thus maintains DRTF1 in a constitutively active state. The Rb protein and adenovirus E1a therefore have opposite effects on the activity of a common molecular target. Transcriptional repression mediated by the Rb protein and inactivation of repression by the E1a protein are likely to play an important role in mediating their biological effects. Images PMID:1385776

  9. Functional and structural insights into novel DREB1A transcription factors in common wheat (Triticum aestivum L.): A molecular modeling approach.

    PubMed

    Kumar, Anuj; Kumar, Sanjay; Kumar, Upendra; Suravajhala, Prashanth; Gajula, M N V Prasad

    2016-10-01

    Triticum aestivum L. known as common wheat is one of the most important cereal crops feeding a large and growing population. Various environmental stress factors including drought, high salinity and heat etc. adversely affect wheat production in a significant manner. Dehydration-responsive element-binding (DREB1A) factors, a class of transcription factors (TF) play an important role in combating drought stress. It is known that DREB1A specifically interacts with the dehydration responsive elements (DRE/CRT) inducing expression of genes involved in environmental stress tolerance in plants. Despite its critical interplay in plants, the structural and functional aspects of DREB1A TF in wheat remain unresolved. Previous studies showed that wheat DREBs (DREB1 and DREB2) were isolated using various methods including yeast two-hybrid screens but no extensive structural models were reported. In this study, we made an extensive in silico study to gain insight into DREB1A TF and reported the location of novel DREB1A in wheat chromosomes. We inferred the three-dimensional structural model of DREB1A using homology modelling and further evaluated them using molecular dynamics(MD) simulations yielding refined modelled structures. Our biochemical function predictions suggested that the wheat DREB1A orthologs have similar biochemical functions and pathways to that of AtDREB1A. In conclusion, the current study presents a structural perspective of wheat DREB1A and helps in understanding the molecular basis for the mechanism of DREB1A in response to environmental stress. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Transcriptomic analysis of neuregulin-1 regulated genes following ischemic stroke by computational identification of promoter binding sites: A role for the ETS-1 transcription factor.

    PubMed

    Surles-Zeigler, Monique C; Li, Yonggang; Distel, Timothy J; Omotayo, Hakeem; Ge, Shaokui; Ford, Byron D

    2018-01-01

    Ischemic stroke is a major cause of mortality in the United States. We previously showed that neuregulin-1 (NRG1) was neuroprotective in rat models of ischemic stroke. We used gene expression profiling to understand the early cellular and molecular mechanisms of NRG1's effects after the induction of ischemia. Ischemic stroke was induced by middle cerebral artery occlusion (MCAO). Rats were allocated to 3 groups: (1) control, (2) MCAO and (3) MCAO + NRG1. Cortical brain tissues were collected three hours following MCAO and NRG1 treatment and subjected to microarray analysis. Data and statistical analyses were performed using R/Bioconductor platform alongside Genesis, Ingenuity Pathway Analysis and Enrichr software packages. There were 2693 genes differentially regulated following ischemia and NRG1 treatment. These genes were organized by expression patterns into clusters using a K-means clustering algorithm. We further analyzed genes in clusters where ischemia altered gene expression, which was reversed by NRG1 (clusters 4 and 10). NRG1, IRS1, OPA3, and POU6F1 were central linking (node) genes in cluster 4. Conserved Transcription Factor Binding Site Finder (CONFAC) identified ETS-1 as a potential transcriptional regulator of NRG1 suppressed genes following ischemia. A transcription factor activity array showed that ETS-1 activity was increased 2-fold, 3 hours following ischemia and this activity was attenuated by NRG1. These findings reveal key early transcriptional mechanisms associated with neuroprotection by NRG1 in the ischemic penumbra.

  11. The correlation between birth weight and insulin-like growth factor-binding protein-1 (IGFBP-1), kisspeptin-1 (KISS-1), and three-dimensional fetal volume.

    PubMed

    Kimyon Comert, Gunsu; Esin, Sertac; Caglar, Gamze Sinem; Yirci, Bulent; Ozdemir, Sedat; Demirtas, Selda; Kandemir, Omer

    2018-01-24

    This study aimed to determine the relationship between birth weight, and maternal serum insulin-like growth factor-binding protein-1 (IGFBP-1) and kisspeptin-1 (KISS-1) levels, and first-trimester fetal volume (FV) based on three-dimensional ultrasonography. The study included 142 pregnant women at gestational week 11°-13 6 . All fetuses were imaged ultrasonographically by the same physician. Maternal blood samples were collected at the time of ultrasonographic evaluation and analyzed for IGFBP-1 and KISS-1 levels via enzyme-linked immunosorbent assay (ELISA). Maternal and neonatal weights were recorded at birth. Birth weight ≤10th and the >90th percentiles was defined as small and large for gestational age (SGA and LGA), respectively. Median crown-rump length (CRL), FV, and maternal serum IGFBP-1 and KISS-1 levels were 58.2 mm (35.3-79.2 mm), 16.3 cm 3 (3.8-34.4 cm 3 ), 68.1 ng mL -1 (3.8-377.9 mL -1 ), and 99.7 ng L -1 (42.1-965.3 ng L -1 ), respectively. First-trimester IGFBP-1 levels were significantly lower in the mothers with LGA neonates (p < .05). There was a significant positive correlation between CRL and FV, and between the IGFBP-1 and KISS-1 levels. IGFBP-1 levels and maternal weight at delivery were negatively correlated with neonatal birth weight. There was no correlation between CRL or FV and maternal IGFBP-1 or KISS1 levels (p > .05). The maternal IGFBP-1 level during the first trimester was a significant independent factor for SGA and LGA neonates (Odds ratio (OR): 0.011, 95%CI: 1.005-1.018, p < .001; and OR: 1.297, 95%CI: 1.074-1.566, p = .007, respectively). There was no significant relationship between SGA or LGA, and CRL, FV, or the KISS-1 level. As compared to the maternal KISS-1 level, the maternal IGFBP-1 level during the first trimester might be a better biomarker of fetal growth. Additional larger scale studies are needed to further delineate the utility of IGFBP-1 as a marker of abnormal birth

  12. Extreme Suppression of Lateral Floret Development by a Single Amino Acid Change in the VRS1 Transcription Factor1[OPEN

    PubMed Central

    Lundqvist, Udda; Kakei, Yusuke; Suzuki, Takako; Hori, Kiyosumi; Wu, Jianzhong; Shimada, Yukihisa; Thomas, William T.B.; Komatsuda, Takao

    2017-01-01

    Increasing grain yield is an endless challenge for cereal crop breeding. In barley (Hordeum vulgare), grain number is controlled mainly by Six-rowed spike 1 (Vrs1), which encodes a homeodomain leucine zipper class I transcription factor. However, little is known about the genetic basis of grain size. Here, we show that extreme suppression of lateral florets contributes to enlarged grains in deficiens barley. Through a combination of fine-mapping and resequencing of deficiens mutants, we have identified that a single amino acid substitution at a putative phosphorylation site in VRS1 is responsible for the deficiens phenotype. deficiens mutant alleles confer an increase in grain size, a reduction in plant height, and a significant increase in thousand grain weight in contemporary cultivated germplasm. Haplotype analysis revealed that barley carrying the deficiens allele (Vrs1.t1) originated from two-rowed types carrying the Vrs1.b2 allele, predominantly found in germplasm from northern Africa. In situ hybridization of histone H4, a marker for cell cycle or proliferation, showed weaker expression in the lateral spikelets compared with central spikelets in deficiens. Transcriptome analysis revealed that a number of histone superfamily genes were up-regulated in the deficiens mutant, suggesting that enhanced cell proliferation in the central spikelet may contribute to larger grains. Our data suggest that grain yield can be improved by suppressing the development of specific organs that are not positively involved in sink/source relationships. PMID:29101279

  13. The growth hormone-insulin-like growth factor axis in glycogen storage disease type 1: evidence of different growth patterns and insulin-like growth factor levels in patients with glycogen storage disease type 1a and 1b.

    PubMed

    Melis, Daniela; Pivonello, Rosario; Parenti, Giancarlo; Della Casa, Roberto; Salerno, Mariacarolina; Balivo, Francesca; Piccolo, Pasquale; Di Somma, Carolina; Colao, Annamaria; Andria, Generoso

    2010-04-01

    To investigate the growth hormone (GH)-insulin-like growth factor (IGF) system in patients with glycogen storage disease type 1 (GSD1). This was a prospective, case-control study. Ten patients with GSD1a and 7 patients with GSD1b who were given dietary treatment and 34 sex-, age-, body mass index-, and pubertal stage-matched control subjects entered the study. Auxological parameters were correlated with circulating GH, either at basal or after growth hormone releasing hormone plus arginine test, insulin-like growth factors (IGF-I and IGF-II), and anti-pituitary antibodies (APA). Short stature was detected in 10.0% of patients with GSD1a, 42.9% of patients with GSD1b (P = .02), and none of the control subjects. Serum IGF-I levels were lower in patients with GSD1b (P = .0001). An impaired GH secretion was found in 40% of patients with GSD1a (P = .008), 57.1% of patients with GSD1b (P = .006), and none of the control subjects. Short stature was demonstrated in 3 of 4 patients with GSD1b and GH deficiency. The prevalence of APA was significantly higher in patients with GSD1b than in patients with GSD1a (P = .02) and control subjects (P = .03). The GH response to the provocative test inversely correlated with the presence of APA (P = .003). Compared with levels in control subjects, serum IGF-II and insulin levels were higher in both groups of patients, in whom IGF-II levels directly correlated with height SD scores (P = .003). Patients with GSD1a have an impaired GH secretion associated with reference range serum IGF-I levels and normal stature, whereas in patients with GSD1b, the impaired GH secretion, probably because of the presence of APA, was associated with reduced IGF-I levels and increased prevalence of short stature. The increased IGF-II levels, probably caused by increased insulin levels, in patients with GSD1 are presumably responsible for the improved growth pattern observed in patients receiving strict dietary treatment. Copyright 2010 Mosby, Inc. All

  14. -383 A/C tumor necrosis factor receptor 1 polymorphism and ankylosing spondylitis in Mexicans: a preliminary study.

    PubMed

    Corona-Sanchez, Esther Guadalupe; Muñoz-Valle, José Francisco; Gonzalez-Lopez, Laura; Sanchez-Hernandez, Julia Dolores; Vazquez-Del Mercado, Monica; Ontiveros-Mercado, Heriberto; Huerta, Miguel; Trujillo, Xochitl; Rocha-Muñoz, Alberto Daniel; Celis, Alfredo; Ortega-Flores, Ricardo; Gamez-Nava, Jorge Ivan

    2012-08-01

    The objective of this study was to evaluate the differences in allele and genotype frequencies of -383 tumor necrosis factor receptor 1 (TNFR1) polymorphism between ankylosing spondylitis (AS) and controls. Mexican Mestizos with AS were matched by gender, age, and ethnicity with healthy controls and compared in allele and genotype frequencies of the -383 TNFR1 polymorphism. Polymorphisms were genotyped using PCR-RFLP. The AA genotype occurred at a higher frequency in the AS group (92%) compared with controls (79%, P = 0.03). A allele was increased in AS (96% vs. 88%, P = 0.015) and was associated with genetic susceptibility for AS (odds ratio = 3.48, 95% CI = 1.23-10.61). This preliminary study is the first assessing the association of the -383 A/C TNFR1 polymorphism with AS, although it has the limitation of a small sample size. These data are of interest for the genetic epidemiology of AS in the Mexican population, requiring further investigation in other countries.

  15. Molecular stress-inducing compounds increase osteoclast formation in a heat shock factor 1 protein-dependent manner.

    PubMed

    Chai, Ryan C; Kouspou, Michelle M; Lang, Benjamin J; Nguyen, Chau H; van der Kraan, A Gabrielle J; Vieusseux, Jessica L; Lim, Reece C; Gillespie, Matthew T; Benjamin, Ivor J; Quinn, Julian M W; Price, John T

    2014-05-09

    Many anticancer therapeutic agents cause bone loss, which increases the risk of fractures that severely reduce quality of life. Thus, in drug development, it is critical to identify and understand such effects. Anticancer therapeutic and HSP90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) causes bone loss by increasing osteoclast formation, but the mechanism underlying this is not understood. 17-AAG activates heat shock factor 1 (Hsf1), the master transcriptional regulator of heat shock/cell stress responses, which may be involved in this negative action of 17-AAG upon bone. Using mouse bone marrow and RAW264.7 osteoclast differentiation models we found that HSP90 inhibitors that induced a heat shock response also enhanced osteoclast formation, whereas HSP90 inhibitors that did not (including coumermycin A1 and novobiocin) did not affect osteoclast formation. Pharmacological inhibition or shRNAmir knockdown of Hsf1 in RAW264.7 cells as well as the use of Hsf1 null mouse bone marrow cells demonstrated that 17-AAG-enhanced osteoclast formation was Hsf1-dependent. Moreover, ectopic overexpression of Hsf1 enhanced 17-AAG effects upon osteoclast formation. Consistent with these findings, protein levels of the essential osteoclast transcription factor microphthalmia-associated transcription factor were increased by 17-AAG in an Hsf1-dependent manner. In addition to HSP90 inhibitors, we also identified that other agents that induced cellular stress, such as ethanol, doxorubicin, and methotrexate, also directly increased osteoclast formation, potentially in an Hsf1-dependent manner. These results, therefore, indicate that cellular stress can enhance osteoclast differentiation via Hsf1-dependent mechanisms and may significantly contribute to pathological and therapeutic related bone loss.

  16. SAMHD1 host restriction factor: a link with innate immune sensing of retrovirus infection.

    PubMed

    Sze, Alexandre; Olagnier, David; Lin, Rongtuan; van Grevenynghe, Julien; Hiscott, John

    2013-12-13

    SAMHD1 [sterile alpha motif and histidine-aspartic domain (HD) containing protein 1] is the most recent addition to a unique group of host restriction factors that limit retroviral replication at distinct stages of the viral life cycle. SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase that degrades the intracellular pool of deoxynucleoside triphosphates available during early reverse transcription. SAMHD1 activity is blocked by the Vpx accessory function present in human immunodeficiency virus type 2 and SIVsm. Mutations in SAMHD1 are associated with the autoimmune disorder Aicardi-Goutières syndrome, thus emphasizing its role in regulation of the immune response. SAMHD1 antiretroviral activity is modulated by post-translational modifications, cell-cycle-dependent functions and cytokine-mediated changes. Innate receptors that sense retroviral DNA intermediates are the focus of intense study, and recent studies have established a link among SAMHD1 restriction, innate sensing of DNA and protective immune responses. Cell-cycle-dependent regulation of SAMHD1 by phosphorylation and the increasingly broad range of viruses inhibited by SAMHD1 further emphasize the importance of these mechanisms of host restriction. This review highlights current knowledge regarding SAMHD1 regulation and its impact on innate immune signaling and retroviral restriction. © 2013.

  17. Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior.

    PubMed

    Vahid-Ansari, Faranak; Daigle, Mireille; Manzini, M Chiara; Tanaka, Kenji F; Hen, René; Geddes, Sean D; Béïque, Jean-Claude; James, Jonathan; Merali, Zul; Albert, Paul R

    2017-12-06

    Freud-1/Cc2d1a represses the gene transcription of serotonin-1A (5-HT1A) autoreceptors, which negatively regulate 5-HT tone. To test the role of Freud-1 in vivo , we generated mice with adulthood conditional knock-out of Freud-1 in 5-HT neurons ( cF1ko ). In cF1ko mice, 5-HT1A autoreceptor protein, binding and hypothermia response were increased, with reduced 5-HT content and neuronal activity in the dorsal raphe. The cF1ko mice displayed increased anxiety- and depression-like behavior that was resistant to chronic antidepressant (fluoxetine) treatment. Using conditional Freud-1/5-HT1A double knock-out ( cF1/1A dko ) to disrupt both Freud-1 and 5-HT1A genes in 5-HT neurons, no increase in anxiety- or depression-like behavior was seen upon knock-out of Freud-1 on the 5-HT1A autoreceptor-negative background; rather, a reduction in depression-like behavior emerged. These studies implicate transcriptional dysregulation of 5-HT1A autoreceptors by the repressor Freud-1 in anxiety and depression and provide a clinically relevant genetic model of antidepressant resistance. Targeting specific transcription factors, such as Freud-1, to restore transcriptional balance may augment response to antidepressant treatment. SIGNIFICANCE STATEMENT Altered regulation of the 5-HT1A autoreceptor has been implicated in human anxiety, major depression, suicide, and resistance to antidepressants. This study uniquely identifies a single transcription factor, Freud-1, as crucial for 5-HT1A autoreceptor expression in vivo Disruption of Freud-1 in serotonin neurons in mice links upregulation of 5-HT1A autoreceptors to anxiety/depression-like behavior and provides a new model of antidepressant resistance. Treatment strategies to reestablish transcriptional regulation of 5-HT1A autoreceptors could provide a more robust and sustained antidepressant response. Copyright © 2017 the authors 0270-6474/17/3711967-12$15.00/0.

  18. Preventable Lifestyle Risk Factors for Non-Communicable Diseases in the Pakistan Adolescents Schools Study 1 (PASS-1)

    PubMed Central

    Khawaja, Saleem; Motwani, Komal; Khoja, Adeel Akbar; Azam, Iqbal Syed; Fatmi, Zafar; Ali, Badar Sabir; Kadir, Muhammad Masood

    2011-01-01

    Objectives The rising burden of preventable risk factors for non-communicable diseases (NCDs) among adolescents is a major public health challenge worldwide. We identified the preventable risk factors for NCDs in adolescents. Methods In a school-based study, pre-tested structured questionnaires were completed by 414 adolescents (14 to 17 years) at six schools in three cities in Pakistan. The chi-squared test and adjusted odds ratio (aOR) with 95% confidence interval (CI) were calculated in a multinomial logistic regression analysis. Results Over 80% of the adolescents had unhealthy diets, and 54% were physically inactive. Most adolescents were exposed to passive smoking, and 14% were also current smokers. More than one-third of participants chewed betel nut, and one-quarter used oral tobacco. More girls were physically inactive (OR, 4.07; 95% CI, 2.69 to 6.17), whereas a greater proportion of boys were current smokers (OR, 2.17; 95% CI, 1.19 to 3.91), exposed to passive smoking (OR, 2.57; 95% CI, 1.72 to 3.83), and using betel nut (OR, 2.03; 95% CI, 1.34 to 3.06). Only 3.1% of the participants were without any preventable lifestyle risk factor for NCDs, and over 80% had ≥2 factors. Co-existence of risk factors was independently associated with fathers being blue-collar workers (aOR, 3.57; 95% CI, 1.07 to 11.92) and parents not treating their child fairly (aOR, 5.05; 95% CI, 1.29 to 19.78). Conclusions Most of the adolescents studied had preventable risk factors for NCDs. These results warrant comprehensive and integrated interventions to prevent lifestyle risk factors, and parents are front-line stakeholders. PMID:22020186

  19. Molecular Characterization of the Schistosoma mansoni Zinc Finger Protein SmZF1 as a Transcription Factor

    PubMed Central

    D'Astolfo, Diego S.; Cardoso, Fernanda C.; Rajão, Matheus A.; Mourão, Marina M.; Gava, Elisandra; Oliveira, Sérgio C.; Macedo, Andréa M.; Machado, Carlos R.; Pena, Sérgio D. J.; Kitten, Gregory T.; Franco, Glória R.

    2009-01-01

    Background During its development, the parasite Schistosoma mansoni is exposed to different environments and undergoes many morphological and physiological transformations as a result of profound changes in gene expression. Characterization of proteins involved in the regulation of these processes is of importance for the understanding of schistosome biology. Proteins containing zinc finger motifs usually participate in regulatory processes and are considered the major class of transcription factors in eukaryotes. It has already been shown, by EMSA (Eletrophoretic Mobility Shift Assay), that SmZF1, a S. mansoni zinc finger (ZF) protein, specifically binds both DNA and RNA oligonucleotides. This suggests that this protein might act as a transcription factor in the parasite. Methodology/Principal Findings In this study we extended the characterization of SmZF1 by determining its subcellular localization and by verifying its ability to regulate gene transcription. We performed immunohistochemistry assays using adult male and female worms, cercariae and schistosomula to analyze the distribution pattern of SmZF1 and verified that the protein is mainly detected in the cells nuclei of all tested life cycle stages except for adult female worms. Also, SmZF1 was heterologously expressed in mammalian COS-7 cells to produce the recombinant protein YFP-SmZF1, which was mainly detected in the nucleus of the cells by confocal microscopy and Western blot assays. To evaluate the ability of this protein to regulate gene transcription, cells expressing YFP-SmZF1 were tested in a luciferase reporter system. In this system, the luciferase gene is downstream of a minimal promoter, upstream of which a DNA region containing four copies of the SmZF1 putative best binding site (D1-3DNA) was inserted. SmZF1 increased the reporter gene transcription by two fold (p≤0.003) only when its specific binding site was present. Conclusion Taken together, these results strongly support the hypothesis

  20. Association of hypoxia inducible factor-1 alpha gene polymorphism with both type 1 and type 2 diabetes in a Caucasian (Hungarian) sample

    PubMed Central

    Nagy, Geza; Kovacs-Nagy, Reka; Kereszturi, Eva; Somogyi, Aniko; Szekely, Anna; Nemeth, Nora; Hosszufalusi, Nora; Panczel, Pal; Ronai, Zsolt; Sasvari-Szekely, Maria

    2009-01-01

    Background Hypoxia inducible factor-1 alpha (HIF-1α) is a transcription factor that plays an important role in neo-vascularisation, embryonic pancreas beta-cell mass development, and beta cell protection. Recently a non synonymous single nucleotide polymorphism (g.C45035T SNP, rs11549465) of HIF-1α gene, resulting in the p.P582S amino acid change has been shown to be associated with type 2 diabetes (T2DM) in a Japanese population. Our aim was to replicate these findings on a Caucasian (Hungarian) population, as well as to study whether this genetic effect is restricted to T2DM or can be expanded to diabetes in general. Methods A large Caucasian sample (N = 890) was recruited including 370 T2DM, 166 T1DM and 354 healthy subjects. Genotyping was validated by two independent methods: a restriction fragment analysis (RFLP) and a real time PCR using TaqMan probes. An overestimation of heterozygotes by RFLP was observed as a consequence of a nearby SNP (rs34005929). Therefore genotyping results of the justified TaqMan system were accepted. The measured genotype distribution corresponded to Hardy-Weinberg equilibrium (P = 0.740) Results As the TT genotype was extremely rare in the population (0.6% in clinical sample and 2.5% in controls), the genotypes were grouped as T absent (CC) and T present (CT and TT). Genotype-wise analysis showed a significant increase of T present group in controls (24.0%) as compared to patients (16.8%, P = 0.008). This genetic effect was demonstrated in the separated samples of type 1 (15.1%, P = 0.020), and also in type 2 (17.6%, P = 0.032) diabetes. Allele-wise analysis gave identical results showing a higher frequency of the T allele in the control sample (13.3%) than in the clinical sample (8.7%, P = 0.002) with similar results in type 1 (7.8%, P = 0.010) and type 2 (9.1%, P = 0.011) diabetes. The odds ratio for diabetes (either type 1 or 2) was 1.56 in the presence of the C allele. Conclusion We confirmed the protective effect of a rare

  1. CHEK2, MGMT, SULT1E1 and SULT1A1 polymorphisms and endometrial cancer risk.

    PubMed

    O'Mara, Tracy A; Ferguson, Kaltin; Fahey, Paul; Marquart, Louise; Yang, Hannah P; Lissowska, Jolanta; Chanock, Stephen; Garcia-Closas, Montserrat; Thompson, Deborah J; Healey, Catherine S; Dunning, Alison M; Easton, Douglas F; Webb, Penelope M; Spurdle, Amanda B

    2011-08-01

    Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65-1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups, to confirm risk associations and better prioritize downstream studies to assess the causal relationship between genetic variants and cancer risk. Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer.

  2. Heat shock factor 1 upregulates transcription of Epstein-Barr Virus nuclear antigen 1 by binding to a heat shock element within the BamHI-Q promoter

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Feng-Wei; Wu, Xian-Rui; Liu, Wen-Ju

    Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is essential for maintenance of the episome and establishment of latency. In this study, we observed that heat treatment effectively induced EBNA1 transcription in EBV-transformed B95-8 and human LCL cell lines. Although Cp is considered as the sole promoter used for the expression of EBNA1 transcripts in the lymphoblastoid cell lines, the RT-PCR results showed that the EBNA1 transcripts induced by heat treatment arise from Qp-initiated transcripts. Using bioinformatics, a high affinity and functional heat shock factor 1 (HSF1)-binding element within the - 17/+4 oligonucleotide of the Qp was found, and was determinedmore » by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Moreover, heat shock and exogenous HSF1 expression induced Qp activity in reporter assays. Further, RNA interference-mediated HSF1 gene silencing attenuated heat-induced EBNA1 expression in B95-8 cells. These results provide evidence that EBNA1 is a new target for the transcription factor HSF1.« less

  3. E2F1 transcription factor and its impact on growth factor and cytokine signaling.

    PubMed

    Ertosun, Mustafa Gokhan; Hapil, Fatma Zehra; Osman Nidai, Ozes

    2016-10-01

    E2F1 is a transcription factor involved in cell cycle regulation and apoptosis. The transactivation capacity of E2F1 is regulated by pRb. In its hypophosphorylated form, pRb binds and inactivates DNA binding and transactivating functions of E2F1. The growth factor stimulation of cells leads to activation of CDKs (cyclin dependent kinases), which in turn phosphorylate Rb and hyperphosphorylated Rb is released from E2F1 or E2F1/DP complex, and free E2F1 can induce transcription of several genes involved in cell cycle entry, induction or inhibition of apoptosis. Thus, growth factors and cytokines generally utilize E2F1 to direct cells to either fate. Furthermore, E2F1 regulates expressions of various cytokines and growth factor receptors, establishing positive or negative feedback mechanisms. This review focuses on the relationship between E2F1 transcription factor and cytokines (IL-1, IL-2, IL-3, IL-6, TGF-beta, G-CSF, LIF), growth factors (EGF, KGF, VEGF, IGF, FGF, PDGF, HGF, NGF), and interferons (IFN-α, IFN-β and IFN-γ). Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer.

    PubMed

    Kim, Ji Hun; Kim, Min Kyu; Lee, Hee Eun; Cho, Sung Jin; Cho, Yu Jin; Lee, Byung Lan; Lee, Hye Seung; Nam, Seon Young; Lee, Jae-Seon; Kim, Woo Ho

    2007-08-01

    Increased phosphorylation of FOXO1A, a FOXO transcription factor, has been implicated in several human cancers; however, it has not been studied in the gastric cancer to date. To determine the status of pFOXO1A expression in human gastric cancers and to determine its relationship with other tumor-associated proteins, we performed immunohistochemical staining on tissue array slides containing 272 human gastric carcinoma specimens. In non-neoplastic gastric mucosa, the expression of pFOXO1A was observed primarily in cells in the proliferative zone and in areas of intestinal metaplasia. In gastric carcinomas, the expression of pFOXO1A was observed in 230 (84.6%) out of 272 cases examined, and was positively correlated with the Ki-67-labeling index (P=0.026). The expression of pFOXO1A was higher in the early stages of pTNM (P<0.001), and was inversely correlated with the intestinal type by Lauren's classification (P=0.001), lymphatic invasion (P=0.017) and lymph node metastasis (P<0.001). Moreover, the expression of pFOXO1A was correlated with a longer patient survival (P=0.004). In addition, the expression of pFOXO1A was correlated with that of pAKT1 (P<0.001), PTEN (P=0.009), CDKN2A (P=0.012), APC (P=0.048), SMAD4 (P<0.001), CD82 (P=0.011), and BCL2 (P=0.011). In conclusion, our results showed that the expression of pFOXO1A is a frequent and early event in gastric tumorigenesis and that there is a significant correlation between pFOXO1A and better prognosis. Thus, our data suggest that the expression of pFOXO1A may serve as a valuable prognostic variable in gastric carcinoma and have significant implications for the development and application of targeted therapy.

  5. Transforming Growth Factor1 Accelerates Resorption of a Calcium Carbonate Biomaterial in Periodontal Defects.

    PubMed

    Koo, Ki-Tae; Susin, Cristiano; Wikesjö, Ulf M E; Choi, Seong-Ho; Kim, Chong-Kwan

    2007-04-01

    In a previous study, recombinant human transforming growth factor-beta1 (rhTGF-β 1 ) in a calcium carbonate carrier was implanted into critical-size, supraalveolar periodontal defects under conditions for guided tissue regeneration (GTR) to study whether rhTGF-β 1 would enhance or accelerate periodontal regeneration. The results showed minimal benefits of rhTGF-β 1 , and a clear account for this could not be offered. One potential cause may be that the rhTGF-β 1 formulation was biologically inactive. Several growth or differentiation factors have been suggested to accelerate degradation of biomaterials used as carriers. The objective of this study was to evaluate possible activity of rhTGF-β 1 on biodegradation of the calcium carbonate carrier. rhTGF-β 1 in a putty-formulated particulate calcium carbonate carrier was implanted into critical-size, supraalveolar periodontal defects under conditions for GTR in five beagle dogs. Contralateral defects received the calcium carbonate carrier combined with GTR without rhTGF-β 1 (control). The animals were euthanized at week 4 post-surgery and block biopsies of the defect sites were collected for histologic and histometric analysis. Radiographs were obtained at defect creation and weeks 2 and 4 after defect creation. No statistically significant differences were observed in new bone formation (bone height and area) among the treatments. However, total residual carrier was significantly reduced in sites receiving rhTGF-β 1 compared to control (P = 0.04). Similarly, carrier density was considerably reduced in sites receiving rhTGF-β 1 compared to control; the difference was borderline statistically significant (P = 0.06). Within the limitations of the study, it may be concluded that rhTGF-β 1 accelerates biodegradation of a particulate calcium carbonate biomaterial, indicating a biologic activity of the rhTGF-β 1 formulation apparently not encompassing enhanced or accelerated periodontal regeneration. © 2007

  6. 17β-estradiol-induced regulation of the novel 5-HT1A-related transcription factors NUDR and Freud-1 in SH SY5Y cells.

    PubMed

    Adeosun, Samuel O; Albert, Paul R; Austin, Mark C; Iyo, Abiye H

    2012-05-01

    Nuclear deformed epidermal autoregulatory factor-1 (NUDR/Deaf-1) and five prime repressor element under dual repression (Freud-1) are novel transcriptional regulators of the 5-HT(1A) receptor, a receptor that has been implicated in the pathophysiology of various psychiatric illnesses. The antidepressant effect of 17β-Estradiol (17βE(2)) is purported to involve the downregulation of this receptor. We investigated the possible role of NUDR and Freud-1 in 17βE(2)-induced downregulation of the 5-HT(1A) receptor in the neuroblastoma cell line SH SY5Y. Cells were treated with 10 nM of 17βE(2) for 3 or 48 h, followed by a 24-h withdrawal period. Proteins were isolated and analyzed by western blotting. 17βE(2) treatment increased NUDR immunoreactivity while Freud-1 and the 5-HT(1A) receptor showed significant decreases. Upon withdrawal of 17βE(2), protein expression returned to control levels, except for NUDR, which remained significantly elevated in the 3-h treatment. Taken together, these data support a non-genomic downregulation of 5-HT(1A) receptor protein by 17βE(2), which does not involve NUDR and Freud-1. Rather, changes in both transcription factors seem to be compensatory/homeostatic responses to changes in 5-HT(1A) receptor induced by 17βE(2). These observations further highlight the importance of NUDR and Freud-1 in regulating 5-HT(1A) receptor expression.

  7. Effect of exogenous transforming growth factor β1 (TGF-β1) on early bovine embryo development.

    PubMed

    Barrera, Antonio D; García, Elina V; Miceli, Dora C

    2018-06-08

    SummaryDuring preimplantation development, embryos are exposed and have the capacity to respond to different growth factors present in the maternal environment. Among these factors, transforming growth factor β1 (TGF-β1) is a well known modulator of embryonic growth and development. However, its action during the first stages of development, when the embryo transits through the oviduct, has not been yet elucidated. The objective of the present study was to examine the effect of early exposure to exogenous TGF-β1 on embryo development and expression of pluripotency (OCT4, NANOG) and DNA methylation (DNMT1, DNMT3A, DNMT3B) genes in bovine embryos produced in vitro. First, gene expression analysis of TGF-β receptors confirmed a stage-specific expression pattern, showing greater mRNA abundance of TGFBR1 and TGFBR2 from the 2- to the 8-cell stage, before embryonic genome activation. Second, embryo culture for the first 48 h in serum-free CR1aa medium supplemented with 50 or 100 ng/ml recombinant TGF-β1 did not affect the cleavage and blastocyst rate (days 7 and 8). However, RT-qPCR analysis showed a significant increase in the relative abundance of NANOG and DNMT3A in the 8-cell stage embryos and expanded blastocysts (day 8) derived from TGF-β1 treated embryos. These results suggest an early action of exogenous TGF-β1 on the bovine embryo, highlighting the importance to provide a more comprehensive understanding of the role of TGF-β signalling during early embryogenesis.

  8. Detection of placental alpha microglobulin-1 versus insulin-like growth factor-binding protein-1 in amniotic fluid at term: a comparative study.

    PubMed

    Pollet-Villard, Marie; Cartier, Régine; Gaucherand, Pascal; Doret, Muriel

    2011-06-01

    We compared two biochemical tests of premature rupture of membranes (PROM) in vitro: Actim PROM (Medix Biochemica, Kauniainen, Finland), which detects insulin-like growth factor binding protein-1, and AmniSure (AmniSure International LLC, Cambridge, MA), which detects placental alpha microglobulin-1. Samples of amniotic fluid were collected during caesarean section in 41 patients. A dilution series was prepared and both tests were performed twice at each dilution. Sensitivity, detection limit, response time, and reproducibility of both tests were compared. Both tests' sensitivity was 100% at dilution 1:10 and 1:20. AmniSure sensitivity was higher at dilution 1:40 and 1:80 ( P < 0.05). In 29 of 40 cases, AmniSure had a lower detection limit than Actim PROM. AmniSure response times were shorter and reproducibility was higher than Actim PROM ( P < 0.05). AmniSure had a lower detection limit of amniotic fluid than Actim PROM, with a shorter response time, a higher sensitivity, and a better reproducibility. © Thieme Medical Publishers.

  9. HTR1A Gene Polymorphisms and 5-HT1A Receptor Partial Agonist Antipsychotics Efficacy in Schizophrenia.

    PubMed

    Takekita, Yoshiteru; Fabbri, Chiara; Kato, Masaki; Nonen, Shinpei; Sakai, Shiho; Sunada, Naotaka; Koshikawa, Yosuke; Wakeno, Masataka; Okugawa, Gaku; Kinoshita, Toshihiko; Serretti, Alessandro

    2015-06-01

    Individual differences in serotonin 1A (5-HT1A) receptor may result in variable response to antipsychotics with 5-HT1A receptor partial agonism. We investigated the relationship between 5-HT1A receptor gene (HTR1A) single nucleotide polymorphisms (SNPs) and efficacy of antipsychotics with 5-HT1A receptor partial agonism in Japanese patients with schizophrenia. Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. Candidate SNPs were rs6295 (which affects HTR1A expression and function), rs1364043, rs878567, and rs10042486. Efficacy at week 12 of treatment was evaluated using the Positive and Negative Syndrome Scale (PANSS) 5-factor subscales (excitement/hostility, depression/anxiety, cognition, positive, and negative). Rs1364043 T allele was correlated with the percent change in the PANSS 5-factor negative score (P < 0.01). Haplotype analysis showed that the rs10042486-rs6295-rs1364043 T-C-G haplotype was correlated with worse negative score improvement (haplotype frequency, 0.675; P = 0.014), and the relatively rare T-G-T haplotype correlated with better efficacy (haplotype frequency, 0.05; P = 0.031). This is the first study to show that rs10042486-rs6295-rs1364043 HTR1A variants may be correlated with the improvement of the PANSS 5-factor negative score during treatment with 5-HT1A partial agonist antipsychotics. Studies with larger sample sizes and in different ethnic groups are warranted.

  10. Regulation of Memory Formation by the Transcription Factor XBP1.

    PubMed

    Martínez, Gabriela; Vidal, René L; Mardones, Pablo; Serrano, Felipe G; Ardiles, Alvaro O; Wirth, Craig; Valdés, Pamela; Thielen, Peter; Schneider, Bernard L; Kerr, Bredford; Valdés, Jose L; Palacios, Adrian G; Inestrosa, Nibaldo C; Glimcher, Laurie H; Hetz, Claudio

    2016-02-16

    Contextual memory formation relies on the induction of new genes in the hippocampus. A polymorphism in the promoter of the transcription factor XBP1 was identified as a risk factor for Alzheimer's disease and bipolar disorders. XBP1 is a major regulator of the unfolded protein response (UPR), mediating adaptation to endoplasmic reticulum (ER) stress. Using a phenotypic screen, we uncovered an unexpected function of XBP1 in cognition and behavior. Mice lacking XBP1 in the nervous system showed specific impairment of contextual memory formation and long-term potentiation (LTP), whereas neuronal XBP1s overexpression improved performance in memory tasks. Gene expression analysis revealed that XBP1 regulates a group of memory-related genes, highlighting brain-derived neurotrophic factor (BDNF), a key component in memory consolidation. Overexpression of BDNF in the hippocampus reversed the XBP1-deficient phenotype. Our study revealed an unanticipated function of XBP1 in cognitive processes that is apparently unrelated to its role in ER stress. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  11. A PROP1-binding factor, AES cloned by yeast two-hybrid assay represses PROP1-induced Pit-1 gene expression.

    PubMed

    Sugiyama, Yuka; Ikeshita, Nobuko; Shibahara, Hiromi; Yamamoto, Daisuke; Kawagishi, Mayuko; Iguchi, Genzo; Iida, Keiji; Takahashi, Yutaka; Kaji, Hidesuke; Chihara, Kazuo; Okimura, Yasuhiko

    2013-08-25

    PROP1 mutation causes combined pituitary hormone deficiency (CPHD). Several mutations are located in a transactivation domain (TAD) of Prop1, and the loss of TAD binding to cofactors is likely the cause of CPHD. PROP1 cofactors have not yet been identified. In the present study, we aimed to identify the PROP1-interacting proteins from the human brain cDNA library. Using a yeast two-hybrid assay, we cloned nine candidate proteins that may bind to PROP1. Of those nine candidates, amino-terminal enhancer of split (AES) was the most abundant, and we analyzed the AES function. AES dose-dependently decreased the PROP1-induced Pit-1 reporter gene expression. An immunoprecipitation assay revealed the relationship between AES and PROP1. In a mammalian two-hybrid assay, a leucine zipper-like motif of the AES Q domain was identified as a region that interacted with TAD. These results indicated that AES was a corepressor of PROP1. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Persisting mild hypothermia suppresses hypoxia-inducible factor-1alpha protein synthesis and hypoxia-inducible factor-1-mediated gene expression.

    PubMed

    Tanaka, Tomoharu; Wakamatsu, Takuhiko; Daijo, Hiroki; Oda, Seiko; Kai, Shinichi; Adachi, Takehiko; Kizaka-Kondoh, Shinae; Fukuda, Kazuhiko; Hirota, Kiichi

    2010-03-01

    The transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in regulating gene expression in response to hypoxia-ischemia. Ischemia causes the tissue not only to be hypoxic but also to be hypothermic because of the hypoperfusion under certain circumstances. On the other hand, the induced hypothermia is one of the most common therapeutic modalities to extend tolerance to hypoxia. Although hypoxia elicits a variety of cellular and systemic responses at different organizational levels in the body, little is known about how hypoxia-induced responses are affected by low temperature. We examined the influence of mild hypothermic conditions (28-32 degrees C) on HIF-1 in both in vitro and in vivo settings. In vitro experiments adopting cultured cells elucidated that hypoxia-induced HIF-1 activation was resistant to 4-h exposure to the low temperature. In contrast, exposure to the low temperature as long as 24 h suppressed HIF-1 activation and the subsequent upregulation of HIF-1 target genes such as VEGF or GLUT-1. HIF-1alpha protein stability in the cell was not affected by hypothermic treatment. Furthermore, intracellular ATP content was reduced under 1% O(2) conditions but was not largely affected by hypothermic treatment. The evidence indicates that reduction of oxygen consumption is not largely involved in suppression of HIF-1. In addition, we demonstrated that HIF-1 DNA-binding activity and HIF-1-dependent gene expressions induced under 10% O(2) atmosphere in mouse brain were not influenced by treatment under 3-h hypothermic temperature but were inhibited under 5-h treatment. On the other hand, we indicated that warming ischemic legs of mice for 24 h preserved HIF-1 activity. In this report we describe for the first time that persisting low temperature significantly reduced HIF-1alpha neosynthesis under hypoxic conditions, leading to a decrease in gene expression for adaptation to hypoxia in both in vitro and in vivo settings.

  13. [Insulin-like growth factor-1 (IGF-1) - structure and the role in the human body].

    PubMed

    Filus, Alicja; Zdrojewicz, Zygmunt

    2015-01-01

    In the recent years, managed to broadly explore the structure and role of insulin-like growth factors type 1 and 2 (IGF1 I 2). They belong to the structure of polypeptide hormones homologous to proinsulin. They are characterized by a wide range of activities. IGF-1 is a key mediator of most tissue effects of growth hormone (GH). In addition to effects on growth processes of the body, is also an important factor for cell homeostasis, is subject to both endocrine and tissue-specific auto- and paracrine regulation. In this paper, the current, general knowledge on the structure, function and mechanism of biological effects of IGF-1 in the human body was presented. Attention was also drawn to the directions of use of IGf-1 in the treatment of other diseases than the diseases of the hypothalamic-pituitary and growth disorders in children. © Polish Society for Pediatric Endocrinology and Diabetology.

  14. The sirtuin 1/2 inhibitor tenovin-1 induces a nonlinear apoptosis-inducing factor-dependent cell death in a p53 null Ewing's sarcoma cell line.

    PubMed

    Marx, Christian; Marx-Blümel, Lisa; Lindig, Nora; Thierbach, René; Hoelzer, Doerte; Becker, Sabine; Wittig, Susan; Lehmann, Roland; Slevogt, Hortense; Heinzel, Thorsten; Wang, Zhao-Qi; Beck, James F; Sonnemann, Jürgen

    2018-06-01

    The sirtuin 1/2 inhibitor tenovin-1 activates p53 and may have potential in the management of cancer. Here, we investigated the responsiveness of Ewing's sarcoma cells to tenovin-1. We examined its effects in two Ewing's sarcoma cell lines with different p53 status, i.e. in p53 wild-type and p53 null cells. Effects were assessed by flow cytometric analyses of cell death, mitochondrial membrane depolarization and reactive oxygen species (ROS) generation, by caspase 3/7 activity measurement, by mRNA expression profiling and by immunoblotting. Tenovin-1 elicited caspase-mediated cell death in p53 wild-type cells, but caspase-independent cell death in p53 null cells. Remarkably, it induced a nonlinear concentration response in the latter: low concentrations of tenovin-1 were much more effective than were higher concentrations. Tenovin-1's effects in p53 null cells involved gene expression changes of Bcl-2 family members, mitochondrial membrane depolarization, nuclear translocation of apoptosis-inducing factor, ROS formation and DNA damage; all these effects followed a bell-shaped pattern. In conclusion, our results provide new insights into tenovin-1's mode of action by demonstrating that it can induce different pathways of cell death.

  15. A phase I dose-escalation study to a predefined dose of a transforming growth factor1 monoclonal antibody (TβM1) in patients with metastatic cancer

    PubMed Central

    COHN, ALLEN; LAHN, MICHAEL M.; WILLIAMS, KRISTEN E.; CLEVERLY, ANN L.; PITOU, CELINE; KADAM, SUNIL K.; FARMEN, MARK W.; DESAIAH, DURISALA; RAJU, ROBERT; CONKLING, PAUL; RICHARDS, DONALD

    2014-01-01

    Transforming growth factor β (TGF-β) plays an important role in cancer. Monoclonal antibodies (mAb) designed to specifically block the TGF-β ligands, are expected to inhibit tumor progression in patients with metastatic cancer. TβM1 is a humanized mAb optimized for neutralizing activity against TGF-β1. The objective of this clinical trial was to assess the safety and tolerability of TβM1 in patients with metastatic cancer. In this phase I, uncontrolled, non-randomized, dose-escalation study, 18 eligible adult patients who had measurable disease per RECIST and a performance status of ≤2 on the ECOG scale were administered TβM1 intravenously over 10 min at doses of 20, 60, 120 and 240 mg on day 1 of each 28-day cycle. Safety was assessed by adverse events (as defined by CTCAE version 3.0) and possible relationship to study drug, dose-limiting toxicities and laboratory changes. Systemic drug exposure and pharmacodynamic (PD) parameters were assessed. TβM1 was safe when administered once monthly. The pharmacokinetic (PK) profile was consistent with a mAb with a mean elimination half-life approximately 9 days. Although anticipated changes in PD markers such as serum VEGF, bFGF and mRNA expression of SMAD7 were observed in whole-blood, suggesting activity of TβM1 on the targeted pathway, these changes were not consistent to represent a PD effect. Additionally, despite the presence of an activated TGF-β1 expression signature in patients’ whole blood, the short dosing duration did not translate into significant antitumor effect in the small number of patients investigated in this study PMID:25270361

  16. Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes.

    PubMed

    Cellier, Mathieu F M

    2017-05-03

    NRAMP1 (SLC11A1) is a professional phagocyte membrane importer of divalent metals that contributes to iron recycling at homeostasis and to nutritional immunity against infection. Analyses of data generated by several consortia and additional studies were integrated to hypothesize mechanisms restricting NRAMP1 expression to mature phagocytes. Results from various epigenetic and transcriptomic approaches were collected for mesodermal and hematopoietic cell types and compiled for combined analysis with results of genetic studies associating single nucleotide polymorphisms (SNPs) with variations in NRAMP1 expression (eQTLs). Analyses establish that NRAMP1 is part of an autonomous topologically associated domain delimited by ubiquitous CCCTC-binding factor (CTCF) sites. NRAMP1 locus contains five regulatory regions: a predicted super-enhancer (S-E) key to phagocyte-specific expression; the proximal promoter; two intronic areas, including 3' inhibitory elements that restrict expression during development; and a block of upstream sites possibly extending the S-E domain. Also the downstream region adjacent to the 3' CTCF locus boundary may regulate expression during hematopoiesis. Mobilization of the locus 14 predicted transcriptional regulatory elements occurs in three steps, beginning with hematopoiesis; at the onset of myelopoiesis and through myelo-monocytic differentiation. Basal expression level in mature phagocytes is further influenced by genetic variation, tissue environment, and in response to infections that induce various epigenetic memories depending on microorganism nature. Constitutively associated transcription factors (TFs) include CCAAT enhancer binding protein beta (C/EBPb), purine rich DNA binding protein (PU.1), early growth response 2 (EGR2) and signal transducer and activator of transcription 1 (STAT1) while hypoxia-inducible factors (HIFs) and interferon regulatory factor 1 (IRF1) may stimulate iron acquisition in pro-inflammatory conditions. Mouse

  17. Pre-announcement of symbiotic guests: transcriptional reprogramming by mycorrhizal lipochitooligosaccharides shows a strict co-dependency on the GRAS transcription factors NSP1 and RAM1.

    PubMed

    Hohnjec, Natalija; Czaja-Hasse, Lisa F; Hogekamp, Claudia; Küster, Helge

    2015-11-23

    More than 80 % of all terrestrial plant species establish an arbuscular mycorrhiza (AM) symbiosis with Glomeromycota fungi. This plant-microbe interaction primarily improves phosphate uptake, but also supports nitrogen, mineral, and water aquisition. During the pre-contact stage, the AM symbiosis is controled by an exchange of diffusible factors from either partner. Amongst others, fungal signals were identified as a mix of sulfated and non-sulfated lipochitooligosaccharides (LCOs), being structurally related to rhizobial nodulation (Nod)-factor LCOs that in legumes induce the formation of nitrogen-fixing root nodules. LCO signals are transduced via a common symbiotic signaling pathway (CSSP) that activates a group of GRAS transcription factors (TFs). Using complex gene expression fingerprints as molecular phenotypes, this study primarily intended to shed light on the importance of the GRAS TFs NSP1 and RAM1 for LCO-activated gene expression during pre-symbiotic signaling. We investigated the genome-wide transcriptional responses in 5 days old primary roots of the Medicago truncatula wild type and four symbiotic mutants to a 6 h challenge with LCO signals supplied at 10(-7/-8) M. We were able to show that during the pre-symbiotic stage, sulfated Myc-, non-sulfated Myc-, and Nod-LCO-activated gene expression almost exclusively depends on the LysM receptor kinase NFP and is largely controled by the CSSP, although responses independent of this pathway exist. Our results show that downstream of the CSSP, gene expression activation by Myc-LCOs supplied at 10(-7/-8) M strictly required both the GRAS transcription factors RAM1 and NSP1, whereas those genes either co- or specifically activated by Nod-LCOs displayed a preferential NSP1-dependency. RAM1, a central regulator of root colonization by AM fungi, controled genes activated by non-sulfated Myc-LCOs during the pre-symbiotic stage that are also up-regulated in areas with early physical contact, e.g. hyphopodia and

  18. Suppression of polyglutamine toxicity by a Drosophila homolog of myeloid leukemia factor 1.

    PubMed

    Kazemi-Esfarjani, Parsa; Benzer, Seymour

    2002-10-01

    The toxicity of an abnormally long polyglutamine [poly(Q)] tract within specific proteins is the molecular lesion shared by Huntington's disease (HD) and several other hereditary neurodegenerative disorders. By a genetic screen in Drosophila, devised to uncover genes that suppress poly(Q) toxicity, we discovered a Drosophila homolog of human myeloid leukemia factor 1 (MLF1). Expression of the Drosophila homolog (dMLF) ameliorates the toxicity of poly(Q) expressed in the eye and central nervous system. In the retina, whether endogenously or ectopically expressed, dMLF co-localized with aggregates, suggesting that dMLF alone, or through an intermediary molecular partner, may suppress toxicity by sequestering poly(Q) and/or its aggregates.

  19. Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ladziata, Vladimir; Glunz, Peter W.; Zou, Yan

    Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.

  20. Regulation of the mammalian heat shock factor 1.

    PubMed

    Dayalan Naidu, Sharadha; Dinkova-Kostova, Albena T

    2017-06-01

    Living organisms are endowed with the capability to tackle various forms of cellular stress due to the presence of molecular chaperone machinery complexes that are ubiquitous throughout the cell. During conditions of proteotoxic stress, the transcription factor heat shock factor 1 (HSF1) mediates the elevation of heat shock proteins, which are crucial components of the chaperone complex machinery and function to ameliorate protein misfolding and aggregation and restore protein homeostasis. In addition, HSF1 orchestrates a versatile transcriptional programme that includes genes involved in repair and clearance of damaged macromolecules and maintenance of cell structure and metabolism, and provides protection against a broad range of cellular stress mediators, beyond heat shock. Here, we discuss the structure and function of the mammalian HSF1 and its regulation by post-translational modifications (phosphorylation, sumoylation and acetylation), proteasomal degradation, and small-molecule activators and inhibitors. © 2017 Federation of European Biochemical Societies.

  1. Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 (PITX1) on chromosome 5q31: a candidate gene analysis

    PubMed Central

    Philippi, Anne; Tores, Frédéric; Carayol, Jérome; Rousseau, Francis; Letexier, Mélanie; Roschmann, Elke; Lindenbaum, Pierre; Benajjou, Abdel; Fontaine, Karine; Vazart, Céline; Gesnouin, Philippe; Brooks, Peter; Hager, Jörg

    2007-01-01

    Background Autism is a complex, heterogeneous, behaviorally-defined disorder characterized by disruptions of the nervous system and of other systems such as the pituitary-hypothalamic axis. In a previous genome wide screen, we reported linkage of autism with a 1.2 Megabase interval on chromosome 5q31. For the current study, we hypothesized that 3 of the genes in this region could be involved in the development of autism: 1) paired-like homeodomain transcription factor 1 (PITX1), which is a key regulator of hormones within the pituitary-hypothalamic axis, 2) neurogenin 1, a transcription factor involved in neurogenesis, and 3) histone family member Y (H2AFY), which is involved in X-chromosome inactivation in females and could explain the 4:1 male:female gender distortion present in autism. Methods A total of 276 families from the Autism Genetic Resource Exchange (AGRE) repository composed of 1086 individuals including 530 affected children were included in the study. Single nucleotide polymorphisms tagging the three candidate genes were genotyped on the initial linkage sample of 116 families. A second step of analysis was performed using tightly linked SNPs covering the PITX1 gene. Association was evaluated using the FBAT software version 1.7.3 for single SNP analysis and the HBAT command from the same package for haplotype analysis respectively. Results Association between SNPs and autism was only detected for PITX1. Haplotype analysis within PITX1 showed evidence for overtransmission of the A-C haplotype of markers rs11959298 – rs6596189 (p = 0.0004). Individuals homozygous or heterozygous for the A-C haplotype risk allele were 2.54 and 1.59 fold more likely to be autistic than individuals who were not carrying the allele, respectively. Conclusion Strong and consistent association was observed between a 2 SNPs within PITX1 and autism. Our data suggest that PITX1, a key regulator of hormones within the pituitary-hypothalamic axis, may be implicated in the

  2. Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 (PITX1) on chromosome 5q31: a candidate gene analysis.

    PubMed

    Philippi, Anne; Tores, Frédéric; Carayol, Jérome; Rousseau, Francis; Letexier, Mélanie; Roschmann, Elke; Lindenbaum, Pierre; Benajjou, Abdel; Fontaine, Karine; Vazart, Céline; Gesnouin, Philippe; Brooks, Peter; Hager, Jörg

    2007-12-06

    Autism is a complex, heterogeneous, behaviorally-defined disorder characterized by disruptions of the nervous system and of other systems such as the pituitary-hypothalamic axis. In a previous genome wide screen, we reported linkage of autism with a 1.2 Megabase interval on chromosome 5q31. For the current study, we hypothesized that 3 of the genes in this region could be involved in the development of autism: 1) paired-like homeodomain transcription factor 1 (PITX1), which is a key regulator of hormones within the pituitary-hypothalamic axis, 2) neurogenin 1, a transcription factor involved in neurogenesis, and 3) histone family member Y (H2AFY), which is involved in X-chromosome inactivation in females and could explain the 4:1 male:female gender distortion present in autism. A total of 276 families from the Autism Genetic Resource Exchange (AGRE) repository composed of 1086 individuals including 530 affected children were included in the study. Single nucleotide polymorphisms tagging the three candidate genes were genotyped on the initial linkage sample of 116 families. A second step of analysis was performed using tightly linked SNPs covering the PITX1 gene. Association was evaluated using the FBAT software version 1.7.3 for single SNP analysis and the HBAT command from the same package for haplotype analysis respectively. Association between SNPs and autism was only detected for PITX1. Haplotype analysis within PITX1 showed evidence for overtransmission of the A-C haplotype of markers rs11959298 - rs6596189 (p = 0.0004). Individuals homozygous or heterozygous for the A-C haplotype risk allele were 2.54 and 1.59 fold more likely to be autistic than individuals who were not carrying the allele, respectively. Strong and consistent association was observed between a 2 SNPs within PITX1 and autism. Our data suggest that PITX1, a key regulator of hormones within the pituitary-hypothalamic axis, may be implicated in the etiology of autism.

  3. Dissecting the expression of EEF1A1/2 genes in human prostate cancer cells: the potential of EEF1A2 as a hallmark for prostate transformation and progression.

    PubMed

    Scaggiante, B; Dapas, B; Bonin, S; Grassi, M; Zennaro, C; Farra, R; Cristiano, L; Siracusano, S; Zanconati, F; Giansante, C; Grassi, G

    2012-01-03

    In prostate adenocarcinoma, the dissection of the expression behaviour of the eukaryotic elongation factors (eEF1A1/2) has not yet fully elucidated. The EEF1A1/A2 expressions were investigated by real-time PCR, western blotting (cytoplasmic and cytoskeletal/nuclear-enriched fractions) and immunofluorescence in the androgen-responsive LNCaP and the non-responsive DU-145 and PC-3 cells, displaying a low, moderate and high aggressive phenotype, respectively. Targeted experiments were also conducted in the androgen-responsive 22Rv1, a cell line marking the progression towards androgen-refractory tumour. The non-tumourigenic prostate PZHPV-7 cell line was the control. Compared with PZHPV-7, cancer cells showed no major variations in EEF1A1 mRNA; eEF1A1 protein increased only in cytoskeletal/nuclear fraction. On the contrary, a significant rise of EEF1A2 mRNA and protein were found, with the highest levels detected in LNCaP. Eukaryotic elongation factor 1A2 immunostaining confirmed the western blotting results. Pilot evaluation in archive prostate tissues showed the presence of EEF1A2 mRNA in near all neoplastic and perineoplastic but not in normal samples or in benign adenoma; in contrast, EEF1A1 mRNA was everywhere detectable. Eukaryotic elongation factor 1A2 switch-on, observed in cultured tumour prostate cells and in human prostate tumour samples, may represent a feature of prostate cancer; in contrast, a minor involvement is assigned to EEF1A1. These observations suggest to consider EEF1A2 as a marker for prostate cell transformation and/or possibly as a hallmark of cancer progression.

  4. Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration.

    PubMed

    Formiga, Fabio R; Pelacho, Beatriz; Garbayo, Elisa; Imbuluzqueta, Izaskun; Díaz-Herráez, Paula; Abizanda, Gloria; Gavira, Juan J; Simón-Yarza, Teresa; Albiasu, Edurne; Tamayo, Esther; Prósper, Felipe; Blanco-Prieto, Maria J

    2014-01-10

    Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment were detected. Our data support the therapeutic benefit of NRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies. © 2013.

  5. Identification of novel host factors via conserved domain search: Cns1 cochaperone is a novel restriction factor of tombusvirus replication in yeast.

    PubMed

    Lin, Jing-Yi; Nagy, Peter D

    2013-12-01

    A large number of host-encoded proteins affect the replication of plus-stranded RNA viruses by acting as susceptibility factors. Many other cellular proteins are known to function as restriction factors of viral infections. Previous studies with tomato bushy stunt tombusvirus (TBSV) in a yeast model host have revealed the inhibitory function of TPR (tetratricopeptide repeat) domain-containing cyclophilins, which are members of the large family of host prolyl isomerases, in TBSV replication. In this paper, we tested additional TPR-containing yeast proteins in a cell-free TBSV replication assay and identified the Cns1p cochaperone for heat shock protein 70 (Hsp70) and Hsp90 chaperones as a strong inhibitor of TBSV replication. Cns1p interacted with the viral replication proteins and inhibited the assembly of the viral replicase complex and viral RNA synthesis in vitro. Overexpression of Cns1p inhibited TBSV replication in yeast. The use of a temperature-sensitive (TS) mutant of Cns1p in yeast revealed that at a semipermissive temperature, TS Cns1p could not inhibit TBSV replication. Interestingly, Cns1p and the TPR-containing Cpr7p cyclophilin have similar inhibitory functions during TBSV replication, although some of the details of their viral restriction mechanisms are different. Our observations indicate that TPR-containing cellular proteins could act as virus restriction factors.

  6. Risk factors for work-related injury among farm workers: a 1-year study.

    PubMed

    Molineri, A; Signorini, M L; Tarabla, H D

    2015-01-01

    A 1-year prospective study was carried out to look for risk factors of farm-related injuries in Egusquiza, Santa Fe (Argentina). Information on demographic characteristics and occupational accidents was collected on (N=110, n=78) farm workers by means of personal interviews using a structured questionnaire. Monthly telephone contact was then maintained with the workers for 1 year to document all farm-related injuries. Data analysis included incidence rate, χ2 and logistic regression. Sixty-nine farm-related injuries were reported during the study period, six injuries being the maximum number affecting one worker. A total of 46.3% of the workers suffered at least one injury during the year. The incidence rate was 7.5 injuries/100 individual-month at risk. Medical assistance was needed in 26.8% of the cases and 5.8% of the injuries caused at least 1 day off work. Hospitalization for at least 1 day was required for 2.9% of the injured workers. Previous work-related injury in the family (p=0.005) (odds ratio (OR)=4.6, 95% confidence interval (CI)=1.6-13.3) and worker's activity (p=0.021) (OR=3.7, 95%CI=1.2-11.6) were associated with the dependent variable work injury. Agricultural and livestock farming are of great importance for the national economy. Workers' training on farm safety may play a key role to prevent work-related injuries and diseases.

  7. 26 CFR 54.9802-1 - Prohibiting discrimination against participants and beneficiaries based on a health factor.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... employees who complete a health risk assessment regarding current health status, without any further action... assessment. (See also § 54.9802-3T for rules prohibiting collection of genetic information.) (iii) Health... and beneficiaries based on a health factor. 54.9802-1 Section 54.9802-1 Internal Revenue INTERNAL...

  8. Individual, physical and psychological risk factors for neck pain in Australian office workers: a 1-year longitudinal study.

    PubMed

    Hush, Julia M; Michaleff, Zoe; Maher, Christopher G; Refshauge, Kathryn

    2009-10-01

    Neck pain is more prevalent in office workers than in the general community. To date, findings from prospective studies that investigated causal relationships between putative risk factors and the onset of neck pain in this population have been limited by high loss to follow-up. The aim of this research was to prospectively evaluate a range of risk factors for neck pain in office workers, using validated and reliable objective measures as well as attain an estimate of 1-year incidence. We assembled a cohort of 53 office workers without neck pain and measured individual, physical, workplace and psychological factors at baseline. We followed participants for 1 year to measure the incidence of neck pain. We achieved 100% participant follow-up. Cox regression analysis was applied to examine the relationship between the putative risk factors and the cumulative incidence of neck pain. The 1-year incidence proportion of neck pain in Australian office workers was estimated in this study to be 0.49 (95% CI 0.36-0.62). Predictors of neck pain with moderate to large effect sizes were female gender (HR: 3.07; 95% CI: 1.18-7.99) and high psychological stress (HR: 1.64; 95% CI: 0.66-4.07). Protective factors included increased mobility of the cervical spine (HR: 0.44; 95% CI: 0.19-1.05) and frequent exercise (HR: 0.64; 95% CI: 0.27-1.51). These results reveal that neck pain is common in Australian office workers and that there are risk factors that are potentially modifiable.

  9. Microtubule actin crosslinking factor 1b: a novel plakin that localizes to the Golgi complex.

    PubMed

    Lin, Chung-Ming; Chen, Hui-Jye; Leung, Conrad L; Parry, David A D; Liem, Ronald K H

    2005-08-15

    MACF1 (microtubule actin crosslinking factor), also called ACF7 (actin crosslinking family 7) is a cytoskeletal linker protein that can associate with both actin filaments and microtubules. We have identified a novel alternatively spliced isoform of MACF1. We named this isoform MACF1b and renamed the original isoform MACF1a. MACF1b is identical to MACF1a, except that it has a region containing plakin (or plectin) repeats in the middle of the molecule. MACF1b is ubiquitously expressed in adult tissues with especially high levels in the lung. We studied the subcellular localization of MACF1b proteins in mammalian cell lines. In two lung cell lines, MACF1b was chiefly localized to the Golgi complex. Upon treatments that disrupt the Golgi complex, MACF1b redistributed into the cytosol, but remained co-localized with the dispersed Golgi ministacks. MACF1b proteins can be detected in the enriched Golgi fraction by western blotting. The domain of MACF1b that targets it to the Golgi was found at the N-terminal part of the region that contains the plakin repeats. Reducing the level of MACF1 proteins by small-interfering RNA resulted in the dispersal of the Golgi complex.

  10. Regulation of myeloid leukemia factor-1 interacting protein (MLF1IP) expression in glioblastoma.

    PubMed

    Hanissian, Silva H; Teng, Bin; Akbar, Umar; Janjetovic, Zorica; Zhou, Qihong; Duntsch, Christopher; Robertson, Jon H

    2005-06-14

    The myelodysplasia/myeloid leukemia factor 1-interacting protein MLF1IP is a novel gene which encodes for a putative transcriptional repressor. It is localized to human chromosome 4q35.1 and is expressed in both the nuclei and cytoplasm of cells. Northern and Western blot analyses have revealed MLF1IP to be present at very low amounts in normal brain tissues, whereas a number of human and rat glioblastoma (GBM) cell lines demonstrated a high level expression of the MLF1IP protein. Immunohistochemical analysis of rat F98 and C6 GBM tumor models showed that MLF1IP was highly expressed in the tumor core where it was co-localized with MLF1 and nestin. Moreover, MLF1IP expression was elevated in the contralateral brain where no tumor cells were detected. These observations, together with previous data demonstrating a role for MLF1IP in erythroleukemias, suggest a possible function for this protein in glioma pathogenesis and potentially in other types of malignancies.

  11. 49 CFR 325.75 - Ground surface correction factors. 1

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Ground surface correction factors. 1 325.75... MOTOR CARRIER NOISE EMISSION STANDARDS Correction Factors § 325.75 Ground surface correction factors. 1... account both the distance correction factors contained in § 325.73 and the ground surface correction...

  12. 49 CFR 325.75 - Ground surface correction factors. 1

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Ground surface correction factors. 1 325.75... MOTOR CARRIER NOISE EMISSION STANDARDS Correction Factors § 325.75 Ground surface correction factors. 1... account both the distance correction factors contained in § 325.73 and the ground surface correction...

  13. Factors associated with health-related quality of life after stroke: a 1-year prospective cohort study.

    PubMed

    Algurén, Beatrix; Fridlund, Bengt; Cieza, Alarcos; Sunnerhagen, Katharina Stibrant; Christensson, Lennart

    2012-01-01

    In line with patient-centered health care, it is necessary to understand patients' perceptions of health. How stroke survivors perceive their health at different time points after stroke and which factors are associated with these feelings provide important information about relevant rehabilitation targets. This study aimed to identify the independent factors of health-related quality of life (HRQoL) from a biopsychosocial perspective using the methods of multivariate regression at 3 different time points poststroke. Included in the study were 99 patients from stroke units with diagnosed first-ever stroke. At admission and at 6 weeks, 3 months, and 1 year poststroke, HRQoL was assessed using the EuroQoL-5D Visual Analogue Scale (EQ-5D VAS). Consequences in Body Functions and Activities and Participation, and Environmental Factors were documented using 155 categories of the International Classification of Functioning, Disability and Health (ICF) Core Set for Stroke. For a period of 1 year, problems with recreation and leisure, personality functions, energy and drive functions, and gait pattern functions were repeatedly associated with worse HRQoL. Whereas Body Functions and Activities and Participation explained more than three-fourths of the variances of HRQoL at 6 weeks and 3 months (R² = 0.80-0.93), the variation at 1 year was best explained by either Body Functions or Environmental Factors (R² = 0.51). The results indicate the importance of Body Functions and Activities and Participation (mainly personality functions and recreation and leisure) on HRQoL within 3 months poststroke, but increased impact of Environmental Factors on HRQoL at 1 year.

  14. Taci Is a Traf-Interacting Receptor for Tall-1, a Tumor Necrosis Factor Family Member Involved in B Cell Regulation

    PubMed Central

    Xia, Xing-Zhong; Treanor, James; Senaldi, Giorgio; Khare, Sanjay D.; Boone, Tom; Kelley, Michael; Theill, Lars E.; Colombero, Anne; Solovyev, Irina; Lee, Frances; McCabe, Susan; Elliott, Robin; Miner, Kent; Hawkins, Nessa; Guo, Jane; Stolina, Marina; Yu, Gang; Wang, Judy; Delaney, John; Meng, Shi-Yuan; Boyle, William J.; Hsu, Hailing

    2000-01-01

    We and others recently reported tumor necrosis factor (TNF) and apoptosis ligand–related leukocyte-expressed ligand 1 (TALL-1) as a novel member of the TNF ligand family that is functionally involved in B cell proliferation. Transgenic mice overexpressing TALL-1 have severe B cell hyperplasia and lupus-like autoimmune disease. Here, we describe expression cloning of a cell surface receptor for TALL-1 from a human Burkitt's lymphoma RAJI cell library. The cloned receptor is identical to the previously reported TNF receptor (TNFR) homologue transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI). Murine TACI was subsequently isolated from the mouse B lymphoma A20 cells. Human and murine TACI share 54% identity overall. Human TACI exhibits high binding affinities to both human and murine TALL-1. Soluble TACI extracellular domain protein specifically blocks TALL-1–mediated B cell proliferation without affecting CD40- or lipopolysaccharide-mediated B cell proliferation in vitro. In addition, when injected into mice, soluble TACI inhibits antibody production to both T cell–dependent and –independent antigens. By yeast two-hybrid screening of a B cell library with TACI intracellular domain, we identified that, like many other TNFR family members, TACI intracellular domain interacts with TNFR-associated factor (TRAF)2, 5, and 6. Correspondingly, TACI activation in a B cell line results in nuclear factor κB and c-Jun NH2-terminal kinase activation. The identification and characterization of the receptor for TALL-1 provides useful information for the development of a treatment for B cell–mediated autoimmune diseases such as systemic lupus erythematosus. PMID:10880535

  15. Stromal derived factor 1α: A chemokine that delivers a two-pronged defence of the myocardium☆

    PubMed Central

    Bromage, Daniel I.; Davidson, Sean M.; Yellon, Derek M.

    2014-01-01

    Alleviating myocardial injury associated with ST elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) has dual potential benefit in this regard. Firstly, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (AMI) and regulates stem cell migration to sites of injury. SDF-1α delivery to the myocardium after AMI is associated with improved stem cell homing, angiogenesis, and left ventricular function in animal models, and improvements in heart failure and quality of life in humans. Secondly, SDF-1α may have a role in remote ischaemic conditioning (RIC), the phenomenon whereby non-lethal ischaemia–reperfusion applied to an organ or tissue remote from the heart protects the myocardium from lethal ischaemia–reperfusion injury (IRI). SDF-1α is increased in the serum of rats subjected to RIC and protects against myocardial IRI in ex vivo studies. Despite these potential pleiotropic effects, a limitation of SDF-1α is its short plasma half-life due to cleavage by dipeptidyl peptidase-4 (DPP-4). However, DPP-4 inhibitors increase the half-life of SDF-1α by preventing its degradation and are also protective against lethal IRI. In summary, SDF-1 potentially delivers a ‘two-pronged’ defence of the myocardium: acutely protecting it from IRI while simultaneously stimulating repair by recruiting stem cells to the site of injury. In this article we examine the evidence for acute and chronic cardioprotective roles of SDF-1α and discuss potential therapeutic manipulations of this mechanism with DPP-4 inhibitors to protect against lethal tissue injury in the clinical setting. PMID:24704323

  16. Structural and functional insight into TAF1-TAF7, a subcomplex of transcription factor II D

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bhattacharya, Suparna; Lou, Xiaohua; Hwang, Peter

    2014-07-01

    Transcription factor II D (TFIID) is a multiprotein complex that nucleates formation of the basal transcription machinery. TATA binding protein-associated factors 1 and 7 (TAF1 and TAF7), two subunits of TFIID, are integral to the regulation of eukaryotic transcription initiation and play key roles in preinitiation complex (PIC) assembly. Current models suggest that TAF7 acts as a dissociable inhibitor of TAF1 histone acetyltransferase activity and that this event ensures appropriate assembly of the RNA polymerase II-mediated PIC before transcriptional initiation. Here, we report the 3D structure of a complex of yeast TAF1 with TAF7 at 2.9 Å resolution. The structuremore » displays novel architecture and is characterized by a large predominantly hydrophobic heterodimer interface and extensive cofolding of TAF subunits. There are no obvious similarities between TAF1 and known histone acetyltransferases. Instead, the surface of the TAF1–TAF7 complex contains two prominent conserved surface pockets, one of which binds selectively to an inhibitory trimethylated histone H3 mark on Lys27 in a manner that is also regulated by phosphorylation at the neighboring H3 serine. Our findings could point toward novel roles for the TAF1–TAF7 complex in regulation of PIC assembly via reading epigenetic histone marks.« less

  17. Quantitative Proteomic Analysis of Host-virus Interactions Reveals a Role for Golgi Brefeldin A Resistance Factor 1 (GBF1) in Dengue Infection*

    PubMed Central

    Carpp, Lindsay N.; Rogers, Richard S.; Moritz, Robert L.; Aitchison, John D.

    2014-01-01

    Dengue virus is considered to be the most important mosquito-borne virus worldwide and poses formidable economic and health care burdens on many tropical and subtropical countries. Dengue infection induces drastic rearrangement of host endoplasmic reticulum membranes into complex membranous structures housing replication complexes; the contribution(s) of host proteins and pathways to this process is poorly understood but is likely to be mediated by protein-protein interactions. We have developed an approach for obtaining high confidence protein-protein interaction data by employing affinity tags and quantitative proteomics, in the context of viral infection, followed by robust statistical analysis. Using this approach, we identified high confidence interactors of NS5, the viral polymerase, and NS3, the helicase/protease. Quantitative proteomics allowed us to exclude a large number of presumably nonspecific interactors from our data sets and imparted a high level of confidence to our resulting data sets. We identified 53 host proteins reproducibly associated with NS5 and 41 with NS3, with 13 of these candidates present in both data sets. The host factors identified have diverse functions, including retrograde Golgi-to-endoplasmic reticulum transport, biosynthesis of long-chain fatty-acyl-coenzyme As, and in the unfolded protein response. We selected GBF1, a guanine nucleotide exchange factor responsible for ARF activation, from the NS5 data set for follow up and functional validation. We show that GBF1 plays a critical role early in dengue infection that is independent of its role in the maintenance of Golgi structure. Importantly, the approach described here can be applied to virtually any organism/system as a tool for better understanding its molecular interactions. PMID:24855065

  18. Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPα to prevent Trib1-driven acute myeloid leukemia.

    PubMed

    Nakamae, Ikuko; Kato, Jun-Ya; Yokoyama, Takashi; Ito, Hidenori; Yoneda-Kato, Noriko

    2017-09-12

    C/EBPα is a key transcription factor regulating myeloid differentiation and leukemogenesis. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPα for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). Here we show that myeloid leukemia factor 1 (MLF1) stabilizes C/EBPα protein levels by inhibiting the ligase activity of the Trib1-COP1 complex. MLF1 directly interacts with COP1 in the nucleus and interferes with the formation of the Trib1-COP1 complex, thereby blocking its ability to polyubiquitinate C/EBPα for degradation. MLF1 overexpression suppressed the Trib1-induced growth advantage in a murine bone marrow (BM) culture and Trib1-induced AML development in BM-transplanted mouse models. MLF1 was expressed in hematopoietic stem cells and myeloid progenitors (common myeloid progenitors and granulocyte-macrophage progenitors) in normal hematopoiesis, which is consistent with the distribution of C/EBPα. An MLF1 deficiency conferred a more immature phenotype on Trib1-induced AML development. A higher expression ratio of Trib1 to MLF1 was a key determinant for AML development in mouse models, which was also confirmed in human patient samples with acute leukemia. These results indicate that MLF1 is a positive regulator that is critical for C/EBPα stability in the early phases of hematopoiesis and leukemogenesis.

  19. Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPα to prevent Trib1-driven acute myeloid leukemia

    PubMed Central

    Nakamae, Ikuko; Kato, Jun-ya; Yokoyama, Takashi; Ito, Hidenori

    2017-01-01

    C/EBPα is a key transcription factor regulating myeloid differentiation and leukemogenesis. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPα for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). Here we show that myeloid leukemia factor 1 (MLF1) stabilizes C/EBPα protein levels by inhibiting the ligase activity of the Trib1-COP1 complex. MLF1 directly interacts with COP1 in the nucleus and interferes with the formation of the Trib1-COP1 complex, thereby blocking its ability to polyubiquitinate C/EBPα for degradation. MLF1 overexpression suppressed the Trib1-induced growth advantage in a murine bone marrow (BM) culture and Trib1-induced AML development in BM-transplanted mouse models. MLF1 was expressed in hematopoietic stem cells and myeloid progenitors (common myeloid progenitors and granulocyte-macrophage progenitors) in normal hematopoiesis, which is consistent with the distribution of C/EBPα. An MLF1 deficiency conferred a more immature phenotype on Trib1-induced AML development. A higher expression ratio of Trib1 to MLF1 was a key determinant for AML development in mouse models, which was also confirmed in human patient samples with acute leukemia. These results indicate that MLF1 is a positive regulator that is critical for C/EBPα stability in the early phases of hematopoiesis and leukemogenesis. PMID:29296815

  20. [Description of patients with confirmed influenza A(H1N1)pdm09 admitted to an intensive care unit and identification of severity risk factors].

    PubMed

    Payet, C; Lutringer-Magnin, D; Cassier, P; Lina, B; Argaud, L; Allaouchiche, B; Vanhems, P

    2013-02-01

    The authors had for objective to describe patients with confirmed influenza A(H1N1)pdm09 admitted to an intensive care unit (ICU) in a university hospital and to identify risk factors correlated with the severity of the disease. A prospective study was conducted in an university hospital during the A(H1N1)pdm09 influenza pandemic. Severe laboratory confirmed cases (admitted to an ICU) were described and compared with non-severe confirmed cases (not admitted to an ICU). Sixty-nine patients were included; 36 (52%) were 15 to 44 years of age. Sixteen (23%) cases were defined as severe, ten of these (63%) concerned patients 45 to 64 years of age. The independent factors associated with severity were: a history of heart disease, obesity, and tobacco abuse. This work reinforces the need to identify and protect groups at risk of severe outcomes. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  1. Factors associated with high levels of glycated haemoglobin in patients with type 1 diabetes: a multicentre study in Brazil

    PubMed Central

    Andrade, Carine Sousa; Ribeiro, Guilherme Sousa; Santos, Carlos Antonio Souza Teles; Neves, Raimundo Celestino Silva; Moreira, Edson Duarte

    2017-01-01

    Objective Long-term complications of type 1 diabetes mellitus (DM1) can be prevented with adequate glycaemic control. However, high levels of glycated haemoglobin (HbA1c) occur in 60%–90% of the patients with DM1. Thus, we aimed to investigate the role of sociodemographic, behavioural and clinical factors on the HbA1c levels of patients with DM1 in Brazil. Design, setting and participants A cross-sectional study was conducted in ambulatory patients with DM1 aged ≥18 years from 10 Brazilian cities. Sociodemographic, behavioural and clinical data were obtained through interviews. Main outcome measures HbA1c level was measured by liquid chromatography. Hierarchical multiple variable linear regression models were used to identify factors correlated with high levels of HbA1c. Results Of 979 patients with DM1, 63.8% were women, and the mean age was 40 (SD 14.6) years. The mean HbA1c level was 9.4% (SD 2.2%), and 89.6% of the patients had HbA1c ≥7.0%. Factors independently correlated with increased HbA1c levels included: lower education, non-participation in diabetes classes/lecture during the year before, having a self-perception of poor adherence to diet and insulin, not having private medical care and not measuring the HbA1c levels in the prior year. Of note, poor adherence to diet and insulin were the independent factors most strongly associated with high levels of HbA1c (mean increment in HbA1c levels of 0.88% and 1.25%, respectively). Conclusion Poor glycaemic control, which is common among Brazilian patients with DM1, is associated with lower education, self-perception of insufficient adherence to diet and insulin and inadequate monitoring of HbA1c levels. Specific actions, particularly those targeting improving adherence to diet and insulin, may contribute to successful management of patients with DM1. PMID:29247092

  2. Ferrous glycinate regulates cell energy metabolism by restrictinghypoxia-induced factor-1α expression in human A549 cells.

    PubMed

    Kuo, Yung-Ting; Jheng, Jhong-Huei; Lo, Mei-Chen; Chen, Wei-Lu; Wang, Shyang-Guang; Lee, Horng-Mo

    2018-06-04

    Iron or oxygen regulates the stability of hypoxia inducible factor-1α (HIF-1α). We investigated whether ferrous glycinate would affect HIF-1α accumulation, aerobic glycolysis and mitochondrial energy metabolism in human A549 lung cancer cells. Incubation of A549 cells with ferrous glycinate decreased the protein levels of HIF-1α, which was abrogated by proteosome inhibitor, or prolyl hydroxylase inhibitor. The addition of ferrous glycinate decreased protein levels of glucose transporter-1, hexokinase-2, and lactate dehydrogenase A, and decreased pyruvate dehydrogenase kinase-1 (PDK-1) and pyruvate dehydrogenase (PDH) phosphorylation in A549 cells. Ferrous glycinate also increased the expression of the mitochondrial transcription factor A (TFAM), and the mitochondrial protein, cytochrome c oxidase (COX-IV). Silencing of HIF-1α expression mimicked the effects of ferrous glycinate on PDK-1, PDH, TFAM and COX-IV in A549 cells. Ferrous glycinate increased mitochondrial membrane potential and ATP production in A549 cells. These results suggest that ferrous glycinate may reverse Warburg effect through down regulating HIF-1α in A549 cells.

  3. PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy.

    PubMed

    Dong, Lijie; Nian, Hong; Shao, Yan; Zhang, Yan; Li, Qiutang; Yi, Yue; Tian, Fang; Li, Wenbo; Zhang, Hong; Zhang, Xiaomin; Wang, Fei; Li, Xiaorong

    2015-05-01

    Pathological retinal neovascularization, including retinopathy of prematurity and age-related macular degeneration, is the most common cause of blindness worldwide. Insulin-like growth factor-1 (IGF-1) has a direct mitogenic effect on endothelial cells, which is the basis of angiogenesis. Vascular endothelial growth factor (VEGF) activation in response to IGF-1 is well documented; however, the molecular mechanisms responsible for the termination of IGF-1 signaling are still not completely elucidated. Here, we show that the polypyrimidine tract-binding protein-associated splicing factor (PSF) is a potential negative regulator of VEGF expression induced by IGF stimulation. Functional analysis demonstrated that ectopic expression of PSF inhibits IGF-1-stimulated transcriptional activation and mRNA expression of the VEGF gene, whereas knockdown of PSF increased IGF-1-stimulated responses. PSF recruited Hakai to the VEGF transcription complex, resulting in inhibition of IGF-1-mediated transcription. Transfection with Hakai siRNA reversed the PSF-mediated transcriptional repression of VEGF gene transcription. In summary, these results show that PSF can repress the transcriptional activation of VEGF stimulated by IGF-1 via recruitment of the Hakai complex and delineate a novel regulatory mechanism of IGF-1/VEGF signaling that may have implications in the pathogenesis of neovascularization in ocular diseases.

  4. Human NR5A1/SF-1 Mutations Show Decreased Activity on BDNF (Brain-Derived Neurotrophic Factor), an Important Regulator of Energy Balance: Testing Impact of Novel SF-1 Mutations Beyond Steroidogenesis

    PubMed Central

    Malikova, Jana; Camats, Núria; Fernández-Cancio, Mónica; Heath, Karen; González, Isabel; Caimarí, María; del Campo, Miguel; Albisu, Marian; Kolouskova, Stanislava; Audí, Laura; Flück, Christa E.

    2014-01-01

    Context Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. Objective To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. Patients 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. Methods SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). Results Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. Conclusions Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations. PMID:25122490

  5. Human NR5A1/SF-1 mutations show decreased activity on BDNF (brain-derived neurotrophic factor), an important regulator of energy balance: testing impact of novel SF-1 mutations beyond steroidogenesis.

    PubMed

    Malikova, Jana; Camats, Núria; Fernández-Cancio, Mónica; Heath, Karen; González, Isabel; Caimarí, María; del Campo, Miguel; Albisu, Marian; Kolouskova, Stanislava; Audí, Laura; Flück, Christa E

    2014-01-01

    Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.

  6. Proteomic analysis identifies insulin-like growth factor-binding protein-related protein-1 as a podocyte product.

    PubMed

    Matsumoto, Takayuki; Hess, Sonja; Kajiyama, Hiroshi; Sakairi, Toru; Saleem, Moin A; Mathieson, Peter W; Nojima, Yoshihisa; Kopp, Jeffrey B

    2010-10-01

    The podocyte secretory proteome may influence the phenotype of adjacent podocytes, endothelial cells, parietal epithelial cells, and tubular epithelial cells but has not been systematically characterized. We have initiated studies to characterize this proteome, with the goal of further understanding the podocyte cell biology. We cultured differentiated conditionally immortalized human podocytes and subjected the proteins in conditioned medium to mass spectrometry. At a false discovery rate of <3%, we identified 111 candidates from conditioned medium, including 44 proteins that have signal peptides or are described as secreted proteins in the UniProt database. As validation, we confirmed that one of these proteins, insulin-like growth factor-binding protein-related protein-1 (IGFBP-rP1), was expressed in mRNA and protein of cultured podocytes. In addition, transforming growth factor1 stimulation increased IGFBP-rP1 in conditioned medium. We analyzed IGFBP-rP1 glomerular expression in a mouse model of human immunodeficiency virus-associated nephropathy. IGFBP-rP1 was absent from podocytes of normal mice and was expressed in podocytes and pseudocrescents of transgenic mice, where it was coexpressed with desmin, a podocyte injury marker. We conclude that IGFBP-rP1 may be a product of injured podocytes. Further analysis of the podocyte secretory proteome may identify biomarkers of podocyte injury.

  7. Capsicum annuum homeobox 1 (CaHB1) is a nuclear factor that has roles in plant development, salt tolerance, and pathogen defense.

    PubMed

    Oh, Sang-Keun; Yoon, Joonseon; Choi, Gyung Ja; Jang, Hyun A; Kwon, Suk-Yoon; Choi, Doil

    2013-12-06

    Homeodomain-leucine zipper (HD-Zip) family proteins are unique to plants, but little is known about their role in defense responses. CaHB1 is a nuclear factor in peppers, belonging to subfamily II of HD-Zip proteins. Here, we determined the role of CaHB1 in the defense response. CaHB1 expression was induced when pepper plants were challenged with Phytophthora capsici, a plant pathogen to which peppers are susceptible, or environmental stresses such as drought and salt stimuli. CaHB1 was also highly expressed in pepper leaves following application of SA, whereas ethephon and MeJA had a moderate effect. To further investigate the function of CaHB1 in plants, we performed gain-of-function study by overexpression of CaHB1 in tomato. CaHB1-transgenic tomatoes showed significant growth enhancement including increased leaf thickness and enlarged cell size (1.8-fold larger than control plants). Microscopic analysis revealed that leaves from CaHB1-transgenic plants had thicker cell walls and cuticle layers than those from controls. Moreover, CaHB1-transgenic plants displayed enhanced resistance against Phytophthora infestans and increased tolerance to salt stress. Additionally, RT-PCR analysis of CaHB1-transgenic tomatoes revealed constitutive up-regulation of multiple genes involved in plant defense and osmotic stress. Therefore, our findings suggest roles for CaHB1 in development, salt stress, and pathogen defense. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1 and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome

    PubMed Central

    Pande, Mala; Amos, Christopher I.; Osterwisch, Daniel R.; Chen, Jinyun; Lynch, Patrick M.; Broaddus, Russell; Frazier, Marsha L.

    2011-01-01

    Individuals with Lynch syndrome are predisposed to cancer due to an inherited DNA mismatch repair gene mutation. However, there is significant variability observed in disease expression, likely due to the influence of other environmental, lifestyle, or genetic factors. Polymorphisms in genes encoding xenobiotic-metabolizing enzymes may modify cancer risk by influencing the metabolism and clearance of potential carcinogens from the body. In this retrospective analysis, we examined key candidate gene polymorphisms in CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 as modifiers of age at onset of colorectal cancer among 257 individuals with Lynch syndrome. We found that subjects heterozygous for CYP1A1 I462V (c.1384A>G) developed colorectal cancer 4 years earlier than those with the homozygous wild-type genotype (median ages 39 and 43 years, respectively; log-rank test P = 0.018). Furthermore, being heterozygous for the CYP1A1 polymorphisms, I462V and Msp1 (g.6235T>C), was associated with an increased risk for developing colorectal cancer [adjusted hazard ratio for AG relative to AA = 1.78, 95% CI = 1.16–2.74, P = 0.008; and hazard ratio for TC relative to TT = 1.53, 95% CI = 1.06–2.22, P = 0.02]. Since homozygous variants for both CYP1A1 polymorphisms were rare, risk estimates were imprecise. None of the other gene polymorphisms examined were associated with an earlier onset age for colorectal cancer. Our results suggest that the I462V and Msp1 polymorphisms in CYP1A1 may be an additional susceptibility factor for disease expression in Lynch syndrome since they modify the age of colorectal cancer onset by up to 4 years. PMID:18768509

  9. Lentiviral gene therapy against human immunodeficiency virus type 1, using a novel human TRIM21-cyclophilin A restriction factor.

    PubMed

    Chan, Emma; Schaller, Torsten; Eddaoudi, Ayad; Zhan, Hong; Tan, Choon Ping; Jacobsen, Marianne; Thrasher, Adrian J; Towers, Greg J; Qasim, Waseem

    2012-11-01

    TRIM5α (tripartite motif-containing protein-5, isoform α)-cyclophilin A fusion proteins are anti-human immunodeficiency virus (HIV) restriction factors that have evolved in certain nonhuman primates over millions of years and protect against HIV and related viruses. Restriction by TRIM5αCypA is potent and highly resistant to viral escape by mutation and, in combination with a suitable gene delivery platform, offers the possibility of novel therapeutic approaches against HIV. Here we report that lentiviral vector delivery of human mimics of TRIM5α-cyclophilin A (TRIM5CypA) fusion proteins afforded robust and durable protection against HIV-1, but resulted in downregulation of host cell antiviral responses mediated by endogenous TRIM5α. We found that substitution of TRIM5α RING, B-box, and coiled-coil domains with similar domains from a related TRIM protein, TRIM21, produced a novel and equally potent inhibitor of HIV-1. Both TRIM5CypA and TRIM21CypA inhibited transduction by HIV-1-derived viral vectors and prevented propagation of replication-competent HIV-1 in human cell lines and in primary human T cells. Restriction factor-modified T cells exhibited preferential survival in the presence of wild-type HIV. Restriction was dependent on proteasomal degradation and was reversed in the presence of the cyclophilin inhibitor cyclosporin. Importantly, TRIM21CypA did not disturb endogenous TRIM5α-mediated restriction of gammaretroviral infection. Furthermore, endogenous TRIM21 antiviral activity was assessed by measuring inhibition of adenovirus-antibody complexes and was found to be preserved in all TRIMCypA-modified groups. We conclude that lentivirus-mediated expression of the novel chimeric restriction factor TRIM21CypA provides highly potent protection against HIV-1 without loss of normal innate immune TRIM activity.

  10. Early Growth Response-1 Induces and Enhances Vascular Endothelial Growth Factor-A Expression in Lung Cancer Cells

    PubMed Central

    Shimoyamada, Hiroaki; Yazawa, Takuya; Sato, Hanako; Okudela, Koji; Ishii, Jun; Sakaeda, Masashi; Kashiwagi, Korehito; Suzuki, Takehisa; Mitsui, Hideaki; Woo, Tetsukan; Tajiri, Michihiko; Ohmori, Takahiro; Ogura, Takashi; Masuda, Munetaka; Oshiro, Hisashi; Kitamura, Hitoshi

    2010-01-01

    Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal–regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1–inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1α (HIF-1α)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1α and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1α expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression. PMID:20489156

  11. Age as an independent risk factor for intensive care unit admission or death due to 2009 pandemic influenza A (H1N1) virus infection.

    PubMed

    Nickel, Katelin B; Marsden-Haug, Nicola; Lofy, Kathryn H; Turnberg, Wayne L; Rietberg, Krista; Lloyd, Jennifer K; Marfin, Anthony A

    2011-01-01

    This study evaluated risk factors for intensive care unit (ICU) admission or death among people hospitalized with 2009 pandemic influenza A (pH1N1) virus infection. We based analyses on data collected in Washington State from April 27 to September 18, 2009, on deceased or hospitalized people with laboratory-confirmed pH1N1 infection reported by health-care providers and hospitals as part of enhanced public health surveillance. We used bivariate analyses and multivariable logistic regression to identify risk factors associated with ICU admission or death due to pH1N1. We identified 123 patients admitted to the hospital but not an ICU and 61 patients who were admitted to an ICU or died. Independent of high-risk medical conditions, both older age and delayed time to hospital admission were identified as risk factors for ICU admission or death due to pH1N1. Specifically, the odds of ICU admission or death were 4.44 times greater among adults aged 18-49 years (95% confidence interval [CI] 1.97, 10.02) and 5.93 times greater among adults aged 50-64 years (95% CI 2.24, 15.65) compared with pediatric patients < 18 years of age. Likewise, hospitalized cases admitted more than two days after illness onset had 2.17 times higher odds of ICU admission or death than those admitted within two days of illness onset (95% CI 1.10, 4.25). Although certain medical conditions clearly influence the need for hospitalization among people infected with pH1N1 virus, older age and delayed time to admission each played an independent role in the progression to ICU admission or death among hospitalized patients.

  12. Age as Risk Factor for Death from Pandemic (H1N1) 2009, Chile

    PubMed Central

    Dabanch, Jeannette; Nájera, Manuel; González, Claudia; Guerrero, Andrea; Olea, Andrea; Fasce, Rodrigo; Morales, Cecilia; Vega, Jeanette

    2011-01-01

    Pandemic (H1N1) 2009 affected Chile during the winter of 2009. The hospitalization rate was 0.56% overall and 3.47% for persons >60 years of age at risk for severe disease and death independent of concurrent conditions. Age >60 years was the major risk factor for death from pandemic (H1N1) 2009. PMID:21762580

  13. Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1

    PubMed Central

    Eferl, Robert; Hasselblatt, Peter; Rath, Martina; Popper, Helmut; Zenz, Rainer; Komnenovic, Vukoslav; Idarraga, Maria-Helena; Kenner, Lukas; Wagner, Erwin F.

    2008-01-01

    Studies using genetically modified mice have revealed fundamental functions of the transcription factor Fos/AP-1 in bone biology, inflammation, and cancer. However, the biological role of the Fos-related protein Fra-2 is not well defined in vivo. Here we report an unexpected profibrogenic function of Fra-2 in transgenic mice, in which ectopic expression of Fra-2 in various organs resulted in generalized fibrosis with predominant manifestation in the lung. The pulmonary phenotype was characterized by vascular remodeling and obliteration of pulmonary arteries, which coincided with expression of osteopontin, an AP-1 target gene involved in vascular remodeling and fibrogenesis. These alterations were followed by inflammation; release of profibrogenic factors, such as IL-4, insulin-like growth factor 1, and CXCL5; progressive fibrosis; and premature mortality. Genetic experiments and bone marrow reconstitutions suggested that fibrosis developed independently of B and T cells and was not mediated by autoimmunity despite the marked inflammation observed in transgenic lungs. Importantly, strong expression of Fra-2 was also observed in human samples of idiopathic and autoimmune-mediated pulmonary fibrosis. These findings indicate that Fra-2 expression is sufficient to cause pulmonary fibrosis in mice, possibly by linking vascular remodeling and fibrogenesis, and suggest that Fra-2 has to be considered a contributing pathogenic factor of pulmonary fibrosis in humans. PMID:18641127

  14. Expansion of microvascular networks in vivo by phthalimide neovascular factor 1 (PNF1)

    PubMed Central

    Wieghaus, Kristen A.; Nickerson, Meghan M.; Aronin, Caren E. Petrie; Sefcik, Lauren S.; Price, Richard J.; Paige, Mikell A.; Brown, Milton L.; Botchwey, Edward A.

    2010-01-01

    Phthalimide neovascular factor (PNF1, formerly SC-3-149) is a potent stimulator of proangiogenic signaling pathways in endothelial cells. In this study, we evaluated the in vivo effects of sustained PNF1 release to promote ingrowth and expansion of microvascular networks surrounding biomaterial implants. The dorsal skinfold window chamber was used to evaluate the structural remodeling response of the local microvasculature. PNF1 was released from poly(lactic-co-glycolic acid) (PLAGA) films, and a transport model was utilized to predict PNF1 penetration into the surrounding tissue. PNF1 significantly expanded microvascular networks within a 2 mm radius from implants after 3 and 7 days by increasing microvessel length density and lumenal diameter of local arterioles and venules. Staining of histological sections with CD11b showed enhanced recruitment of circulating white blood cells, including monocytes, which are critical for the process of vessel enlargement through arteriogenesis. As PNF1 has been shown to modulate MT1-MMP, a facilitator of CCL2 dependent leukocyte transmigration, aspects of window chamber experiments were repeated in CCR2−/− (CCL2 receptor) mouse chimeras to more fully explore the critical nature of monocyte recruitment on the therapeutic benefits of PNF1 function in vivo. PMID:18804278

  15. Expansion of microvascular networks in vivo by phthalimide neovascular factor 1 (PNF1).

    PubMed

    Wieghaus, Kristen A; Nickerson, Meghan M; Petrie Aronin, Caren E; Sefcik, Lauren S; Price, Richard J; Paige, Mikell A; Brown, Milton L; Botchwey, Edward A

    2008-12-01

    Phthalimide neovascular factor (PNF1, formerly SC-3-149) is a potent stimulator of proangiogenic signaling pathways in endothelial cells. In this study, we evaluated the in vivo effects of sustained PNF1 release to promote ingrowth and expansion of microvascular networks surrounding biomaterial implants. The dorsal skinfold window chamber was used to evaluate the structural remodeling response of the local microvasculature. PNF1 was released from poly(lactic-co-glycolic acid) (PLAGA) films, and a transport model was utilized to predict PNF1 penetration into the surrounding tissue. PNF1 significantly expanded microvascular networks within a 2mm radius from implants after 3 and 7 days by increasing microvessel length density and lumenal diameter of local arterioles and venules. Staining of histological sections with CD11b showed enhanced recruitment of circulating white blood cells, including monocytes, which are critical for the process of vessel enlargement through arteriogenesis. As PNF1 has been shown to modulate MT1-MMP, a facilitator of CCL2 dependent leukocyte transmigration, aspects of window chamber experiments were repeated in CCR2(-/-) (CCL2 receptor) mouse chimeras to more fully explore the critical nature of monocyte recruitment on the therapeutic benefits of PNF1 function in vivo.

  16. Mapping the Complement Factor H-Related Protein 1 (CFHR1):C3b/C3d Interactions

    PubMed Central

    Laskowski, Jennifer; Thurman, Joshua M.; Hageman, Gregory S.; Holers, V. Michael

    2016-01-01

    Complement factor H-related protein 1 (CFHR1) is a complement regulator which has been reported to regulate complement by blocking C5 convertase activity and interfering with C5b surface association. CFHR1 also competes with complement factor H (CFH) for binding to C3b, and may act as an antagonist of CFH-directed regulation on cell surfaces. We have employed site-directed mutagenesis in conjunction with ELISA-based and functional assays to isolate the binding interaction that CFHR1 undertakes with complement components C3b and C3d to a single shared interface. The C3b/C3d:CFHR1 interface is identical to that which occurs between the two C-terminal domains (SCR19-20) of CFH and C3b. Moreover, we have been able to corroborate that dimerization of CFHR1 is necessary for this molecule to bind effectively to C3b and C3d, or compete with CFH. Finally, we have established that CFHR1 competes with complement factor H-like protein 1 (CFHL-1) for binding to C3b. CFHL-1 is a CFH gene splice variant, which is almost identical to the N-terminal 7 domains of CFH (SCR1-7). CFHR1, therefore, not only competes with the C-terminus of CFH for binding to C3b, but also sterically blocks the interaction that the N-terminus of CFH undertakes with C3b, and which is required for CFH-regulation. PMID:27814381

  17. Individual, physical and psychological risk factors for neck pain in Australian office workers: a 1-year longitudinal study

    PubMed Central

    Michaleff, Zoe; Maher, Christopher G.; Refshauge, Kathryn

    2009-01-01

    Neck pain is more prevalent in office workers than in the general community. To date, findings from prospective studies that investigated causal relationships between putative risk factors and the onset of neck pain in this population have been limited by high loss to follow-up. The aim of this research was to prospectively evaluate a range of risk factors for neck pain in office workers, using validated and reliable objective measures as well as attain an estimate of 1-year incidence. We assembled a cohort of 53 office workers without neck pain and measured individual, physical, workplace and psychological factors at baseline. We followed participants for 1 year to measure the incidence of neck pain. We achieved 100% participant follow-up. Cox regression analysis was applied to examine the relationship between the putative risk factors and the cumulative incidence of neck pain. The 1-year incidence proportion of neck pain in Australian office workers was estimated in this study to be 0.49 (95% CI 0.36–0.62). Predictors of neck pain with moderate to large effect sizes were female gender (HR: 3.07; 95% CI: 1.18–7.99) and high psychological stress (HR: 1.64; 95% CI: 0.66–4.07). Protective factors included increased mobility of the cervical spine (HR: 0.44; 95% CI: 0.19–1.05) and frequent exercise (HR: 0.64; 95% CI: 0.27–1.51). These results reveal that neck pain is common in Australian office workers and that there are risk factors that are potentially modifiable. PMID:19399537

  18. Human immunodeficiency virus type 1 envelope proteins traffic toward virion assembly sites via a TBC1D20/Rab1-regulated pathway

    PubMed Central

    2012-01-01

    Background The cellular activity of many factors and pathways is required to execute the complex replication cycle of the human immunodeficiency virus type 1 (HIV-1). To reveal these cellular components, several extensive RNAi screens have been performed, listing numerous 'HIV-dependency factors'. However, only a small overlap between these lists exists, calling for further evaluation of the relevance of specific factors to HIV-1 replication and for the identification of additional cellular candidates. TBC1D20, the GTPase-activating protein (GAP) of Rab1, regulates endoplasmic reticulum (ER) to Golgi trafficking, was not identified in any of these screens, and its involvement in HIV-1 replication cycle is tested here. Findings Excessive TBC1D20 activity perturbs the early trafficking of HIV-1 envelope protein through the secretory pathway. Overexpression of TBC1D20 hampered envelope processing and reduced its association with detergent-resistant membranes, entailing a reduction in infectivity of HIV-1 virion like particles (VLPs). Conclusions These findings add TBC1D20 to the network of host factors regulating HIV replication cycle. PMID:22260459

  19. Heat shock factor-1 knockout induces multidrug resistance gene, MDR1b, and enhances P-glycoprotein (ABCB1)-based drug extrusion in the heart

    PubMed Central

    Krishnamurthy, Karthikeyan; Vedam, Kaushik; Kanagasabai, Ragu; Druhan, Lawrence J.; Ilangovan, Govindasamy

    2012-01-01

    Heat-shock factor 1 (HSF-1), a transcription factor for heat-shock proteins (HSPs), is known to interfere with the transcriptional activity of many oncogenic factors. In the present work, we have discovered that HSF-1 ablation induced the multidrug resistance gene, MDR1b, in the heart and increased the expression of P-glycoprotein (P-gp, ABCB1), an ATP binding cassette that is usually associated with multidrug-resistant cancer cells. The increase in P-gp enhanced the extrusion of doxorubicin (Dox) to alleviate Dox-induced heart failure and reduce mortality in mice. Dox-induced left ventricular (LV) dysfunction was significantly reduced in HSF-1−/− mice. DNA-binding activity of NF-κB was higher in HSF-1−/− mice. IκB, the NF-κB inhibitor, was depleted due to enhanced IκB kinase (IKK)-α activity. In parallel, MDR1b gene expression and a large increase in P-gp and lowering Dox loading were observed in HSF-1−/− mouse hearts. Moreover, application of the P-gp antagonist, verapamil, increased Dox loading in HSF-1−/− cardiomyocytes, deteriorated cardiac function in HSF-1−/− mice, and decreased survival. MDR1 promoter activity was higher in HSF-1−/− cardiomyocytes, whereas a mutant MDR1 promoter with heat-shock element (HSE) mutation showed increased activity only in HSF-1+/+ cardiomyocytes. However, deletion of HSE and NF-κB binding sites diminished luminescence in both HSF-1+/+ and HSF-1−/− cardiomyocytes, suggesting that HSF-1 inhibits MDR1 activity in the heart. Thus, because high levels of HSF-1 are attributed to poor prognosis of cancer, systemic down-regulation of HSF-1 before chemotherapy is a potential therapeutic approach to ameliorate the chemotherapy-induced cardiotoxicity and enhance cancer prognosis. PMID:22615365

  20. VizieR Online Data Catalog: Positions and distances of RR Lyrae stars (Sesar+, 2014)

    NASA Astrophysics Data System (ADS)

    Sesar, B.; Banholzer, S. R.; Cohen, J. G.; Martin, N. F.; Grillmair, C. J.; Levitan, D.; Laher, R. R.; Ofek, E. O.; Surace, J. A.; Kulkarni, S. R.; Prince, T. A.; Rix, H.-W.

    2017-04-01

    RRab stars used in this work were selected by an automated classification algorithm that uses imaging data provided by the Palomar Transient Factory survey (PTF). The PTF (Law et al. 2009PASP..121.1395L; Rau et al. 2009PASP..121.1334R) is a synoptic survey designed to explore the transient sky. The project utilizes the 48-inch Samuel Oschin Schmidt Telescope on Mount Palomar. Each PTF image covers 7.26 deg2 with a pixel scale of 1.01''. The typical PTF cadence consists of two 60 s exposures separated by ~1 hr and repeated every one to five days. By 2013 June, PTF observed ~11000 deg2 of sky at least 25 times in the Mould-R filter (hereafter the R-band filter), and about 2200 deg2 in the SDSS g' filter. PTF photometry is calibrated to an accuracy of about 0.02 mag (Ofek et al. 2012PASP..124...62O, 2012PASP..124..854O) and light curves have relative precision of better than 10 mmag at the bright end, and about 0.2 mag at the survey limiting magnitude of R=20.6 mag. The relative photometry algorithm is described in Ofek et al. (2011, J/ApJ/740/65, see their Appendix A). (1 data file).

  1. The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway.

    PubMed

    Chen, Hui-Jye; Lin, Chung-Ming; Lin, Chyuan-Sheng; Perez-Olle, Raul; Leung, Conrad L; Liem, Ronald K H

    2006-07-15

    MACF1 (microtubule actin cross-linking factor 1) is a multidomain protein that can associate with microfilaments and microtubules. We found that MACF1 was highly expressed in neuronal tissues and the foregut of embryonic day 8.5 (E8.5) embryos and the head fold and primitive streak of E7.5 embryos. MACF1(-/-) mice died at the gastrulation stage and displayed developmental retardation at E7.5 with defects in the formation of the primitive streak, node, and mesoderm. This phenotype was similar to Wnt-3(-/-) and LRP5/6 double-knockout embryos. In the absence of Wnt, MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC. Upon Wnt stimulation, MACF1 appeared to be involved in the translocation and subsequent binding of the Axin complex to LRP6 at the cell membrane. Reduction of MACF1 with small interfering RNA decreased the amount of beta-catenin in the nucleus, and led to an inhibition of Wnt-induced TCF/beta-catenin-dependent transcriptional activation. Similar results were obtained with a dominant-negative MACF1 construct that contained the Axin-binding region. Reduction of MACF1 in Wnt-1-expressing P19 cells resulted in decreased T (Brachyury) gene expression, a DNA-binding transcription factor that is a direct target of Wnt/beta-catenin signaling and required for mesoderm formation. These results suggest a new role of MACF1 in the Wnt signaling pathway.

  2. Analysis of HIV-1 intersubtype recombination breakpoints suggests region with high pairing probability may be a more fundamental factor than sequence similarity affecting HIV-1 recombination.

    PubMed

    Jia, Lei; Li, Lin; Gui, Tao; Liu, Siyang; Li, Hanping; Han, Jingwan; Guo, Wei; Liu, Yongjian; Li, Jingyun

    2016-09-21

    With increasing data on HIV-1, a more relevant molecular model describing mechanism details of HIV-1 genetic recombination usually requires upgrades. Currently an incomplete structural understanding of the copy choice mechanism along with several other issues in the field that lack elucidation led us to perform an analysis of the correlation between breakpoint distributions and (1) the probability of base pairing, and (2) intersubtype genetic similarity to further explore structural mechanisms. Near full length sequences of URFs from Asia, Europe, and Africa (one sequence/patient), and representative sequences of worldwide CRFs were retrieved from the Los Alamos HIV database. Their recombination patterns were analyzed by jpHMM in detail. Then the relationships between breakpoint distributions and (1) the probability of base pairing, and (2) intersubtype genetic similarities were investigated. Pearson correlation test showed that all URF groups and the CRF group exhibit the same breakpoint distribution pattern. Additionally, the Wilcoxon two-sample test indicated a significant and inexplicable limitation of recombination in regions with high pairing probability. These regions have been found to be strongly conserved across distinct biological states (i.e., strong intersubtype similarity), and genetic similarity has been determined to be a very important factor promoting recombination. Thus, the results revealed an unexpected disagreement between intersubtype similarity and breakpoint distribution, which were further confirmed by genetic similarity analysis. Our analysis reveals a critical conflict between results from natural HIV-1 isolates and those from HIV-1-based assay vectors in which genetic similarity has been shown to be a very critical factor promoting recombination. These results indicate the region with high-pairing probabilities may be a more fundamental factor affecting HIV-1 recombination than sequence similarity in natural HIV-1 infections. Our

  3. A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication.

    PubMed

    Griffiths, Samantha J; Koegl, Manfred; Boutell, Chris; Zenner, Helen L; Crump, Colin M; Pica, Francesca; Gonzalez, Orland; Friedel, Caroline C; Barry, Gerald; Martin, Kim; Craigon, Marie H; Chen, Rui; Kaza, Lakshmi N; Fossum, Even; Fazakerley, John K; Efstathiou, Stacey; Volpi, Antonio; Zimmer, Ralf; Ghazal, Peter; Haas, Jürgen

    2013-01-01

    Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to

  4. Duplication in the Microtubule-Actin Cross-linking Factor 1 gene causes a novel neuromuscular condition

    PubMed Central

    Jørgensen, Louise H.; Mosbech, Mai-Britt; Færgeman, Nils J.; Graakjaer, Jesper; Jacobsen, Søren V.; Schrøder, Henrik D.

    2014-01-01

    Spectrins and plakins are important communicators linking cytoskeletal components to each other and to cellular junctions. Microtubule-actin cross-linking factor 1 (MACF1) belongs to the spectraplakin family and is involved in control of microtubule dynamics. Complete knock out of MACF1 in mice is associated with developmental retardation and embryonic lethality. Here we present a family with a novel neuromuscular condition. Genetic analyses show a heterozygous duplication resulting in reduced MACF1 gene product. The functional consequence is affected motility observed as periodic hypotonia, lax muscles and diminished motor skills, with heterogeneous presentation among the affected family members. To corroborate these findings we used RNA interference to knock down the VAB-10 locus containing the MACF1 homologue in C. elegans, and we could show that this also causes movement disturbances. These findings suggest that changes in the MACF1 gene is implicated in this neuromuscular condition, which is an important observation since MACF1 has not previously been associated with any human disease and thus presents a key to understanding the essential nature of this gene. PMID:24899269

  5. Duplication in the microtubule-actin cross-linking factor 1 gene causes a novel neuromuscular condition.

    PubMed

    Jørgensen, Louise H; Mosbech, Mai-Britt; Færgeman, Nils J; Graakjaer, Jesper; Jacobsen, Søren V; Schrøder, Henrik D

    2014-06-05

    Spectrins and plakins are important communicators linking cytoskeletal components to each other and to cellular junctions. Microtubule-actin cross-linking factor 1 (MACF1) belongs to the spectraplakin family and is involved in control of microtubule dynamics. Complete knock out of MACF1 in mice is associated with developmental retardation and embryonic lethality. Here we present a family with a novel neuromuscular condition. Genetic analyses show a heterozygous duplication resulting in reduced MACF1 gene product. The functional consequence is affected motility observed as periodic hypotonia, lax muscles and diminished motor skills, with heterogeneous presentation among the affected family members. To corroborate these findings we used RNA interference to knock down the VAB-10 locus containing the MACF1 homologue in C. elegans, and we could show that this also causes movement disturbances. These findings suggest that changes in the MACF1 gene is implicated in this neuromuscular condition, which is an important observation since MACF1 has not previously been associated with any human disease and thus presents a key to understanding the essential nature of this gene.

  6. HIF-1 Alpha and Placental Growth Factor in Pregnancies Complicated With Preeclampsia: A Qualitative and Quantitative Analysis.

    PubMed

    Rath, Gayatri; Aggarwal, Ruby; Jawanjal, Poonam; Tripathi, Richa; Batra, Aruna

    2016-01-01

    The pathophysiology of preeclampsia is not clearly understood worldwide. Hypoxia inducible factor 1α (HIF-1α) is thought to be the preliminary factor for the hypoxic conditions prevailing in preeclampsia, which causes imbalance in the expression of angiogenic proteins. A proangiogenic protein, placental growth factor (PIGF), is reported to be dysregulated in preeclampsia. Therefore, this study focuses on the investigation of HIF-1α and PIGF in preeclamptic conditions and a possible molecular association between them. Placental tissue (n = 45 + 45) and serum samples (n = 80 + 80) of preeclamptic patients and healthy control were collected and processed for the analysis of HIF-1α and PIGF by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). In preeclamptic group, the significant nuclear and cytoplasmic expression of HIF-1α was noticed in syncytiotrophoblast (P = 0.0001) but in control placenta, it was localized to cytoplasm (P = 0.0001). The intensity of PIGF expression was lower in syncytiotrophoblast cytoplasm (P = 0.0001) in preeclamptic cases as compared with control. Also, the significant upregulated concentration of HIF-1α and downregulated PIGF was observed in serum samples of preeclamptic woman (P = 0.0001). Thus, there was a significant direct negative correlation between HIF-1α and PIGF both at tissue and serum level (P < 0.01). The direct inverse association between HIF-1α and PIGF in serum and placental tissues may be responsible for the low oxidative stress and endothelial dysfunction, leading to the pathogenesis of preeclampsia. © 2014 Wiley Periodicals, Inc.

  7. Perinatal factors and type 1 diabetes-associated dysbiosis in Mexican infants.

    PubMed

    Mejía-León, María Esther; Calderón de la Barca, Ana María

    Type 1 diabetes (T1D) is currently an autoimmune disease occurring more frequently and early in life. T1D development requires genetic predisposition and environmental factors, which influence the gut microbiota in early infancy and could increase the risk for T1D-associated autoimmunity. In Mexico there are no published microbiota studies in children <6 years old with T1D. We report two contrasting Mexican T1D cases of children <6 years of age and a third case of a healthy child prior to autoimmunity and T1D onset. Perinatal factors, feeding regimes in the first year of life and gut microbiota composition are discussed and related to the T1D onset. The three cases show a particular microbiota profile with decreased bacterial diversity as compared with healthy children, which could be related to environmental factors prior to the development of T1D and disease control. T1D infant cases presented a decreased bacterial diversity, which appeared before autoimmunity and T1D onset. Glycemic control could tend to correct the gut dysbiosis in T1D children. Prospective studies are needed to follow-up healthy children at high genetic risk to assess factors related to the microbiota structure. Copyright © 2015 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

  8. Plasticity in interactions of fibroblast growth factor 1 (FGF1) N terminus with FGF receptors underlies promiscuity of FGF1.

    PubMed

    Beenken, Andrew; Eliseenkova, Anna V; Ibrahimi, Omar A; Olsen, Shaun K; Mohammadi, Moosa

    2012-01-27

    Tissue-specific alternative splicing in the second half of Ig-like domain 3 (D3) of fibroblast growth factor receptors 1-3 (FGFR1 to -3) generates epithelial FGFR1b-FGFR3b and mesenchymal FGFR1c-FGFR3c splice isoforms. This splicing event establishes a selectivity filter to restrict the ligand binding specificity of FGFRb and FGFRc isoforms to mesenchymally and epithelially derived fibroblast growth factors (FGFs), respectively. FGF1 is termed the "universal FGFR ligand" because it overrides this specificity barrier. To elucidate the molecular basis for FGF1 cross-reactivity with the "b" and "c" splice isoforms of FGFRs, we determined the first crystal structure of FGF1 in complex with an FGFRb isoform, FGFR2b, at 2.1 Å resolution. Comparison of the FGF1-FGFR2b structure with the three previously published FGF1-FGFRc structures reveals that plasticity in the interactions of the N-terminal region of FGF1 with FGFR D3 is the main determinant of FGF1 cross-reactivity with both isoforms of FGFRs. In support of our structural data, we demonstrate that substitution of three N-terminal residues (Gly-19, His-25, and Phe-26) of FGF2 (a ligand that does not bind FGFR2b) for the corresponding residues of FGF1 (Phe-16, Asn-22, and Tyr-23) enables the FGF2 triple mutant to bind and activate FGFR2b. These findings taken together with our previous structural data on receptor binding specificity of FGF2, FGF8, and FGF10 conclusively show that sequence divergence at the N termini of FGFs is the primary regulator of the receptor binding specificity and promiscuity of FGFs.

  9. C. elegans sym-1 is a downstream target of the hunchback-like-1 developmental timing transcription factor

    PubMed Central

    Niwa, Ryusuke; Hada, Kazumasa; Moliyama, Kouichi; Ohniwa, Ryosuke L.; Tan, Yi-Meng; Olsson-Carter, Katherine; Chi, Woo; Reinke, Valerie; Slack, Frank J.

    2010-01-01

    In the nematode Caenorhabditis elegans, the let-7 microRNA (miRNA) and its family members control the timing of key developmental events in part by directly regulating expression of hunchback-like-1 (hbl-1). C. elegans hbl-1 mutants display multiple developmental timing deficiencies, including cell cycle defects during larval development. While hbl-1 is predicted to encode a transcriptional regulator, downstream targets of HBL-1 have not been fully elucidated. Here we report using microarray analysis to uncover genes downstream of HBL-1. We established a transgenic strain that overexpresses hbl-1 under the control of a heat shock promoter. Heat shock-induced hbl-1 overexpression led to retarded hypodermal structures at the adult stage, opposite to the effect seen in loss of function (lf) hbl-1 mutants. The microarray screen identified numerous potential genes that are upregulated or downregulated by HBL-1, including sym-1, which encodes a leucine-rich repeat protein with a signal sequence. We found an increase in sym-1 transcription in the heat shock-induced hbl-1 overexpression strain, while loss of hbl-1 function caused a decrease in sym-1 expression levels. Furthermore, we found that sym-1(lf) modified the hypodermal abnormalities in hbl-1 mutants. Given that SYM-1 is a protein secreted from hypodermal cells to the surrounding cuticle, we propose that the adult-specific cuticular structures may be under the temporal control of HBL-1 through regulation of sym-1 transcription. PMID:19923914

  10. Transcription Factor CBF4 Is a Regulator of Drought Adaptation in Arabidopsis1

    PubMed Central

    Haake, Volker; Cook, Daniel; Riechmann, José Luis; Pineda, Omaira; Thomashow, Michael F.; Zhang, James Z.

    2002-01-01

    In plants, low temperature and dehydration activate a set of genes containing C-repeat/dehydration-responsive elements in their promoter. It has been shown previously that the Arabidopsis CBF/DREB1 transcription activators are critical regulators of gene expression in the signal transduction of cold acclimation. Here, we report the isolation of an apparent homolog of the CBF/DREB1 proteins (CBF4) that plays the equivalent role during drought adaptation. In contrast to the three already identified CBF/DREB1 homologs, which are induced under cold stress, CBF4 gene expression is up-regulated by drought stress, but not by low temperature. Overexpression of CBF4 in transgenic Arabidopsis plants results in the activation of C-repeat/dehydration-responsive element containing downstream genes that are involved in cold acclimation and drought adaptation. As a result, the transgenic plants are more tolerant to freezing and drought stress. Because of the physiological similarity between freezing and drought stress, and the sequence and structural similarity of the CBF/DREB1 and the CBF4 proteins, we propose that the plant's response to cold and drought evolved from a common CBF-like transcription factor, first through gene duplication and then through promoter evolution. PMID:12376631

  11. Vascular Induction of a Disintegrin and Metalloprotease 17 by Angiotensin II Through Hypoxia Inducible Factor 1α

    PubMed Central

    Obama, Takashi; Takayanagi, Takehiko; Kobayashi, Tomonori; Bourne, Allison M.; Elliott, Katherine J.; Charbonneau, Martine; Dubois, Claire M.

    2015-01-01

    BACKGROUND A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature. METHODS Cultured vascular smooth muscle cells were stimulated with 100nM angiotensin II. Mice were infused with 1 μg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter–reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II–infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry. CONCLUSIONS Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α–dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system. PMID:24871629

  12. The transcription factor WIN1/SHN1 regulates Cutin biosynthesis in Arabidopsis thaliana.

    PubMed

    Kannangara, Rubini; Branigan, Caroline; Liu, Yan; Penfield, Teresa; Rao, Vijaya; Mouille, Grégory; Höfte, Herman; Pauly, Markus; Riechmann, José Luis; Broun, Pierre

    2007-04-01

    The composition and permeability of the cuticle has a large influence on its ability to protect the plant against various forms of biotic and abiotic stress. WAX INDUCER1 (WIN1) and related transcription factors have recently been shown to trigger wax production, enhance drought tolerance, and modulate cuticular permeability when overexpressed in Arabidopsis thaliana. We found that WIN1 influences the composition of cutin, a polyester that forms the backbone of the cuticle. WIN1 overexpression induces compositional changes and an overall increase in cutin production in vegetative and reproductive organs, while its downregulation has the opposite effect. Changes in cutin composition are preceded by the rapid and coordinated induction of several genes known or likely to be involved in cutin biosynthesis. This transcriptional response is followed after a delay by the induction of genes associated with wax biosynthesis, suggesting that the regulation of cutin and wax production by WIN1 is a two-step process. We demonstrate that at least one of the cutin pathway genes, which encodes long-chain acyl-CoA synthetase LACS2, is likely to be directly targeted by WIN1. Overall, our results suggest that WIN1 modulates cuticle permeability in Arabidopsis by regulating genes encoding cutin pathway enzymes.

  13. Vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase signaling facilitates granulation tissue formation with recruitment of VEGFR1+ cells from bone marrow.

    PubMed

    Park, Keiichi; Amano, Hideki; Ito, Yoshiya; Mastui, Yoshio; Kamata, Mariko; Yamazaki, Yasuharu; Takeda, Akira; Shibuya, Masabumi; Majima, Masataka

    2018-06-01

    Vascular endothelial growth factor (VEGF)-A facilitates wound healing. VEGF-A binds to VEGF receptor 1 (VEGFR1) and VEGFR2 and induces wound healing through the receptor's tyrosine kinase (TK) domain. During blood flow recovery and lung regeneration, expression of VEGFR1 is elevated. However, the precise mechanism of wound healing, especially granulation formation on VEGFR1, is not well understood. We hypothesized that VEGFR1-TK signaling induces wound healing by promoting granulation tissue formation. A surgical sponge implantation model was made by implanting a sponge disk into dorsal subcutaneous tissue of mice. Granulation formation was estimated from the weight of the sponge and the granulation area from the immunohistochemical analysis of collagen I. The expression of fibroblast markers was estimated from the expression of transforming growth factor-beta (TGF-β) and cellular fibroblast growth factor-2 (FGF-2) using real-time PCR (polymerase chain reaction) and from the immunohistochemical analysis of S100A4. VEGFR1 TK knockout (TK -/- ) mice exhibited suppressed granulation tissue formation compared to that in wild-type (WT) mice. Expression of FGF-2, TGF-β, and VEGF-A was significantly suppressed in VEGFR1 TK -/- mice, and the accumulation of VEGFR1 + cells in granulation tissue was reduced in VEGFR1 TK -/- mice compared to that in WT mice. The numbers of VEGFR1 + cells and S100A4 + cells derived from bone marrow (BM) were higher in WT mice transplanted with green fluorescent protein (GFP) transgenic WT BM than in VEGFR1 TK -/- mice transplanted with GFP transgenic VEGFR1 TK -/- BM. These results indicated that VEGFR1-TK signaling induced the accumulation of BM-derived VEGFR1 + cells expressing F4/80 and S100A4 and contributed to granulation formation around the surgically implanted sponge area in a mouse model.

  14. The role of transforming growth factor β1 in fractional laser resurfacing with a carbon dioxide laser.

    PubMed

    Jiang, Xia; Ge, Hongmei; Zhou, Chuanqing; Chai, Xinyu; Deng, Hui

    2014-03-01

    The aim of this study was to investigate the role of transforming growth factor β1 in mechanisms of cutaneous remodeling induced by fractional carbon dioxide laser treatment. The dorsal skin of Kunming mice was exposed to a single-pass fractional CO2 laser treatment. Biopsies were taken at 1 h and at 1, 3, 7, 14, 21, 28, and 56 days after treatment. Transforming growth factor (TGF) β1 expression in skin samples was evaluated by ELISA, dermal thickness by hematoxylin-eosin staining, collagen and elastic fibers by Ponceau S and Victoria blue double staining, and types I and III collagens by ELISA. The level of TGF β1 in the laser-treated areas of skin was significantly increased compared with that in the control areas on days 1 (p < 0.05), 3 (p < 0.01), and 7 (p < 0.05) and then decreased by day 14 after treatment, at which time it had returned to the baseline level. Dermal thickness and the amount of type I collagen of the skin of the laser-treated areas had increased significantly (p < 0.05) compared with that in control areas on days 28 and 56. Fibroblast proliferation showed a positive correlation with TGF β1 expression during the early stages (r = 0.789, p < 0.01), and there was a negative correlation between the level of TGF β1 and type I collagen in the late stages, after laser treatment (r = -0.546, p < 0.05). TGF β1 appears to be an important factor in fractional laser resurfacing.

  15. Huntingtin interacting protein 1 is a novel brain tumor marker that associates with epidermal growth factor receptor.

    PubMed

    Bradley, Sarah V; Holland, Eric C; Liu, Grace Y; Thomas, Dafydd; Hyun, Teresa S; Ross, Theodora S

    2007-04-15

    Huntingtin interacting protein 1 (HIP1) is a multidomain oncoprotein whose expression correlates with increased epidermal growth factor receptor (EGFR) levels in certain tumors. For example, HIP1-transformed fibroblasts and HIP1-positive breast cancers have elevated EGFR protein levels. The combined association of HIP1 with huntingtin, the protein that is mutated in Huntington's disease, and the known overexpression of EGFR in glial brain tumors prompted us to explore HIP1 expression in a group of patients with different types of brain cancer. We report here that HIP1 is overexpressed with high frequency in brain cancers and that this overexpression correlates with EGFR and platelet-derived growth factor beta receptor expression. Furthermore, serum samples from patients with brain cancer contained anti-HIP1 antibodies more frequently than age-matched brain cancer-free controls. Finally, we report that HIP1 physically associates with EGFR and that this association is independent of the lipid, clathrin, and actin interacting domains of HIP1. These findings suggest that HIP1 may up-regulate or maintain EGFR overexpression in primary brain tumors by directly interacting with the receptor. This novel HIP1-EGFR interaction may work with or independent of HIP1 modulation of EGFR degradation via clathrin-mediated membrane trafficking pathways. Further investigation of HIP1 function in brain cancer biology and validation of its use as a prognostic or predictive brain tumor marker are now warranted.

  16. High-accuracy calculations of the ground, 1 1A1', and the 2 1A1', 2 3A1', and 1 1E' excited states of H3+.

    PubMed

    Pavanello, Michele; Adamowicz, Ludwik

    2009-01-21

    Accurate variational Born-Oppenheimer calculations of the 1 (1)A(1) ('), 2 (1)A(1) ('), 2 (3)A(1) ('), and 1 (1)E(') states of the H(3) (+) ion at the ground-state equilibrium geometry are reported. The wave functions of the states are expanded in terms of explicitly correlated spherical Gaussian functions with shifted centers. In the variational optimization the analytical gradient of the energy with respect to the nonlinear exponential parameters of the Gaussians has been employed. The energies obtained in the calculations are the best variational estimates ever calculated for the four states. One-electron densities for the states, as well as a D(3h)-restricted potential energy surface of the ground state calculated around the equilibrium geometry, are also presented and discussed.

  17. Copy number variations of E2F1: a new genetic risk factor for testicular cancer.

    PubMed

    Rocca, Maria Santa; Di Nisio, Andrea; Marchiori, Arianna; Ghezzi, Marco; Opocher, Giuseppe; Foresta, Carlo; Ferlin, Alberto

    2017-03-01

    Testicular germ cell tumor (TGCT) is one of the most heritable forms of cancer. In last years, many evidence suggested that constitutional genetic factors, mainly single nucleotide polymorphisms, can increase its risk. However, the possible contribution of copy number variations (CNVs) in TGCT susceptibility has not been substantially addressed. Indeed, an increasing number of studies have focused on the effect of CNVs on gene expression and on the role of these structural genetic variations as risk factors for different forms of cancer. E2F1 is a transcription factor that plays an important role in regulating cell growth, differentiation, apoptosis and response to DNA damage. Therefore, deficiency or overexpression of this protein might significantly influence fundamental biological processes involved in cancer development and progression, including TGCT. We analyzed E2F1 CNVs in 261 cases with TGCT and 165 controls. We found no CNVs in controls, but 17/261 (6.5%) cases showed duplications in E2F1 Blot analysis demonstrated higher E2F1 expression in testicular samples of TGCT cases with three copies of the gene. Furthermore, we observed higher phosphorylation of Akt and mTOR in samples with E2F1 duplication. Interestingly, normal, non-tumoral testicular tissue in patient with E2F1 duplication showed lower expression of E2F1 and lower AKT/mTOR phosphorylation with respect to adjacent tumor tissue. Furthermore, increased expression of E2F1 obtained in vitro in NTERA-2 testicular cell line induced increased AKT/mTOR phosphorylation. This study suggests for the first time an involvement of E2F1 CNVs in TGCT susceptibility and supports previous preliminary data on the importance of AKT/mTOR signaling pathway in this cancer. © 2017 Society for Endocrinology.

  18. Regulatory factors controlling transcription of Saccharomyces cerevisiae IXR1 by oxygen levels: a model of transcriptional adaptation from aerobiosis to hypoxia implicating ROX1 and IXR1 cross-regulation.

    PubMed

    Castro-Prego, Raquel; Lamas-Maceiras, Mónica; Soengas, Pilar; Carneiro, Isabel; González-Siso, Isabel; Cerdán, M Esperanza

    2009-12-14

    Ixr1p from Saccharomyces cerevisiae has been previously studied because it binds to DNA containing intrastrand cross-links formed by the anticancer drug cisplatin. Ixr1p is also a transcriptional regulator of anaerobic/hypoxic genes, such as SRP1/TIR1, which encodes a stress-response cell wall manoprotein, and COX5B, which encodes the Vb subunit of the mitochondrial complex cytochrome c oxidase. However, factors controlling IXR1 expression remained unexplored. In the present study we show that IXR1 mRNA levels are controlled by oxygen availability and increase during hypoxia. In aerobiosis, low levels of IXR1 expression are maintained by Rox1p repression through the general co-repressor complex Tup1-Ssn6. Ixr1p itself is necessary for full IXR1 expression under hypoxic conditions. Deletion analyses have identified the region in the IXR1 promoter responsible for this positive auto-control (nucleotides -557 to -376). EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation) assays show that Ixr1p binds to the IXR1 promoter both in vitro and in vivo. Ixr1p is also required for hypoxic repression of ROX1 and binds to its promoter. UPC2 deletion has opposite effects on IXR1 and ROX1 transcription during hypoxia. Ixr1p is also necessary for resistance to oxidative stress generated by H2O2. IXR1 expression is moderately activated by H2O2 and this induction is Yap1p-dependent. A model of IXR1 regulation as a relay for sensing different signals related to change in oxygen availability is proposed. In this model, transcriptional adaptation from aerobiosis to hypoxia depends on ROX1 and IXR1 cross-regulation.

  19. Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis

    PubMed Central

    Fantauzzo, Katherine A.; Christiano, Angela M.

    2012-01-01

    Mutations in TRPS1 cause trichorhinophalangeal syndrome types I and III, which are characterized by sparse scalp hair in addition to craniofacial and skeletal abnormalities. Trps1 is a vertebrate transcription factor that contains nine zinc-finger domains, including a GATA-type zinc finger through which it binds DNA. Mice in which the GATA domain of Trps1 has been deleted (Trps1Δgt/Δgt) have a reduced number of pelage follicles and lack vibrissae follicles postnatally. To identify the transcriptional targets of Trps1 in the developing vibrissa follicle, we performed microarray hybridization analysis, comparing expression patterns in the whisker pads of wild-type versus Trps1Δgt/Δgt embryos. We identified a number of transcription factors and Wnt inhibitors among transcripts downregulated in the mutant embryos and several extracellular matrix proteins that were upregulated in the mutant samples, and demonstrated that target gene expression levels were altered in vivo in Trps1Δgt/Δgt vibrissae. Unexpectedly, we discovered that Trps1 can directly bind the promoters of its target genes to activate transcription, expanding upon its established role as a transcriptional repressor. Our findings identify Trps1 as a novel regulator of the Wnt signaling pathway and of early hair follicle progenitors in the developing vibrissa follicle. PMID:22115758

  20. The complement factor 5a receptor 1 has a pathogenic role in chronic inflammation and renal fibrosis in a murine model of chronic pyelonephritis.

    PubMed

    Choudhry, Naheed; Li, Ke; Zhang, Ting; Wu, Kun-Yi; Song, Yun; Farrar, Conrad A; Wang, Na; Liu, Cheng-Fei; Peng, Qi; Wu, Weiju; Sacks, Steven H; Zhou, Wuding

    2016-09-01

    Complement factor 5a (C5a) interaction with its receptor (C5aR1) contributes to the pathogenesis of inflammatory diseases, including acute kidney injury. However, its role in chronic inflammation, particularly in pathogen-associated disorders, is largely unknown. Here we tested whether the development of chronic inflammation and renal fibrosis is dependent on C5aR1 in a murine model of chronic pyelonephritis. C5aR1-deficient (C5aR1-/-) mice showed a significant reduction in bacterial load, tubule injury and tubulointerstitial fibrosis in the kidneys following infection, compared with C5aR1-sufficient mice. This was associated with reduced renal leukocyte infiltration specifically for the population of Ly6Chi proinflammatory monocytes/macrophages and reduced intrarenal gene expression of key proinflammatory and profibrogenic factors in C5aR1-/- mice following infection. Antagonizing C5aR1 decreased renal bacterial load, tissue inflammation and tubulointerstitial fibrosis. Ex vivo and in vitro studies showed that under infection conditions, C5a/C5aR1 interaction upregulated the production of proinflammatory and profibrogenic factors by renal tubular epithelial cells and monocytes/macrophages, whereas the phagocytic function of monocytes/macrophages was down-regulated. Thus, C5aR1-dependent bacterial colonization of the tubular epithelium, C5a/C5aR1-mediated upregulation of local inflammatory responses to uropathogenic E. coli and impairment of phagocytic function of phagocytes contribute to persistent bacterial colonization of the kidney, chronic renal inflammation and subsequent tubulointerstitial fibrosis. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  1. A Myeloid Hypoxia-inducible Factor 1α-Krüppel-like Factor 2 Pathway Regulates Gram-positive Endotoxin-mediated Sepsis*

    PubMed Central

    Mahabeleshwar, Ganapati H.; Qureshi, Muhammad Awais; Takami, Yoichi; Sharma, Nikunj; Lingrel, Jerry B.; Jain, Mukesh K.

    2012-01-01

    Although Gram-positive infections account for the majority of cases of sepsis, the molecular mechanisms underlying their effects remains poorly understood. We investigated how cell wall components of Gram-positive bacteria contribute to the development of sepsis. Experimental observations derived from cultured primary macrophages and the cell line indicate that Gram-positive bacterial endotoxins induce hypoxia-inducible factor 1α (HIF-1α) mRNA and protein expression. Inoculation of live or heat-inactivated Gram-positive bacteria with macrophages induced HIF-1 transcriptional activity in macrophages. Concordant with these results, myeloid deficiency of HIF-1α attenuated Gram-positive bacterial endotoxin-induced cellular motility and proinflammatory gene expression in macrophages. Conversely, Gram-positive bacteria and their endotoxins reduced expression of the myeloid anti-inflammatory transcription factor Krüppel-like transcription factor 2 (KLF2). Sustained expression of KLF2 reduced and deficiency of KLF2 enhanced Gram-positive endotoxins induced HIF-1α mRNA and protein expression in macrophages. More importantly, KLF2 attenuated Gram-positive endotoxins induced cellular motility and proinflammatory gene expression in myeloid cells. Consistent with these results, mice deficient in myeloid HIF-1α were protected from Gram-positive endotoxin-induced sepsis mortality and clinical symptomatology. By contrast, myeloid KLF2-deficient mice were susceptible to Gram-positive sepsis induced mortality and clinical symptoms. Collectively, these observations identify HIF-1α and KLF2 as critical regulators of Gram-positive endotoxin-mediated sepsis. PMID:22110137

  2. Activation of the transcription factor nuclear factor-kappa B in uterine luminal epithelial cells by interleukin 1 Beta 2: a novel interleukin 1 expressed by the elongating pig conceptus.

    PubMed

    Mathew, Daniel J; Newsom, Emily M; Guyton, Jennifer M; Tuggle, Christopher K; Geisert, Rodney D; Lucy, Matthew C

    2015-04-01

    Conceptus mortality is greatest in mammals during the peri-implantation period, a time when conceptuses appose and attach to the uterine surface epithelium while releasing proinflammatory molecules. Interleukin 1 beta (IL1B), a master proinflammatory cytokine, is released by the primate, rodent, and pig blastocyst during the peri-implantation period and is believed to be essential for establishment of pregnancy. The gene encoding IL1B has duplicated in the pig, resulting in a novel gene. Preliminary observations indicate that the novel IL1B is specifically expressed by pig conceptuses during the peri-implantation period. To verify this, IL1B was cloned from mRNA isolated from Day 12 pig conceptuses and compared with IL1B cloned from mRNA isolated from pig peripheral blood leukocytes (PBLs). The pig conceptuses, but not the PBLs, expressed a novel IL1B, referred to here as interleukin 1 beta 2 (IL1B2). Porcine endometrium was treated with recombinant porcine interleukin 1 beta 1 (IL1B1), the prototypical cytokine, and IL1B2 proteins. Immunohistochemistry and real-time RT-PCR were used to measure activation of nuclear factor-kappa B (NFKB) and NFKB-regulated transcripts, respectively, within the endometrium. Both IL1B1 and IL1B2 activated NFKB in the uterine luminal epithelium within 4 h. The NFKB activation and related gene expression, however, were lower in endometrium treated with IL1B2, suggesting that the conceptus-derived cytokine may have reduced activity within the uterus. In conclusion, the peri-implantation pig conceptus expresses a novel IL1B that can activate NFKB within the uterine surface epithelium, likely creating a proinflammatory microenvironment during establishment of pregnancy in the pig. © 2015 by the Society for the Study of Reproduction, Inc.

  3. 26 CFR 1.611-4 - Depletion as a factor in computing earnings and profits for dividend purposes.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Depletion as a factor in computing earnings and profits for dividend purposes. 1.611-4 Section 1.611-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1...

  4. 26 CFR 1.611-4 - Depletion as a factor in computing earnings and profits for dividend purposes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Depletion as a factor in computing earnings and profits for dividend purposes. 1.611-4 Section 1.611-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1...

  5. Disruption of Hypoxia-Inducible Transcription Factor-Prolyl Hydroxylase Domain-1 (PHD-1−/−) Attenuates Ex Vivo Myocardial Ischemia/Reperfusion Injury Through Hypoxia-Inducible Factor-1α Transcription Factor and Its Target Genes in Mice

    PubMed Central

    Adluri, Ram Sudheer; Thirunavukkarasu, Mahesh; Dunna, Nageswara Rao; Zhan, Lijun; Oriowo, Babatunde; Takeda, Kotaro; Sanchez, Juan A.; Otani, Hajime; Maulik, Gautam; Fong, Guo-Hua

    2011-01-01

    Abstract Hypoxia-inducible transcription factor (HIF)-prolyl hydroxylases domain (PHD-1–3) are oxygen sensors that regulate the stability of the HIFs in an oxygen-dependent manner. Suppression of PHD enzymes leads to stabilization of HIFs and offers a potential treatment option for many ischemic disorders, such as peripheral artery occlusive disease, myocardial infarction, and stroke. Here, we show that homozygous disruption of PHD-1 (PHD-1−/−) could facilitate HIF-1α-mediated cardioprotection in ischemia/reperfused (I/R) myocardium. Wild-type (WT) and PHD-1−/− mice were randomized into WT time-matched control (TMC), PHD-1−/− TMC (PHD1TMC), WT I/R, and PHD-1−/− I/R (PHD1IR). Isolated hearts from each group were subjected to 30 min of global ischemia followed by 2 h of reperfusion. TMC hearts were perfused for 2 h 30 min without ischemia. Decreased infarct size (35% ± 0.6% vs. 49% ± 0.4%) and apoptotic cardiomyocytes (106 ± 13 vs. 233 ± 21 counts/100 high-power field) were observed in PHD1IR compared to wild-type ischemia/reperfusion (WTIR). Protein expression of HIF-1α was significantly increased in PHD1IR compared to WTIR. mRNA expression of β-catenin (1.9-fold), endothelial nitric oxide synthase (1.9-fold), p65 (1.9-fold), and Bcl-2 (2.7-fold) were upregulated in the PHD1IR compared with WTIR, which was studied by real-time quantitative polymerase chain reaction. Further, gel-shift analysis showed increased DNA binding activity of HIF-1α and nuclear factor-kappaB in PHD1IR compared to WTIR. In addition, nuclear translocation of β-catenin was increased in PHD1IR compared with WTIR. These findings indicated that silencing of PHD-1 attenuates myocardial I/R injury probably by enhancing HIF-1α/β-catenin/endothelial nitric oxide synthase/nuclear factor-kappaB and Bcl-2 signaling pathway. Antioxid. Redox Signal. 15, 1789–1797. PMID:21083501

  6. Churg-Strauss Syndrome Following Vaccination Against 2010 Influenza A (H1N1): A Case Report.

    PubMed

    Fu, Mu-Hui; Tsai, Wan-Chen; Lan, Jui; Lu, Cheng-Hsien; Lee, Lian-Hui; Huang, Chih-Cheng

    2014-09-01

    Churg-Strauss syndrome (CSS) is a systemic inflammatory disorder characterized by asthma, transient pulmonary infiltration, hyper-eosinophilia, and systemic vasculitis. Reported triggering factors include infections, drugs, allergic desensitization, and vaccinations, although cases involving the latter two are extremely rare. Herein, we describe a patient who developed CSS after receiving an H1N1 vaccination. A 55-year-old woman presented with fever, skin eruptions, and sensory impairment of her feet within one week after an H1N1 vaccine injection. A chest X-ray showed pulmonary infiltrations in both lower lung fields. Eosinophilia was noted in a hematological test, and an electrophysiological study revealed a pattern of mononeuritis multiplex. A skin biopsy was performed which revealed palisading necrotizing granuloma around a degenerated dermis and eosinophilic infiltration of the blood vessel walls. These findings combined with the hematological and electrophysiological findings met the criteria of CSS according to the American College of Rheumatology. The patient recovered well after steroid treatment. This case highlights the possibility that the H1N1 vaccination can trigger CSS. Due to the rarity of reported autoimmune events after vaccine administration and the obscure causal association between autoimmunity and a vaccine, further post-marketing surveillance and research are necessary to clarify the relationship and identify risk factors.

  7. Testicular differentiation factor SF-1 is required for human spleen development

    PubMed Central

    Zangen, David; Kaufman, Yotam; Banne, Ehud; Weinberg-Shukron, Ariella; Abulibdeh, Abdulsalam; Garfinkel, Benjamin P.; Dweik, Dima; Kanaan, Moein; Camats, Núria; Flück, Christa; Renbaum, Paul; Levy-Lahad, Ephrat

    2014-01-01

    The transcription factor steroidogenic factor 1 (SF-1; also known as NR5A1) is a crucial mediator of both steroidogenic and nonsteroidogenic tissue differentiation. Mutations within SF1 underlie different disorders of sexual development (DSD), including sex reversal, spermatogenic failure, ovarian insufficiency, and adrenocortical deficiency. Here, we identified a recessive mutation within SF1 that resulted in a substitution of arginine to glutamine at codon 103 (R103Q) in a child with both severe 46,XY-DSD and asplenia. The R103Q mutation decreased SF-1 transactivation of TLX1, a transcription factor that has been shown to be essential for murine spleen development. Additionally, the SF1 R103Q mutation impaired activation of steroidogenic genes, without affecting synergistic SF-1 and sex-determining region Y (SRY) coactivation of the testis development gene SOX9. Together, our data provide evidence that SF-1 is required for spleen development in humans via transactivation of TLX1 and that mutations that only impair steroidogenesis, without altering the SF1/SRY transactivation of SOX9, can lead to 46,XY-DSD. PMID:24905461

  8. Transcription factor specificity protein 1 modulates TGFβ1/Smad signaling to negatively regulate SIGIRR expression by human M1 macrophages stimulated with substance P.

    PubMed

    Yamaguchi, Rui; Sakamoto, Arisa; Yamaguchi, Reona; Haraguchi, Misa; Narahara, Shinji; Sugiuchi, Hiroyuki; Yamaguchi, Yasuo

    2018-08-01

    The stimuli inducing expression of single immunoglobulin IL-1-related receptor (SIGIRR) and the relevant regulatory mechanisms are not well defined. Transforming growth factor β1 (TGFβ1) delays internalization of neurokinin-1 receptor (NK1R) and subsequently enhances cellular signaling. This study investigated the effect of TGFβ1 on SIGIRR protein production by human M1 macrophages in response to stimulation with substance P (SP). SP caused upregulation of SIGIRR expression in a concentration-dependent manner, whereas aprepitant (an NK1R inhibitor) blunted this response. Silencing p38γMAPK or TAK-1 partially attenuated the response to SP stimulation, while TGFβ1/2/3 siRNA dramatically diminished it. SP induced much greater SIGIRR protein production than either lipopolysaccharide (a TLR4 agonist) or resiquimod (a TLR7/8 agonist). Unexpectedly, silencing of transcription factor specificity protein 1 (Sp1) led to significant upregulation of SIGIRR expression after SP stimulation, while KLF2 siRNA only partially enhanced it and Fli-1 siRNA reduced it. SP also upregulated TGFβ1 expression, along with a corresponding increase of SIGIRR protein, whereas silencing TGFβ1/2/3 blunted these responses. Sp1 siRNA or mithramycin (a gene-selective Sp1 inhibitor) significantly enhanced the expression of TGFβ1 and SIGIRR by macrophages after SP stimulation. Importantly, this effect of Sp1 siRNA on TGFβ1 and SIGIRR was blunted by siRNA for Smad2, Smad3, or Smad4, but not by TAK-1 siRNA. Next, we investigated the influence of transcription factor cross-talk on SIGIRR expression in response to SP. Co-transfection of macrophages with Sp1 siRNA and C/EBPβ or TIF1β siRNA attenuated the upregulation of SIGIRR by SP, while a combination of Sp1 siRNA and Fli-1 siRNA dramatically diminished it. In conclusion, TGFβ1 may be an intermediary between SP/NK1R activation and SIGIRR expression in Sp1 siRNA-transfected macrophages. In addition, Sp1 modulates TGFβ1/Smad signaling and

  9. Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson's Disease.

    PubMed

    Wang, Xin; Li, Nuomin; Xiong, Nian; You, Qi; Li, Jie; Yu, Jinlong; Qing, Hong; Wang, Tao; Cordell, Heather J; Isacson, Ole; Vance, Jeffery M; Martin, Eden R; Zhao, Ying; Cohen, Bruce M; Buttner, Edgar A; Lin, Zhicheng

    2017-05-01

    The cytoskeleton not only provides structure, it is an active component of cell function, and in several neurodegenerative disorders, there is evidence of cytoskeletal collapse. Cytoskeletal proteins have been specifically implicated in the pathogenesis of Parkinson's disease (PD), where degeneration of dopaminergic (DA) neurons is the hallmark, but in which many factors may determine the resilience of DA neurons during aging and stress. Here we report that the human Microtubule Actin Cross-linking Factor 1 gene (MACF1), a downstream target of PD biochemical pathways, was significantly associated with PD in 713 nuclear families. A significant allelic association between PD and rs12118033, with P = 0.0098, was observed, and a P < 0.03 was observed in the association analysis by both a trend test and an allelic test. We further observed that it is the MACF1b isoform, not the MACF1a isoform, which is expressed in DA neurons from six human postmortem brains. In a Caenorhabditis elegans system, used to explore the effect of altered MACF1b on neurons, knockdown or knockout of the MACF1b orthologue vab-10 resulted in the selective loss of DA neurons, which validated MACF1's risk candidacy in PD. These findings strongly suggest that MACF1b may contribute to the genetic etiology and mechanistic causation of PD.

  10. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor X (RFX) transcription factors through X-box promoter motifs

    PubMed Central

    Tammimies, Kristiina; Bieder, Andrea; Lauter, Gilbert; Sugiaman-Trapman, Debora; Torchet, Rachel; Hokkanen, Marie-Estelle; Burghoorn, Jan; Castrén, Eero; Kere, Juha; Tapia-Páez, Isabel; Swoboda, Peter

    2016-01-01

    DYX1C1, DCDC2, and KIAA0319 are three of the most replicated dyslexia candidate genes (DCGs). Recently, these DCGs were implicated in functions at the cilium. Here, we investigate the regulation of these DCGs by Regulatory Factor X transcription factors (RFX TFs), a gene family known for transcriptionally regulating ciliary genes. We identify conserved X-box motifs in the promoter regions of DYX1C1, DCDC2, and KIAA0319 and demonstrate their functionality, as well as the ability to recruit RFX TFs using reporter gene and electrophoretic mobility shift assays. Furthermore, we uncover a complex regulation pattern between RFX1, RFX2, and RFX3 and their significant effect on modifying the endogenous expression of DYX1C1 and DCDC2 in a human retinal pigmented epithelial cell line immortalized with hTERT (hTERT-RPE1). In addition, induction of ciliogenesis increases the expression of RFX TFs and DCGs. At the protein level, we show that endogenous DYX1C1 localizes to the base of the cilium, whereas DCDC2 localizes along the entire axoneme of the cilium, thereby validating earlier localization studies using overexpression models. Our results corroborate the emerging role of DCGs in ciliary function and characterize functional noncoding elements, X-box promoter motifs, in DCG promoter regions, which thus can be targeted for mutation screening in dyslexia and ciliopathies associated with these genes.—Tammimies, K., Bieder, A., Lauter, G., Sugiaman-Trapman, D., Torchet, R., Hokkanen, M.-E., Burghoorn, J., Castrén, E., Kere, J., Tapia-Páez, I., Swoboda, P. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor (RF) X transcription factors through X-box promoter motifs. PMID:27451412

  11. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor X (RFX) transcription factors through X-box promoter motifs.

    PubMed

    Tammimies, Kristiina; Bieder, Andrea; Lauter, Gilbert; Sugiaman-Trapman, Debora; Torchet, Rachel; Hokkanen, Marie-Estelle; Burghoorn, Jan; Castrén, Eero; Kere, Juha; Tapia-Páez, Isabel; Swoboda, Peter

    2016-10-01

    DYX1C1, DCDC2, and KIAA0319 are three of the most replicated dyslexia candidate genes (DCGs). Recently, these DCGs were implicated in functions at the cilium. Here, we investigate the regulation of these DCGs by Regulatory Factor X transcription factors (RFX TFs), a gene family known for transcriptionally regulating ciliary genes. We identify conserved X-box motifs in the promoter regions of DYX1C1, DCDC2, and KIAA0319 and demonstrate their functionality, as well as the ability to recruit RFX TFs using reporter gene and electrophoretic mobility shift assays. Furthermore, we uncover a complex regulation pattern between RFX1, RFX2, and RFX3 and their significant effect on modifying the endogenous expression of DYX1C1 and DCDC2 in a human retinal pigmented epithelial cell line immortalized with hTERT (hTERT-RPE1). In addition, induction of ciliogenesis increases the expression of RFX TFs and DCGs. At the protein level, we show that endogenous DYX1C1 localizes to the base of the cilium, whereas DCDC2 localizes along the entire axoneme of the cilium, thereby validating earlier localization studies using overexpression models. Our results corroborate the emerging role of DCGs in ciliary function and characterize functional noncoding elements, X-box promoter motifs, in DCG promoter regions, which thus can be targeted for mutation screening in dyslexia and ciliopathies associated with these genes.-Tammimies, K., Bieder, A., Lauter, G., Sugiaman-Trapman, D., Torchet, R., Hokkanen, M.-E., Burghoorn, J., Castrén, E., Kere, J., Tapia-Páez, I., Swoboda, P. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor (RF) X transcription factors through X-box promoter motifs. © The Author(s).

  12. The Arabidopsis Polycomb Repressive Complex 1 (PRC1) Components AtBMI1A, B, and C Impact Gene Networks throughout All Stages of Plant Development1[OPEN

    PubMed Central

    Zhou, Yue

    2017-01-01

    Polycomb Group regulation in Arabidopsis (Arabidopsis thaliana) is required to maintain cell differentiation and allow developmental phase transitions. This is achieved by the activity of three PcG repressive complex 2s (PRC2s) and the participation of a yet poorly defined PRC1. Previous results showed that apparent PRC1 components perform discrete roles during plant development, suggesting the existence of PRC1 variants; however, it is not clear in how many processes these components participate. We show that AtBMI1 proteins are required to promote all developmental phase transitions and to control cell proliferation during organ growth and development, expanding their proposed range of action. While AtBMI1 function during germination is closely linked to B3 domain transcription factors VAL1/2 possibly in combination with GT-box binding factors, other AtBMI1 regulatory networks require participation of different factor combinations. Conversely, EMF1 and LHP1 bind many H3K27me3 positive genes up-regulated in atbmi1a/b/c mutants; however, loss of their function affects expression of a different subset, suggesting that even if EMF1, LHP1, and AtBMI1 exist in a common PRC1 variant, their role in repression depends on the functional context. PMID:27837089

  13. Factors predicting weight-bearing asymmetry 1month after unilateral total knee arthroplasty: a cross-sectional study.

    PubMed

    Christiansen, Cory L; Bade, Michael J; Weitzenkamp, David A; Stevens-Lapsley, Jennifer E

    2013-03-01

    Factors predicting weight-bearing asymmetry (WBA) after unilateral total knee arthroplasty (TKA) are not known. However, identifying modifiable and non-modifiable predictors of WBA is needed to optimize rehabilitation, especially since WBA is negatively correlated to poor functional performance. The purpose of this study was to identify factors predictive of WBA during sit-stand transitions for people 1month following unilateral TKA. Fifty-nine people were tested preoperatively and 1month following unilateral TKA for WBA using average vertical ground reaction force under each foot during the Five Times Sit-to-Stand Test. Candidate variables tested in the regression analysis represented physical impairments (strength, muscle activation, pain, and motion), demographics, anthropometrics, and movement compensations. WBA, measured as the ratio of surgical/non-surgical limb vertical ground reaction force, was 0.69 (0.18) (mean (SD)) 1month after TKA. Regression analysis identified preoperative WBA (β=0.40), quadriceps strength ratio (β=0.31), and hamstrings strength ratio (β=0.19) as factors predictive of WBA 1month after TKA (R(2)=0.30). Greater amounts of WBA 1month after TKA are predicted by modifiable factors including habitual movement pattern and asymmetry in quadriceps and hamstrings strength. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors.

    PubMed

    Bortvedt, Sarah F; Lund, P Kay

    2012-03-01

    To summarize the recent evidence that insulin-like growth factor 1 (IGF1) mediates growth effects of multiple trophic factors and discuss clinical relevance. Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogs in short bowel syndrome and Crohn's disease. This review highlights the evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn's disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that suppressor of cytokine signaling protein induction by GH or GLP2 in normal or inflamed intestine may limit IGF1-induced growth, but protect against risk of dysplasia or fibrosis, is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed. IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed.

  15. The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway

    PubMed Central

    Chen, Hui-Jye; Lin, Chung-Ming; Lin, Chyuan-Sheng; Perez-Olle, Raul; Leung, Conrad L.; Liem, Ronald K.H.

    2006-01-01

    MACF1 (microtubule actin cross-linking factor 1) is a multidomain protein that can associate with microfilaments and microtubules. We found that MACF1 was highly expressed in neuronal tissues and the foregut of embryonic day 8.5 (E8.5) embryos and the head fold and primitive streak of E7.5 embryos. MACF1−/− mice died at the gastrulation stage and displayed developmental retardation at E7.5 with defects in the formation of the primitive streak, node, and mesoderm. This phenotype was similar to Wnt-3−/− and LRP5/6 double-knockout embryos. In the absence of Wnt, MACF1 associated with a complex that contained Axin, β-catenin, GSK3β, and APC. Upon Wnt stimulation, MACF1 appeared to be involved in the translocation and subsequent binding of the Axin complex to LRP6 at the cell membrane. Reduction of MACF1 with small interfering RNA decreased the amount of β-catenin in the nucleus, and led to an inhibition of Wnt-induced TCF/β-catenin-dependent transcriptional activation. Similar results were obtained with a dominant-negative MACF1 construct that contained the Axin-binding region. Reduction of MACF1 in Wnt-1-expressing P19 cells resulted in decreased T (Brachyury) gene expression, a DNA-binding transcription factor that is a direct target of Wnt/β-catenin signaling and required for mesoderm formation. These results suggest a new role of MACF1 in the Wnt signaling pathway. PMID:16815997

  16. E2fl1 is a meiosis-specific transcription factor in the protist Tetrahymena thermophila

    PubMed Central

    Zhang, Jing; Tian, Miao; Miao, Wei

    2017-01-01

    ABSTRACT Members of the E2F family of transcription factors have been reported to regulate the expression of genes involved in cell cycle control, DNA replication, and DNA repair in multicellular eukaryotes. Here, E2FL1, a meiosis-specific E2F transcription factor gene, was identified in the model ciliate Tetrahymena thermophila. Loss of this gene resulted in meiotic arrest prior to anaphase I. The cytological experiments revealed that the meiotic homologous pairing was not affected in the absence of E2FL1, but the paired homologous chromosomes did not separate and assumed a peculiar tandem arrangement. This is the first time that an E2F family member has been shown to regulate meiotic events. Moreover, BrdU incorporation showed that DSB processing during meiosis was abnormal upon the deletion of E2FL1. Transcriptome sequencing analysis revealed that E2FL1 knockout decreased the expression of genes involved in DNA replication and DNA repair in T. thermophila, suggesting that the function of E2F is highly conserved in eukaryotes. In addition, E2FL1 deletion inhibited the expression of related homologous chromosome segregation genes in T. thermophila. The result may explain the meiotic arrest phenotype at anaphase I. Finally, by searching for E2F DNA-binding motifs in the entire T. thermophila genome, we identified 714 genes containing at least one E2F DNA-binding motif; of these, 235 downregulated represent putative E2FL1 target genes. PMID:27892792

  17. Immunohistochemical study of the neural development transcription factors (TTF1, ASCL1 and BRN2) in neuroendocrine prostate tumours.

    PubMed

    Rodríguez-Zarco, E; Vallejo-Benítez, A; Umbría-Jiménez, S; Pereira-Gallardo, S; Pabón-Carrasco, S; Azueta, A; González-Cámpora, R; Espinal, P S; García-Escudero, A

    2017-10-01

    Prostatic small-cell neuroendocrine carcinoma is an uncommon malignancy that constitutes 0.5-1% of all prostate malignancies. The median cancer-specific survival of patients with prostatic small-cell neuroendocrine carcinoma is 19 months, and 60.5% of the patients have metastatic disease. Neural development transcription factors are molecules involved in the organogenesis of the central nervous system and of neuroendocrine precursors of various tissues, including the suprarenal gland, thyroid glands, lungs and prostate. We present 3 cases of this uncommon condition, applying the new World Health Organisation criteria. We conducted studies through haematoxylin and eosin staining and analysed the expression of the neural development transcription factors achaete-scute homolog like 1, thyroid transcription factor 1 and the class III/IV POU transcription factors, as a new research line in the carcinogenesis of prostatic neuroendocrine tumours. In case 1, there was no TTF1 immunoexpression. Cases 2 and 3 had positive immunostaining for ASCL1, and Case 1 had negative immunostaining. BRN2 immunostaining was negative in case 1 and positive in cases 2 and 3. The World Health Organisation does not recognise any molecular or genetic marker with prognostic value. ASCL-1 is related to the NOTCH and WNT signalling pathways. ASCL-1, TTF1 and BRN2 could be used for early diagnosis and as prognostic factors and therapeutic targets. Copyright © 2017 AEU. All rights reserved.

  18. Factors associated with poor Hemoglobin A1c control in Patients with Type 2 Diabetes.

    PubMed

    Alqudah, Salam; Jarab, Anan S; Alefishat, Eman A; Mayyas, Fadia; Khdour, Maher; Pinto, Sharrel

    2018-05-10

    Background The limited implementation of clinical pharmacy service programs and the lack of studies identifying barriers to achieve blood glucose control have all attributed to the increased proportion of type 2 diabetes patients who have poor glycemic control in Jordan. Objective To explore factors associated with higher HbA1c in patients with type 2 diabetes in Jordan. Method Variables including socio-demographics, disease and treatment factors were collected from171 patients with type2 diabetes at an outpatient diabetes clinic in Amman. Validated questionnaires were used to assess medication adherence, self-care activities, diabetes knowledge and health-related quality of life in addition to data collected from medical records. After the single-predictor analysis, stepwise linear regression was performed to develop a model with variables that best predicted hemoglobin A1c. Results Medication adherence was inversely associated with HbA1c values (β = -0.275; t = 2.666; P < 0.01), indicating better glycemic control. Receiving insulin therapy was also associated with less HbA1c values and better glycemic control (β = - 0.184; t = 2.080; P < 0.05). Patients who had one or more comorbid conditions (β = 0.215; t = 2.264; P < 0.05) and those with longer diabetes duration (β = 0.092; t = 1.339; P < 0.05) were found to have significantly higher HbA1c values. Conclusions Emphasizing medication adherence, particularly for patients with longer duration of diabetes and those with multiple comorbid diseases should be strongly considered in future diabetes management programs implemented to improve glycemic control in patients with type 2 diabetes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis

    PubMed Central

    Reichert, Maximilian; Takano, Shigetsugu; von Burstin, Johannes; Kim, Sang-Bae; Lee, Ju-Seog; Ihida-Stansbury, Kaori; Hahn, Christopher; Heeg, Steffen; Schneider, Günter; Rhim, Andrew D.; Stanger, Ben Z.; Rustgi, Anil K.

    2013-01-01

    Pancreatic exocrine cell plasticity can be observed during development, pancreatitis with subsequent regeneration, and also transformation. For example, acinar–ductal metaplasia (ADM) occurs during acute pancreatitis and might be viewed as a prelude to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) development. To elucidate regulatory processes that overlap ductal development, ADM, and the progression of normal cells to PanIN lesions, we undertook a systematic approach to identify the Prrx1 paired homeodomain Prrx1 transcriptional factor as a highly regulated gene in these processes. Prrx1 annotates a subset of pancreatic ductal epithelial cells in Prrx1creERT2-IRES-GFP mice. Furthermore, sorted Prrx1+ cells have the capacity to self-renew and expand during chronic pancreatitis. The two isoforms, Prrx1a and Prrx1b, regulate migration and invasion, respectively, in pancreatic cancer cells. In addition, Prrx1b is enriched in circulating pancreatic cells (Pdx1cre;LSL-KrasG12D/+;p53fl/+;R26YFP). Intriguingly, the Prrx1b isoform, which is also induced in ADM, binds the Sox9 promoter and positively regulates Sox9 expression. This suggests a new hierarchical scheme whereby a Prrx1–Sox9 axis may influence the emergence of acinar–ductal metaplasia and regeneration. Furthermore, our data provide a possible explanation of why pancreatic cancer is skewed toward a ductal fate. PMID:23355395

  20. Liquid-air partition coefficients of 1,1-difluoroethane (HFC152a), 1,1,1-trifluoroethane (HFC143a), 1,1,1,2-tetrafluoroethane (HFC134a), 1,1,1,2,2-pentafluoroethane (HFC125) and 1,1,1,3,3-pentafluoropropane (HFC245fa).

    PubMed

    Ernstgård, Lena; Lind, Birger; Andersen, Melvin E; Johanson, Gunnar

    2010-01-01

    Blood-air and tissue-blood coefficients (lambda) are essential to characterize the uptake and disposition of volatile substances, e.g. by physiologically based pharmacokinetic (PBPK) modelling. Highly volatile chemicals, including many hydrofluorocarbons (HFC) have low solubility in liquid media. These characteristics pose challenges for determining lambda values. A modified head-space vial equilibrium method was used to determine lambda values for five widely used HFCs. The method is based on automated head-space gas chromatography and injection of equal amount of chemical in two head-space vials with identical air phase volumes but different volumes of the liquid phase. The liquids used were water (physiological saline), fresh human blood, and olive oil. The average lambda values (n = 8) were as follows: 1,1-difluoroethane (HFC152a) - 1.08 (blood-air), 1.11 (water-air) and 5.6 (oil-air); 1,1,1-trifluoroethane (HFC143a) - 0.15, 0.15 and 1.90; 1,1,1,2-tetrafluoroethane (HFC134a) - 0.36, 0.35 and 3.5; 1,1,1,2,2-pentafluoroethane (HFC125) - 0.083, 0.074 and 1.71; and 1,1,1,3,3-pentafluoropropane (HFC245fa) - 0.62, 0.58 and 12.1. The lambda values appeared to be concentration-independent in the investigated range (2-200 ppm). In spite of the low lambda values, the method errors were modest, with coefficients of variation of 9, 11 and 10% for water, blood and oil, respectively.

  1. FOXN1 Transcription Factor in Epithelial Growth and Wound Healing.

    PubMed

    Grabowska, Anna I; Wilanowski, Tomasz

    2017-09-01

    FOXN1 is a prodifferentiation transcription factor in the skin epithelium. Recently, it has also emerged as an important player in controlling the skin wound healing process, as it actively participates in reepithelialization and is thought to be responsible for scar formation. FOXN1 positivity is also a feature of pigmented keratinocytes, including nevi, and FOXN1 is an attribute of benign epithelial tumors. The lack of FOXN1 favors the skin regeneration process displayed by nude mice, pointing to FOXN1 as a switch between regeneration and reparative processes. The stem cell niche provides a functional source of cells after the loss of tissue following wounding. The involvement of prodifferentiation factors in the regulation of this pool of stem cells is suggested. However, the exact mechanism is still under question, and we speculate that the FOXN1 transcription factor is involved in this process. This review analyzes the pleiotropic effects of FOXN1 in the skin, its function in the tumorigenesis process, and its potential role in depletion of the stem cell niche after injury, as well as its suggested mechanistic role, acting in a cell-autonomous and a non-cell-autonomous manner during skin self-renewal. Copyright © 2017 American Society for Microbiology.

  2. Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

    PubMed Central

    Audette, Dylan S.; Anand, Deepti; So, Tammy; Rubenstein, Troy B.; Lachke, Salil A.; Lovicu, Frank J.; Duncan, Melinda K.

    2016-01-01

    Lens epithelial cells differentiate into lens fibers (LFs) in response to a fibroblast growth factor (FGF) gradient. This cell fate decision requires the transcription factor Prox1, which has been hypothesized to promote cell cycle exit in differentiating LF cells. However, we find that conditional deletion of Prox1 from mouse lenses results in a failure in LF differentiation despite maintenance of normal cell cycle exit. Instead, RNA-seq demonstrated that Prox1 functions as a global regulator of LF cell gene expression. Intriguingly, Prox1 also controls the expression of fibroblast growth factor receptors (FGFRs) and can bind to their promoters, correlating with decreased downstream signaling through MAPK and AKT in Prox1 mutant lenses. Further, culturing rat lens explants in FGF increased their expression of Prox1, and this was attenuated by the addition of inhibitors of MAPK. Together, these results describe a novel feedback loop required for lens differentiation and morphogenesis, whereby Prox1 and FGFR signaling interact to mediate LF differentiation in response to FGF. PMID:26657765

  3. Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression.

    PubMed

    Audette, Dylan S; Anand, Deepti; So, Tammy; Rubenstein, Troy B; Lachke, Salil A; Lovicu, Frank J; Duncan, Melinda K

    2016-01-15

    Lens epithelial cells differentiate into lens fibers (LFs) in response to a fibroblast growth factor (FGF) gradient. This cell fate decision requires the transcription factor Prox1, which has been hypothesized to promote cell cycle exit in differentiating LF cells. However, we find that conditional deletion of Prox1 from mouse lenses results in a failure in LF differentiation despite maintenance of normal cell cycle exit. Instead, RNA-seq demonstrated that Prox1 functions as a global regulator of LF cell gene expression. Intriguingly, Prox1 also controls the expression of fibroblast growth factor receptors (FGFRs) and can bind to their promoters, correlating with decreased downstream signaling through MAPK and AKT in Prox1 mutant lenses. Further, culturing rat lens explants in FGF increased their expression of Prox1, and this was attenuated by the addition of inhibitors of MAPK. Together, these results describe a novel feedback loop required for lens differentiation and morphogenesis, whereby Prox1 and FGFR signaling interact to mediate LF differentiation in response to FGF. © 2016. Published by The Company of Biologists Ltd.

  4. Growth factor independence-1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia

    PubMed Central

    Khandanpour, Cyrus; Phelan, James D.; Vassen, Lothar; Schütte, Judith; Chen, Riyan; Horman, Shane R.; Gaudreau, Marie-Claude; Krongold, Joseph; Zhu, Jinfang; Paul, William E.; Dührsen, Ulrich; Göttgens, Bertie; Grimes, H. Leighton; Möröy, Tarik

    2013-01-01

    Summary Most patients with acute lymphoblastic leukemia (ALL) fail current treatments highlighting the need for better therapies. Since oncogenic signaling activates a p53-dependent DNA-damage response and apoptosis, leukemic cells must devise appropriate countermeasures. We show here that growth factor independence 1 (Gfi1) can serve such a function, since Gfi1 ablation exacerbates p53 responses, and lowers the threshold for p53-induced cell death. Specifically, Gfi1 restricts p53 activity and expression of pro-apoptotic p53 targets such as Bax, Noxa (Pmaip1) and Puma (Bbc3). Subsequently, Gfi1 ablation cures mice from leukemia and limits the expansion of primary human T-ALL xenografts in mice. This suggests that targeting Gfi1 could improve the prognosis of patients with T-ALL or other lymphoid leukemias. PMID:23410974

  5. Phospholipase C-mediated hydrolysis of phosphatidylcholine is a target of transforming growth factor beta 1 inhibitory signals.

    PubMed Central

    Diaz-Meco, M T; Dominguez, I; Sanz, L; Municio, M M; Berra, E; Cornet, M E; Garcia de Herreros, A; Johansen, T; Moscat, J

    1992-01-01

    Cell growth and tumor transformation can be restrained in certain cell systems by the action of transforming growth factor beta (TGF-beta). It has been established that the mechanism whereby TGF-beta 1 inhibits cell growth does not interfere with the triggering of early mitogenic signal transduction mechanisms. Phospholipase C-catalyzed hydrolysis of phosphatidylcholine (PC) is a relatively late step in the cascade activated by growth factors. Therefore, conceivably activation of phospholipase C-catalyzed hydrolysis of PC could be the target of TGF-beta 1 action. In the study reported here, we demonstrate that TGF-beta 1 inhibits the coupling of ras p21 to the activation of PC hydrolysis, which appears to be critical for the antiproliferative effects of TGF-beta 1. Images PMID:1309592

  6. The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kulebyakin, Konstantin; Penkov, Dmitry; IFOM – the FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, 20139

    Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to searchmore » new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. - Highlights: • A novel model of liver-specific Prep1 knockout is established. • Ablation of Prep1 in hepatocytes increases insulin sensitivity. • Prep1 controls hepatic insulin sensitivity by regulating localization of FOXO1. • Prep1 regulates

  7. CagA, a major virulence factor of Helicobacter pylori, promotes the production and underglycosylation of IgA1 in DAKIKI cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yang, Man; Li, Fu-gang; Xie, Xi-sheng

    Highlights: • CagA stimulated cell proliferation and the production of IgA1 in DAKIKI cells. • CagA promoted the underglycosylation of IgA1 in DAKIKI cells. • CagA decreased the expression of C1GALT1 and its chaperone Cosmc in DAKIKI cells. • Helicobacter pylori infection may participate in the pathogenesis of IgAN via CagA. - Abstract: While Helicobacter pylori (Hp) infection is closely associated with IgA nephropathy (IgAN), the underlying molecular mechanisms remain to be elucidated. This study was to investigate the effect of cytotoxin associated gene A protein (CagA), a major virulence factor of Hp, on the production and underglycosylation of IgA1more » in the B cell line DAKIKI cells. Cells were cultured and treated with recombinant CagA protein. We found that CagA stimulated cell proliferation and the production of IgA1 in a dose-dependent and time-dependent manner. Moreover, CagA promoted the underglycosylation of IgA1, which at least partly attributed to the downregulation of β1,3-galactosyltransferase (C1GALT1) and its chaperone Cosmc. In conclusion, we demonstrated that Hp infection, at least via CagA, may participate in the pathogenesis of IgAN by influencing the production and glycosylation of IgA1 in B cells.« less

  8. Cyclin A recruits p33cdk2 to the cellular transcription factor DRTF1.

    PubMed

    Bandara, L R; Adamczewski, J P; Zamanian, M; Poon, R Y; Hunt, T; Thangue, N B

    1992-01-01

    Cyclins are regulatory molecules that undergo periodic accumulation and destruction during each cell cycle. By activating p34cdc2 and related kinase subunits they control important events required for normal cell cycle progression. Cyclin A, for example, regulates at least two distinct kinase subunits, the mitotic kinase subunit p34cdc2 and related subunit p33cdk2, and is widely believed to be necessary for progression through S phase. However, cyclin A also forms a stable complex with the cellular transcription factor DRTF1 and thus may perform other functions during S phase. DRTF1, in addition, associates with the tumour suppressor retinoblastoma (Rb) gene product and the Rb-related protein p107. We now show, using biologically active fusion proteins, that cyclin A can direct the binding of the cdc2-like kinase subunit, p33cdk2, to complexed DRTF1, containing either Rb or p107, as well as activate its histone H1 kinase activity. Cyclin A cannot, however, direct p34cdc2 to the DRTF1 complex and we present evidence suggesting that the stability of the cyclin A-p33cdk2 complex is influenced by DRTF1 or an associated protein. Cyclin A, therefore, serves as an activating and targeting subunit of p33cdk2. The ability of cyclin A to activate and recruit p33cdk2 to DRTF1 may play an important role in regulating cell cycle progression and moreover defines a mechanism for coupling cell-cycle events to transcriptional initiation.

  9. Regulation of a transcription factor network by Cdk1 coordinates late cell cycle gene expression

    PubMed Central

    Landry, Benjamin D; Mapa, Claudine E; Arsenault, Heather E; Poti, Kristin E; Benanti, Jennifer A

    2014-01-01

    To maintain genome stability, regulators of chromosome segregation must be expressed in coordination with mitotic events. Expression of these late cell cycle genes is regulated by cyclin-dependent kinase (Cdk1), which phosphorylates a network of conserved transcription factors (TFs). However, the effects of Cdk1 phosphorylation on many key TFs are not known. We find that elimination of Cdk1-mediated phosphorylation of four S-phase TFs decreases expression of many late cell cycle genes, delays mitotic progression, and reduces fitness in budding yeast. Blocking phosphorylation impairs degradation of all four TFs. Consequently, phosphorylation-deficient mutants of the repressors Yox1 and Yhp1 exhibit increased promoter occupancy and decreased expression of their target genes. Interestingly, although phosphorylation of the transcriptional activator Hcm1 on its N-terminus promotes its degradation, phosphorylation on its C-terminus is required for its activity, indicating that Cdk1 both activates and inhibits a single TF. We conclude that Cdk1 promotes gene expression by both activating transcriptional activators and inactivating transcriptional repressors. Furthermore, our data suggest that coordinated regulation of the TF network by Cdk1 is necessary for faithful cell division. PMID:24714560

  10. Regulation of a transcription factor network by Cdk1 coordinates late cell cycle gene expression.

    PubMed

    Landry, Benjamin D; Mapa, Claudine E; Arsenault, Heather E; Poti, Kristin E; Benanti, Jennifer A

    2014-05-02

    To maintain genome stability, regulators of chromosome segregation must be expressed in coordination with mitotic events. Expression of these late cell cycle genes is regulated by cyclin-dependent kinase (Cdk1), which phosphorylates a network of conserved transcription factors (TFs). However, the effects of Cdk1 phosphorylation on many key TFs are not known. We find that elimination of Cdk1-mediated phosphorylation of four S-phase TFs decreases expression of many late cell cycle genes, delays mitotic progression, and reduces fitness in budding yeast. Blocking phosphorylation impairs degradation of all four TFs. Consequently, phosphorylation-deficient mutants of the repressors Yox1 and Yhp1 exhibit increased promoter occupancy and decreased expression of their target genes. Interestingly, although phosphorylation of the transcriptional activator Hcm1 on its N-terminus promotes its degradation, phosphorylation on its C-terminus is required for its activity, indicating that Cdk1 both activates and inhibits a single TF. We conclude that Cdk1 promotes gene expression by both activating transcriptional activators and inactivating transcriptional repressors. Furthermore, our data suggest that coordinated regulation of the TF network by Cdk1 is necessary for faithful cell division.

  11. Transcription factor EGR1 directs tendon differentiation and promotes tendon repair

    PubMed Central

    Guerquin, Marie-Justine; Charvet, Benjamin; Nourissat, Geoffroy; Havis, Emmanuelle; Ronsin, Olivier; Bonnin, Marie-Ange; Ruggiu, Mathilde; Olivera-Martinez, Isabel; Robert, Nicolas; Lu, Yinhui; Kadler, Karl E.; Baumberger, Tristan; Doursounian, Levon; Berenbaum, Francis; Duprez, Delphine

    2013-01-01

    Tendon formation and repair rely on specific combinations of transcription factors, growth factors, and mechanical parameters that regulate the production and spatial organization of type I collagen. Here, we investigated the function of the zinc finger transcription factor EGR1 in tendon formation, healing, and repair using rodent animal models and mesenchymal stem cells (MSCs). Adult tendons of Egr1–/– mice displayed a deficiency in the expression of tendon genes, including Scx, Col1a1, and Col1a2, and were mechanically weaker compared with their WT littermates. EGR1 was recruited to the Col1a1 and Col2a1 promoters in postnatal mouse tendons in vivo. Egr1 was required for the normal gene response following tendon injury in a mouse model of Achilles tendon healing. Forced Egr1 expression programmed MSCs toward the tendon lineage and promoted the formation of in vitro–engineered tendons from MSCs. The application of EGR1-producing MSCs increased the formation of tendon-like tissues in a rat model of Achilles tendon injury. We provide evidence that the ability of EGR1 to promote tendon differentiation is partially mediated by TGF-β2. This study demonstrates EGR1 involvement in adult tendon formation, healing, and repair and identifies Egr1 as a putative target in tendon repair strategies. PMID:23863709

  12. A population-based study of risk factors for severe hypoglycaemia in a contemporary cohort of childhood-onset type 1 diabetes.

    PubMed

    Cooper, Matthew N; O'Connell, Susan M; Davis, Elizabeth A; Jones, Timothy W

    2013-10-01

    Severe hypoglycaemia is a major barrier to optimising glycaemic control. Recent changes in therapy, however, may have altered the epidemiology of severe hypoglycaemia and its associated risk factors. The aim of this study was to examine the incidence rates and risk factors associated with severe hypoglycaemia in a contemporary cohort of children and adolescents with type 1 diabetes. Subjects were identified from a population-based register containing data on >99% of patients (<16 years of age) who were being treated for type 1 diabetes in Western Australia. Patients attend the clinic approximately every 3 months, where data pertaining to diabetes management, demographics and complications including hypoglycaemia are prospectively recorded. A severe hypoglycaemic event was defined as an episode of coma or convulsion associated with hypoglycaemia. Risk factors assessed included age, duration of diabetes, glycaemic control, sex, insulin therapy, socioeconomic status and calendar year. Clinical visit data from 1,770 patients, providing 8,214 patient-years of data between 2000 and 2011 were analysed. During follow-up, 841 episodes of severe hypoglycaemia were observed. No difference in risk of severe hypoglycaemia was observed between age groups. Good glycaemic control (HbA1c <7% [53 mmol/mol]) compared with the cohort average (HbA1c 8-9% [64-75 mmol/mol]) was not associated with an increased risk of severe hypoglycaemia. When compared with patients on injection regimens, subjects aged 12-18 years on pump therapy were at reduced risk of severe hypoglycaemia (incidence risk ratio 0.6; 95% CI 0.4, 0.9). In this population-based sample of children and adolescents with type 1 diabetes, contemporary therapy is associated with a changed pattern and incidence of severe hypoglycaemia.

  13. A novel inherited mutation of the transcription factor RUNX1 causes thrombocytopenia and may predispose to acute myeloid leukaemia.

    PubMed

    Walker, Logan C; Stevens, Jane; Campbell, Hamish; Corbett, Rob; Spearing, Ruth; Heaton, David; Macdonald, Donald H; Morris, Christine M; Ganly, Peter

    2002-06-01

    The RUNX1 (AML1, CBFA2) gene is a member of the runt transcription factor family, responsible for DNA binding and heterodimerization of other non-DNA binding transcription factors. RUNX1 plays an important part in regulating haematopoiesis and it is frequently disrupted by illegitimate somatic recombination in both acute myeloid and lymphoblastic leukaemia. Germline mutations of RUNX1 have also recently been described and are dominantly associated with inherited leukaemic conditions. We have identified a unique point mutation of the RUNX1 gene (A107P) in members of a family with autosomal dominant inheritance of thrombocytopenia. One member has developed acute myeloid leukaemia (AML).

  14. Risk factors for infection with highly pathogenic influenza A virus (H5N1) in commercial chickens in Bangladesh.

    PubMed

    Biswas, P K; Christensen, J P; Ahmed, S S U; Barua, H; Das, A; Rahman, M H; Giasuddin, M; Hannan, A S M A; Habib, A M; Debnath, N C

    2009-06-13

    A matched case-control study was carried out to identify risk factors for highly pathogenic avian influenza A virus (subtype H5N1) infection in commercial chickens in Bangladesh. A total of 33 commercial farms diagnosed with H5N1 before September 9, 2007, were enrolled as cases, and 99 geographically matched unaffected farms were enrolled as control farms. Farm data were collected using a pretested questionnaire, and analysed by matched-pair analysis and multivariate conditional logistic regression. Two factors independently and positively associated with H5N1 infection remained in the final model. They were 'farm accessible to feral and wild animals' (odds ratio [OR] 5.71, 95 per cent confidence interval [CI] 1.81 to 18.0, P=0.003) and 'footbath at entry to farm/shed' (OR 4.93, 95 per cent CI 1.61 to 15.1, P=0.005). The use of a designated vehicle for sending eggs to a vendor or market appeared to be a protective factor (OR 0.14, 95 per cent CI 0.02 to 0.88, P=0.036).

  15. Myeloid leukemia factor-1 is a novel modulator of neonatal rat cardiomyocyte proliferation.

    PubMed

    Rangrez, Ashraf Yusuf; Pott, Jost; Kluge, Annika; Frauen, Robert; Stiebeling, Katharina; Hoppe, Phillip; Sossalla, Samuel; Frey, Norbert; Frank, Derk

    2017-04-01

    The present study focuses on the identification of the gene expression profile of neonatal rat cardiomyocytes (NRVCMs) after dynamic mechanical stretch through microarrays of RNA isolated from cells stretched for 2, 6 or 24h. In this analysis, myeloid leukemia factor-1 (MLF1) was found to be significantly downregulated during the course of stretch. We found that MLF1 is highly expressed in the heart, however, its cardiac function is unknown yet. In line with microarray data, MLF1 was profoundly downregulated in in vivo mouse models of cardiomyopathy, and also significantly reduced in the hearts of human patients with dilated cardiomyopathy. Our data indicates that the overexpression of MLF1 in NRVCMs inhibited cell proliferation while augmenting apoptosis. Conversely, knockdown of MLF1 protected NRVCMs from apoptosis and promoted cell proliferation. Moreover, we found that knockdown of MLF1 protected NRVCMs from hypoxia-induced cell death. The observed accelerated apoptosis is attributed to the activation of caspase-3/-7/PARP-dependent apoptotic signaling and upregulation of p53. Most interestingly, MLF1 knockdown significantly upregulated the expression of D cyclins suggesting its possible role in cyclin-dependent cell proliferation. Taken together, we, for the first time, identified an important role for MLF1 in NRVCM proliferation. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function

    PubMed Central

    Kara, Firas M.; Chitu, Violeta; Sloane, Jennifer; Axelrod, Matthew; Fredholm, Bertil B.; Stanley, E. Richard; Cronstein, Bruce N.

    2010-01-01

    Adenosine regulates a wide variety of physiological processes via interaction with one or more G-protein-coupled receptors (A1R, A2AR, A2BR, and A3R). Because A1R occupancy promotes fusion of human monocytes to form giant cells in vitro, we determined whether A1R occupancy similarly promotes osteoclast function and formation. Bone marrow cells (BMCs) were harvested from C57Bl/6 female mice or A1R-knockout mice and their wild-type (WT) littermates and differentiated into osteoclasts in the presence of colony stimulating factor-1 and receptor activator of NF-κB ligand in the presence or absence of the A1R antagonist 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX). Osteoclast morphology was analyzed in tartrate-resistant acid phosphatase or F-actin-stained samples, and bone resorption was evaluated by toluidine blue staining of dentin. BMCs from A1R-knockout mice form fewer osteoclasts than BMCs from WT mice, and the A1R antagonist DPCPX inhibits osteoclast formation (IC50=1 nM), with altered morphology and reduced ability to resorb bone. A1R blockade increased ubiquitination and degradation of TRAF6 in RAW264.7 cells induced to differentiate into osteoclasts. These studies suggest a critical role for adenosine in bone homeostasis via interaction with adenosine A1R and further suggest that A1R may be a novel pharmacologic target to prevent the bone loss associated with inflammatory diseases and menopause.—Kara, F. M., Chitu, V., Sloane, J., Axelrod, M., Fredholm, B. B., Stanley, R., Cronstein, B. N. Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. PMID:20181934

  17. Annexin A1, Annexin A2, and Dyrk 1B are upregulated during GAS1-induced cell cycle arrest.

    PubMed

    Pérez-Sánchez, Gilberto; Jiménez, Adriana; Quezada-Ramírez, Marco A; Estudillo, Enrique; Ayala-Sarmiento, Alberto E; Mendoza-Hernández, Guillermo; Hernández-Soto, Justino; Hernández-Hernández, Fidel C; Cázares-Raga, Febe E; Segovia, Jose

    2018-05-01

    GAS1 is a pleiotropic protein that has been investigated because of its ability to induce cell proliferation, cell arrest, and apoptosis, depending on the cellular or the physiological context in which it is expressed. At this point, we have information about the molecular mechanisms by which GAS1 induces proliferation and apoptosis; but very few studies have been focused on elucidating the mechanisms by which GAS1 induces cell arrest. With the aim of expanding our knowledge on this subject, we first focused our research on finding proteins that were preferentially expressed in cells arrested by serum deprivation. By using a proteomics approach and mass spectrometry analysis, we identified 17 proteins in the 2-DE protein profile of serum deprived NIH3T3 cells. Among them, Annexin A1 (Anxa1), Annexin A2 (Anxa2), dual specificity tyrosine-phosphorylation-regulated kinase 1B (Dyrk1B), and Eukaryotic translation initiation factor 3, F (eIf3f) were upregulated at transcriptional the level in proliferative NIH3T3 cells. Moreover, we demonstrated that Anxa1, Anxa2, and Dyrk1b are upregulated at both the transcriptional and translational levels by the overexpression of GAS1. Thus, our results suggest that the upregulation of Anxa1, Anxa2, and Dyrk1b could be related to the ability of GAS1 to induce cell arrest and maintain cell viability. Finally, we provided further evidence showing that GAS1 through Dyrk 1B leads not only to the arrest of NIH3T3 cells but also maintains cell viability. © 2017 Wiley Periodicals, Inc.

  18. REDOX-SENSITIVE TRANSCRIPTION FACTORS EGR-1 AND SP1 IN THE PATHOGENESIS OF EXPERIMENTAL GASTRIC ULCER.

    PubMed

    Beregovyi, S M; Chervinska, T M; Dranitsina, A S; Szabo, S; Tolstanova, G M

    2015-01-01

    Changes in redox status of gastric mucosa cells are the main pathogenic factor of gastric erosion and gastric ulcer development. Pro-oxidants can affect cell transcription activity via changes in redox-sensitive transcription factors. Egr-1 and Sp-1 may regulate the transcription of genes that are associated with the pathogenesis of gastric ulcer (growthfactors, cell cycle regulators, etc.). The aim of the present study was to reveal the possible involvement of zinc-finger transcriptionfactors Egr-1 & Sp-1 in the molecular mechanisms underlying gastric lesions caused by aspirin administration and stress. Gastric ulcer was induced in male rats (180-220 g) by immobilization stress combined with water-immersion (IMO-WI) or aspirin gavage (10 mg/100 g). The rats were euthanized 20 min, 1 hour, or 3 hours following the ulcerogenic factor exposure. Protein expression was determined by Western blot analysis and RT-PCR; levels of SH-groups of proteins were determined by method of Ellman et al. Development of gastric ulcer lesions was associated with twofold (P < 0.05) decrease in concentration of protein SH-groups in the rat gastric mucosa. These changes were accompanied by significant (P < 0.05) increase in the expression of Egr-1 mRNA and protein in both gastric ulcer models, and the changes in IMO-WI were more profound. Increased levels of Egr-1 were associated with the decrease in SpI protein levels. We showed for the first time the competitive interaction between redox-sensitive transcription factors Egr-1 and Sp1 in the early phases of gastric ulcer development, which might facilitate inducible transcriptional activity of Egr-1 at the expense of reduction in Sp1 activity.

  19. Characterization of RACK7 as a Novel Factor Involved in BRCA1 Mutation Mediated Breast Cancer

    DTIC Science & Technology

    2012-10-01

    Characterization of RACK7 as a Novel Factor Involved in BRCA1 Mutation Mediated Breast Cancer Inder Verma, Quan Zhu, Martin Preyer, and Amy Rommel Salk...samples from 5 more human BRCA1 mutant tumors. We continue to collect more human BRCA1-mutant tumors from Dr. Petra Nederlof at the Netherland Cancer...damage pathway. Abstract: "The Novel Zinc-finger Protein ZMYND8 Is Involved in the Stabilization of Stalled Replication Forks", Martin Preyer and

  20. Human HMG box transcription factor HBP1: a role in hCD2 LCR function.

    PubMed Central

    Zhuma, T; Tyrrell, R; Sekkali, B; Skavdis, G; Saveliev, A; Tolaini, M; Roderick, K; Norton, T; Smerdon, S; Sedgwick, S; Festenstein, R; Kioussis, D

    1999-01-01

    The locus control region (LCR) of the human CD2 gene (hCD2) confers T cell-specific, copy-dependent and position-independent gene expression in transgenic mice. This LCR consists of a strong T cell-specific enhancer and an element without enhancer activity (designated HSS3), which is required for prevention of position effect variegation (PEV) in transgenic mice. Here, we identified the HMG box containing protein-1 (HBP1) as a factor binding to HSS3 of the hCD2 LCR. Within the LCR, HBP1 binds to a novel TTCATTCATTCA sequence that is higher in affinity than other recently reported HBP1-binding sites. Mice transgenic for a hCD2 LCR construct carrying a deletion of the HBP1-binding sequences show a propensity for PEV if the transgene integrates in a heterochromatic region of the chromosome such as the centromere or telomere. We propose that HBP1 plays an important role in chromatin opening and remodelling activities by binding to and bending the DNA, thus allowing DNA-protein and/or protein-protein interactions, which increase the probability of establishing an active locus. PMID:10562551